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Yr Athro Matthew Smalley
BA (Hons) (Oxon) PhD
Timau a rolau for Matthew Smalley
Athro
Ysgol y Biowyddorau
Trosolwyg
Mae fy ngrŵp yn ceisio deall tarddiad heterogenedd canser. Gan weithio gydag amrywiaeth o systemau enghreifftiol, astudiwyd canser y fron yn wreiddiol, gan geisio deall heterogenedd rhyng-diwmor – y gwahaniaethau clinigol rhwng tiwmorau – yn ogystal â heterogenedd o fewn tiwmor ac ymateb gwahanol is-setiau celloedd i bwysau dethol fel therapi. Gwnaethom ddefnyddio dull arbrofol sy'n cael ei yrru gan hypothesis i archwilio sut mae'r cyfuniad o friwiau genetig gwahanol sy'n cychwyn tiwmor sy'n digwydd mewn gwahanol fôn mammari a chelloedd progenitor arferol yn gyrru heterogenedd canser y fron.
Rydym bellach wedi cymryd golwg ehangach ac rydym yn ceisio deall yr amrywiadau genetig sy'n gwneud gwahanol unigolion yn dueddol o wahanol fathau o ganser, gan weithio'n agos gyda phatholegwyr milfeddygol ac oncolegwyr i astudio canser mewn cŵn. Mae gwahanol fridiau cŵn mewn perygl o wahanol fathau o ganser (er enghraifft, mae sbaniels sbringer Saesneg mewn mwy o berygl o ganser mammari, o'i gymharu â chroesfridiau, tra bod rottweilers mewn mwy o berygl o osteosarcoma) ac felly maent yn system ddelfrydol i nodi ffactorau genetig sy'n effeithio ar risg canser.
Fel sgil-gynnyrch cyfeiriad newydd ein gwaith, rydym hefyd wedi dechrau datblygu marcwyr prognostig moleciwlaidd a rhagfynegol newydd i helpu i reoli tiwmorau mewn anifeiliaid anwes yn glinigol.
Cyhoeddiad
2024
- Williams, J. S. et al. 2024. Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc. Cell & Bioscience 14(38) (10.1186/s13578-024-01206-8)
- Tornillo, G., Warrington, L., Kendrick, H., Higgins, A. T., Hay, T., Beck, S. and Smalley, M. J. 2024. Conditional in vivo deletion of LYN kinase has little effect on a BRCA1 loss-of-function-associated mammary tumour model. Disease Models and Mechanisms 17(1), article number: dmm050211. (10.1242/dmm.050211)
2023
- Varney, D. et al. 2023. Epidemiology of mammary tumours in bitches under veterinary care in the UK in 2016. Veterinary Record 193(5), article number: e3054. (10.1002/vetr.3054)
- Ordonez, L., Tornillo, G., Kendrick, H., Hay, T. and Smalley, M. J. 2023. NOTCH and AKT signalling interact to drive mammary tumour heterogeneity. Cancers 15(17), article number: 4324. (10.3390/cancers15174324)
- O'Neill, D., Edmunds, G., Urquhart-Gilmore, J., Church, D., Rutherford, L., Smalley, M. and Brodbelt, D. 2023. Dog breeds and conformations predisposed to osteosarcoma in the UK: a VetCompass study. Canine Medicine and Genetics 10, article number: 8. (10.1186/s40575-023-00131-2)
- Edmunds, G., Beck, S., Umakant Kale, K., Spasic, I., O'Neill, D., Brodbelt, D. and Smalley, M. J. 2023. Associations between dog breed and clinical features of mammary epithelial neoplasia in bitches: an epidemiological study of submissions to a single diagnostic pathology centre between 2008-2021. Journal of Mammary Gland Biology and Neoplasia 28(6) (10.1007/s10911-023-09531-3)
- Shorning, B., Trent, N., Griffiths, D. F., Worzfeld, T., Offermanns, S., Smalley, M. J. and Williamson, M. 2023. Plexin-B1 mutation drives metastasis in prostate cancer mouse models. Cancer Research Communications 3(3), pp. 444-458. (10.1158/2767-9764.CRC-22-0480)
2022
- Dimitriou, P., Li, J., Tornillo, G., Smalley, M. and Barrow, D. 2022. Droplet incubator: a new droplet-based model to investigate living cell-synthetic cell interactions. Presented at: MicroTAS 2022, Hangzhou, China, 23-27 October 2022.
2021
- Castro, J. et al. 2021. A nuclear-directed ribonuclease variant targets cancer stem cells and inhibits migration and invasion of breast cancer cells. Cancers 13(17), article number: 4350. (10.3390/cancers13174350)
- Ordonez, L. D. et al. 2021. Reproductive history determines ErbB2 locus amplification, WNT signalling and tumour phenotype in a murine breast cancer model. Disease Models and Mechanisms 14(5), article number: dmm048736. (10.1242/dmm.048736)
- Edmunds, G. L. et al. 2021. Dog breeds and body conformations with predisposition to osteosarcoma in the UK: a case-control study. Canine Medicine and Genetics 8, article number: 2. (10.1186/s40575-021-00100-7)
2020
- Pires, A. et al. 2020. Immune remodelling of the extracellular matrix drives loss of cancer stem cells and tumor rejection. Cancer Immunology Research 8(12), pp. 1520 - 1531. (10.1158/2326-6066.CIR-20-0070)
- Regan, J. L. and Smalley, M. J. 2020. Integrating single-cell RNA-sequencing and functional assays to decipher mammary cell states and lineage hierarchies. NPJ Breast Cancer 6, article number: 32. (10.1038/s41523-020-00175-8)
- Shorning, B. Y., Dass, M. S., Smalley, M. J. and Pearson, H. B. 2020. The PI3K-AKT-mTOR pathway and prostate cancer: at the crossroads of AR, MAPK, and WNT signaling. International Journal of Molecular Sciences 21(12), article number: 4507. (10.3390/ijms21124507)
2019
- Ordonez, L. D. et al. 2019. Rapid activation of epithelial-mesenchymal transition drives PARP inhibitor resistance in Brca2-mutant mammary tumours. Oncotarget 10(27), pp. 2586-2606. (10.18632/oncotarget.26830)
- Mohamed, N., Hay, T., Reed, K. R., Smalley, M. J. and Clarke, A. R. 2019. APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression. BMC Cancer 19, article number: 677. (10.1186/s12885-019-5867-y)
2018
- Tornillo, G. et al. 2018. Dual mechanisms of LYN kinase dysregulation drive aggressive behaviour in breast cancer cells. Cell Reports 25(13), pp. 3674-3692. (10.1016/j.celrep.2018.11.103)
- Pearson, H. B. et al. 2018. Identification of Pik3ca mutation as a genetic driver of prostate cancer that cooperates with Pten loss to accelerate progression and castration-resistant growth. Cancer Discovery 8(6), pp. 764-779. (10.1158/2159-8290.CD-17-0867)
2017
- Jefferies, M. T. et al. 2017. PTEN loss and activation of K-RAS and β-catenin cooperate to accelerate prostate tumourigenesis. Journal of Pathology 243(4), pp. 442-456. (10.1002/path.4977)
- Chiang, K. et al. 2017. PRMT5 is a critical regulator of breast cancer stem cell function via Histone Methylation and FOXP1 expression. Cell Reports 21(12), pp. 3498-3513. (10.1016/j.celrep.2017.11.096)
- Soady, K. J. et al. 2017. Receptor protein tyrosine phosphatase PTPRB negatively regulates FGF2-dependent branching morphogenesis. Development 144(20), pp. 3777-3788. (10.1242/dev.149120)
2016
- Jardé, T. et al. 2016. Wnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids. Nature Communications 7, article number: 13207. (10.1038/ncomms13207)
- Abraham, T. et al. 2016. Ellipsoid segmentation model for analyzing light-attenuated 3D confocal image stacks of fluorescent multi-cellular spheroids. PLoS ONE 11(6), article number: e0156942. (10.1371/journal.pone.0156942)
- Estrada, M. F. et al. 2016. Modelling the tumour microenvironment in long-term microencapsulated 3D co-cultures recapitulates phenotypic features of disease progression. Biomaterials 78, pp. 50-61. (10.1016/j.biomaterials.2015.11.030)
2015
- Ferrari, N. et al. 2015. Runx2 contributes to the regenerative potential of the mammary epithelium. Scientific Reports 5, article number: 15658. (10.1038/srep15658)
- Greenow, K. R. and Smalley, M. J. 2015. Overview of genetically engineered mouse models of breast cancer used in translational biology and drug development. Current Protocols in Pharmacology 70(1), article number: 70:14.36.1-14.36.14. (10.1002/0471141755.ph1436s70)
- Tornillo, G. and Smalley, M. J. 2015. ERrrr..Where are the progenitors? Hormone receptors and mammary cell heterogeneity. Journal of Mammary Gland Biology and Neoplasia 20(1), pp. 63-73. (10.1007/s10911-015-9336-1)
- Francis, J. C. et al. 2015. Whole exome DNA sequence analysis of Brca2 and Trp53 deficient mouse mammary gland tumours. Journal of Pathology 236(2), pp. 186-200. (10.1002/path.4517)
- Iglesias, J. M. et al. 2015. Annexin A8 identifies a subpopulation of transiently quiescent c-Kit positive luminal progenitor cells of the ductal mammary epithelium. Plos One 10(3), article number: e0119718. (10.1371/journal.pone.0119718)
- Soady, K. J. et al. 2015. Mouse mammary stem cells express prognostic markers for triple-negative breast cancer. Breast Cancer Research 17, article number: 31. (10.1186/s13058-015-0539-6)
2014
- Hickman, J. A. et al. 2014. Three-dimensional models of cancer for pharmacology and cancer cell biology: Capturing tumor complexity in vitro/ex vivo. Biotechnology Journal 9(9), pp. 1115-1128. (10.1002/biot.201300492)
- Melchor, L. et al. 2014. Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models. Journal of Pathology 233(2), pp. 124-137. (10.1002/path.4345)
- Cowley, M. et al. 2014. Developmental programming mediated by complementary roles of imprinted Grb10 in mother and pup. PLoS Biology 12(2), pp. e1001799. (10.1371/journal.pbio.1001799)
2013
- Regan, J. et al. 2013. Aurora A kinase regulates mammary epithelial cell fate by determining mitotic spindle orientation in a Notch-dependent manner. Cell Reports 4(1), pp. 110-123. (10.1016/j.celrep.2013.05.044)
- Gastaldi, S. et al. 2013. Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: implications for basal-like breast cancer. Oncogene 32, pp. 1428-1440. (10.1038/onc.2012.154)
- Smalley, M. J., Piggott, L. and Clarkson, R. W. E. 2013. Breast cancer stem cells: obstacles to therapy. Cancer Letters 338(1), pp. 57-62. (10.1016/j.canlet.2012.04.023)
- Zvelebil, M. et al. 2013. Embryonic mammary signature subsets are activated in Brca1-/- and basal-like breast cancers. Breast Cancer Research 15(2), article number: R25. (10.1186/bcr3403)
- Eccles, S. A. et al. 2013. Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer. Breast Cancer Research 15(5), pp. R92. (10.1186/bcr3493)
2012
- Ordonez, L. and Smalley, M. J. 2012. Who do they think they are? Wnt-responsive cells reveal their family trees. Breast Cancer Research 14(6), article number: 327. (10.1186/bcr3351)
- Soady, K. and Smalley, M. J. 2012. Slugging their way to immortality: Driving mammary epithelial cells into a stem cell-like state. Breast Cancer Research 14(5), article number: 319. (10.1186/bcr3188)
- Hopkins, S. et al. 2012. Mig6 is a sensor of EGF receptor inactivation that directly activates c-Abl to induce apoptosis during epithelial homeostasis. Developmental Cell 23(3), pp. 547-559. (10.1016/j.devcel.2012.08.001)
- Smalley, M. J. et al. 2012. Isolation of mouse mammary epithelial subpopulations: a comparison of leading methods. Journal of Mammary Gland Biology and Neoplasia 17(2), pp. 91-97. (10.1007/s10911-012-9257-1)
- Regan, J. L., Kendrick, H., Magnay, F., Vafaizadeh, V., Groner, B. and Smalley, M. 2012. c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer. Oncogene 31(7), pp. 869-883. (10.1038/onc.2011.289)
- Milani, E. S. et al. 2012. Protein tyrosine phosphatase 1B restrains mammary alveologenesis and secretory differentiation. Development 140(1), pp. 117-125. (10.1242/dev.082941)
2011
- Wansbury, O. et al. 2011. Transcriptome analysis of embryonic mammary cells reveals insights into mammary lineage establishment. Breast Cancer Research 13(4), article number: R79. (10.1186/bcr2928)
- Molyneux, G. and Smalley, M. J. 2011. The cell of origin of BRCA1 mutation-associated breast cancer: a cautionary tale of gene expression profiling. Journal of Mammary Gland Biology and Neoplasia 16(1), pp. 51-55. (10.1007/s10911-011-9202-8)
2010
- Molyneux, G. et al. 2010. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7(3), pp. 403-417. (10.1016/j.stem.2010.07.010)
- Smalley, M. J. 2010. Isolation, culture and analysis of mouse mammary epithelial cells. In: Ward, A. and Tosh, D. eds. Mouse cell culture : methods and protocols. Methods in Molecular Biology Vol. 633. New York: Springer-Verlag, pp. 139-170., (10.1007/978-1-59745-019-5_11)
- Evers, B. et al. 2010. A tissue reconstitution model to study cancer cell-intrinsic and -extrinsic factors in mammary tumourigenesis. Journal of Pathology 220(1), pp. 34-44. (10.1002/path.2655)
2009
- Bentires-Alj, M., Clarke, R. B., Jonkers, J., Smalley, M. J. and Stein, T. 2009. It's all in the details: methods in breast development and cancer [Meeting Report]. Breast Cancer Research 11(4), article number: 305. (10.1186/bcr2346)
- Grigoriadis, A., Oliver, G., Tanney, A., Kendrick, H., Smalley, M. J., Jat, P. and Neville, A. M. 2009. Identification of differentially expressed sense and antisense transcript pairs in breast epithelial tissues. BMC Genomics 10(1), article number: 324. (10.1186/1471-2164-10-324)
- Alexander, C. M. et al. 2009. Separating stem cells by flow cytometry: reducing variability for solid tissues. Cell Stem Cell 5(6), pp. 579-583. (10.1016/j.stem.2009.11.008)
- Huser, C. A. et al. 2009. TSC-22D1 isoforms have opposing roles in mammary epithelial cell survival. Cell Death and Differentiation 17(2), pp. 304-315. (10.1038/cdd.2009.126)
- Britt, K. L., Kendrick, H., Regan, J. L., Molyneux, G., Magnay, F., Ashworth, A. and Smalley, M. J. 2009. Pregnancy in the mature adult mouse does not alter the proportion of mammary epithelial stem/progenitor cells. Breast Cancer Research 11(2), article number: R20. (10.1186/bcr2245)
2008
- Kendrick, H., Regan, J., Magnay, F., Grigoriadis, A., Mitsopoulos, C., Zvelebil, M. and Smalley, M. J. 2008. Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate. BMC Genomics 9(1), article number: 591. (10.1186/1471-2164-9-591)
- Melchor, L. and Smalley, M. J. 2008. Highway to heaven: mammary gland development and differentiation. Breast Cancer Research 10(5), pp. 305-307. (10.1186/bcr2147)
- Lindeman, G., Visvader, J., Smalley, M. J. and Eaves, C. 2008. The future of mammary stem cell biology: the power of in vivo transplants [Letter]. Breast Cancer Research 10(3), pp. 402. (10.1186/bcr1986)
- Cariati, M., Naderi, A., Brown, J. P., Smalley, M. J., Pinder, S. E., Caldas, C. and Purushotham, A. D. 2008. Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. International Journal of Cancer 122(2), pp. 298-304. (10.1002/ijc.23103)
- Smalley, M. J., Reis-Filho, J. and Ashworth, A. 2008. BRCA1 and stem cells: tumour typecasting. Nature Cell Biology 10(4), pp. 377-379. (10.1038/ncb0408-377)
2007
- Smalley, M. J. et al. 2007. Regulator of G-protein signalling 2 (RGS2) mRNA is differentially expressed in mammary epithelial subpopulations and overexpressed in the majority of breast cancers. Breast Cancer Research 9(6), article number: R85. (10.1186/bcr1834)
- Molyneux, G., Regan, J. and Smalley, M. J. 2007. Common molecular mechanisms of mammary gland development and breast cancer. Cellular and Molecular Life Sciences 64(24), pp. 3248-3260. (10.1007/s00018-007-7391-5)
- Britt, K., Ashworth, A. and Smalley, M. J. 2007. Pregnancy and the risk of breast cancer. Endocrine-Related Cancer 14(4), pp. 907-933. (10.1677/ERC-07-0137)
- Sleeman, K. E., Kendrick, H., Robertson, D., Isacke, C. M., Ashworth, A. and Smalley, M. J. 2007. Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. Journal of cell biology 176(1), pp. 19-26. (10.1083/jcb.200604065)
- Regan, J. and Smalley, M. J. 2007. Prospective isolation and functional analysis of stem and differentiated cells from the mouse mammary gland. Stem Cell Reviews 3(2), pp. 124-136. (10.1007/s12015-007-0017-3)
2006
- Sleeman, K. E., Kendrick, H., Ashworth, A., Isacke, C. M. and Smalley, M. J. 2006. CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells. Breast Cancer Research 8(R7) (10.1186/bcr1371)
2005
- Smalley, M. J. et al. 2005. Dishevelled (Dvl-2) activates canonical Wnt signalling in the absence of cytoplasmic puncta. Journal of Cell Science 118(22), pp. 5279-5289. (10.1242/jcs.02647)
- Smalley, M. J., Titley, I. and Ashworth, A. 2005. An improved definition of mouse mammary epithelial side population cells. Cytotherapy 7(6), pp. 497-508. (10.1080/14653240500361145)
- Smalley, M. J. and Clarke, R. B. 2005. The mammary gland “side population”: a putative stem/progenitor cell marker?. Journal of Mammary Gland Biology and Neoplasia 10(1), pp. 37-47. (10.1007/s10911-005-2539-0)
2004
- Ciani, L., Krylova, O., Smalley, M. J., Dale, T. C. and Salinas, P. 2004. A divergent canonical WNT-signaling pathway regulates microtubule dynamics: Dishevelled signals locally to stabilize microtubules. Journal of Cell Biology 164(2), pp. 243-253. (10.1083/jcb.200309096)
2003
- Alvi, A. J. et al. 2003. Functional and molecular characterisation of mammary side population cells. Breast Cancer Research 5(1), pp. R1-R8. (10.1186/bcr547)
- Smalley, M. J. and Ashworth, A. 2003. Stem cells and breast cancer: A field in transit. Nature Reviews Cancer 3, pp. 832-844. (10.1038/nrc1212)
2002
- Fraser, E. et al. 2002. Identification of the Axin and Frat binding region of glycogen synthase kinase-3. Journal of Biological Chemistry 277(3), pp. 2176-2185. (10.1074/jbc.M109462200)
2001
- Smalley, M. J. and Dale, T. C. 2001. Wnt signaling and mammary tumorigenesis. Journal of Mammary Gland Biology and Neoplasia 6(1), pp. 37-52.
- Smalley, M. J., Leiper, K., Tootle, R., McCloskey, P., O'Hare, M. J. and Hodgson, H. 2001. Immortalisation of human hepatocytes by temperature-sensitive SV40 large-T antigen. In Vitro Cellular and Developmental Biology - Animal 37(3), pp. 166-168. (10.1290/1071-2690(2001)037<0166:IOHHBT>2.0.CO;2)
2000
- Webster, M. T. et al. 2000. Sequence variants of the Axin gene in breast, colon, and other cancers: an analysis of mutations that interfere with GSK3 binding. Genes Chromosomes and Cancer 28(4), pp. 443-453. (10.1002/1098-2264(200008)28:4<443::AID-GCC10>3.0.CO;2-D)
- Naylor, S., Smalley, M. J., Robertson, D., Gusterson, B. A., Edwards, P. A. and Dale, T. C. 2000. Retroviral expression of Wnt-1 and Wnt-7b produces different effects in mouse mammary epithelium. Journal of Cell Science 113(12), pp. 2129-2138.
- Sarkar, L., Cobourne, M., Naylor, S., Smalley, M. J., Dale, T. C. and Sharpe, P. T. 2000. Wnt/Shh interactions regulate ectodermal boundary formation during mammalian tooth development. Proceedings of the National Academy of Sciences of the United States of America 97(9), pp. 4520-4524. (10.1073/pnas.97.9.4520)
1999
- Smalley, M. J., Titley, J., Paterson, H., Perusinghe, N., Clarke, C. and O'Hare, M. J. 1999. Differentiation of separated mouse mammary luminal epithelial and myoepithelial cells cultured on EHS matrix analyzed by indirect immunofluorescence of cytoskeletal antigens. Journal of Histochemistry & Cytochemistry 47(12), pp. 1513-1524. (10.1177/002215549904701203)
- Smalley, M. J. and Dale, T. C. 1999. Wnt signalling in mammalian development and cancer. Cancer and Metastasis Reviews 18(2), pp. 215-230. (10.1023/A:1006369223282)
- Smalley, M. J. et al. 1999. Interaction of Axin and Dvl-2 proteins regulates Dvl-2-stimulated TCF-dependent transcription. EMBO Journal 18(10), pp. 2823-2835. (10.1093/emboj/18.10.2823)
- Smalley, M. J. et al. 1999. Behavior of a cell line derived from normal human hepatocytes on non-physiological and physiological-type substrates: Evidence for enhancement of secretion of liver-specific proteins by a three-dimensional growth pattern. In Vitro Cellular and Developmental Biology - Animal 35(1), pp. 22-32. (10.1007/s11626-999-0040-6)
1998
- Smalley, M. J., Titley, J. and O'Hare, M. J. 1998. Clonal characterization of mouse mammary luminal epithelial and myoepithelial cells separated by fluorescence-activated cell sorting. In Vitro Cellular and Developmental Biology - Animal 34(9), pp. 711-721. (10.1007/s11626-998-0067-0)
Articles
- Williams, J. S. et al. 2024. Enhanced bacterial cancer therapy delivering therapeutic RNA interference of c-Myc. Cell & Bioscience 14(38) (10.1186/s13578-024-01206-8)
- Tornillo, G., Warrington, L., Kendrick, H., Higgins, A. T., Hay, T., Beck, S. and Smalley, M. J. 2024. Conditional in vivo deletion of LYN kinase has little effect on a BRCA1 loss-of-function-associated mammary tumour model. Disease Models and Mechanisms 17(1), article number: dmm050211. (10.1242/dmm.050211)
- Varney, D. et al. 2023. Epidemiology of mammary tumours in bitches under veterinary care in the UK in 2016. Veterinary Record 193(5), article number: e3054. (10.1002/vetr.3054)
- Ordonez, L., Tornillo, G., Kendrick, H., Hay, T. and Smalley, M. J. 2023. NOTCH and AKT signalling interact to drive mammary tumour heterogeneity. Cancers 15(17), article number: 4324. (10.3390/cancers15174324)
- O'Neill, D., Edmunds, G., Urquhart-Gilmore, J., Church, D., Rutherford, L., Smalley, M. and Brodbelt, D. 2023. Dog breeds and conformations predisposed to osteosarcoma in the UK: a VetCompass study. Canine Medicine and Genetics 10, article number: 8. (10.1186/s40575-023-00131-2)
- Edmunds, G., Beck, S., Umakant Kale, K., Spasic, I., O'Neill, D., Brodbelt, D. and Smalley, M. J. 2023. Associations between dog breed and clinical features of mammary epithelial neoplasia in bitches: an epidemiological study of submissions to a single diagnostic pathology centre between 2008-2021. Journal of Mammary Gland Biology and Neoplasia 28(6) (10.1007/s10911-023-09531-3)
- Shorning, B., Trent, N., Griffiths, D. F., Worzfeld, T., Offermanns, S., Smalley, M. J. and Williamson, M. 2023. Plexin-B1 mutation drives metastasis in prostate cancer mouse models. Cancer Research Communications 3(3), pp. 444-458. (10.1158/2767-9764.CRC-22-0480)
- Castro, J. et al. 2021. A nuclear-directed ribonuclease variant targets cancer stem cells and inhibits migration and invasion of breast cancer cells. Cancers 13(17), article number: 4350. (10.3390/cancers13174350)
- Ordonez, L. D. et al. 2021. Reproductive history determines ErbB2 locus amplification, WNT signalling and tumour phenotype in a murine breast cancer model. Disease Models and Mechanisms 14(5), article number: dmm048736. (10.1242/dmm.048736)
- Edmunds, G. L. et al. 2021. Dog breeds and body conformations with predisposition to osteosarcoma in the UK: a case-control study. Canine Medicine and Genetics 8, article number: 2. (10.1186/s40575-021-00100-7)
- Pires, A. et al. 2020. Immune remodelling of the extracellular matrix drives loss of cancer stem cells and tumor rejection. Cancer Immunology Research 8(12), pp. 1520 - 1531. (10.1158/2326-6066.CIR-20-0070)
- Regan, J. L. and Smalley, M. J. 2020. Integrating single-cell RNA-sequencing and functional assays to decipher mammary cell states and lineage hierarchies. NPJ Breast Cancer 6, article number: 32. (10.1038/s41523-020-00175-8)
- Shorning, B. Y., Dass, M. S., Smalley, M. J. and Pearson, H. B. 2020. The PI3K-AKT-mTOR pathway and prostate cancer: at the crossroads of AR, MAPK, and WNT signaling. International Journal of Molecular Sciences 21(12), article number: 4507. (10.3390/ijms21124507)
- Ordonez, L. D. et al. 2019. Rapid activation of epithelial-mesenchymal transition drives PARP inhibitor resistance in Brca2-mutant mammary tumours. Oncotarget 10(27), pp. 2586-2606. (10.18632/oncotarget.26830)
- Mohamed, N., Hay, T., Reed, K. R., Smalley, M. J. and Clarke, A. R. 2019. APC2 is critical for ovarian WNT signalling control, fertility and tumour suppression. BMC Cancer 19, article number: 677. (10.1186/s12885-019-5867-y)
- Tornillo, G. et al. 2018. Dual mechanisms of LYN kinase dysregulation drive aggressive behaviour in breast cancer cells. Cell Reports 25(13), pp. 3674-3692. (10.1016/j.celrep.2018.11.103)
- Pearson, H. B. et al. 2018. Identification of Pik3ca mutation as a genetic driver of prostate cancer that cooperates with Pten loss to accelerate progression and castration-resistant growth. Cancer Discovery 8(6), pp. 764-779. (10.1158/2159-8290.CD-17-0867)
- Jefferies, M. T. et al. 2017. PTEN loss and activation of K-RAS and β-catenin cooperate to accelerate prostate tumourigenesis. Journal of Pathology 243(4), pp. 442-456. (10.1002/path.4977)
- Chiang, K. et al. 2017. PRMT5 is a critical regulator of breast cancer stem cell function via Histone Methylation and FOXP1 expression. Cell Reports 21(12), pp. 3498-3513. (10.1016/j.celrep.2017.11.096)
- Soady, K. J. et al. 2017. Receptor protein tyrosine phosphatase PTPRB negatively regulates FGF2-dependent branching morphogenesis. Development 144(20), pp. 3777-3788. (10.1242/dev.149120)
- Jardé, T. et al. 2016. Wnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids. Nature Communications 7, article number: 13207. (10.1038/ncomms13207)
- Abraham, T. et al. 2016. Ellipsoid segmentation model for analyzing light-attenuated 3D confocal image stacks of fluorescent multi-cellular spheroids. PLoS ONE 11(6), article number: e0156942. (10.1371/journal.pone.0156942)
- Estrada, M. F. et al. 2016. Modelling the tumour microenvironment in long-term microencapsulated 3D co-cultures recapitulates phenotypic features of disease progression. Biomaterials 78, pp. 50-61. (10.1016/j.biomaterials.2015.11.030)
- Ferrari, N. et al. 2015. Runx2 contributes to the regenerative potential of the mammary epithelium. Scientific Reports 5, article number: 15658. (10.1038/srep15658)
- Greenow, K. R. and Smalley, M. J. 2015. Overview of genetically engineered mouse models of breast cancer used in translational biology and drug development. Current Protocols in Pharmacology 70(1), article number: 70:14.36.1-14.36.14. (10.1002/0471141755.ph1436s70)
- Tornillo, G. and Smalley, M. J. 2015. ERrrr..Where are the progenitors? Hormone receptors and mammary cell heterogeneity. Journal of Mammary Gland Biology and Neoplasia 20(1), pp. 63-73. (10.1007/s10911-015-9336-1)
- Francis, J. C. et al. 2015. Whole exome DNA sequence analysis of Brca2 and Trp53 deficient mouse mammary gland tumours. Journal of Pathology 236(2), pp. 186-200. (10.1002/path.4517)
- Iglesias, J. M. et al. 2015. Annexin A8 identifies a subpopulation of transiently quiescent c-Kit positive luminal progenitor cells of the ductal mammary epithelium. Plos One 10(3), article number: e0119718. (10.1371/journal.pone.0119718)
- Soady, K. J. et al. 2015. Mouse mammary stem cells express prognostic markers for triple-negative breast cancer. Breast Cancer Research 17, article number: 31. (10.1186/s13058-015-0539-6)
- Hickman, J. A. et al. 2014. Three-dimensional models of cancer for pharmacology and cancer cell biology: Capturing tumor complexity in vitro/ex vivo. Biotechnology Journal 9(9), pp. 1115-1128. (10.1002/biot.201300492)
- Melchor, L. et al. 2014. Identification of cellular and genetic drivers of breast cancer heterogeneity in genetically engineered mouse tumour models. Journal of Pathology 233(2), pp. 124-137. (10.1002/path.4345)
- Cowley, M. et al. 2014. Developmental programming mediated by complementary roles of imprinted Grb10 in mother and pup. PLoS Biology 12(2), pp. e1001799. (10.1371/journal.pbio.1001799)
- Regan, J. et al. 2013. Aurora A kinase regulates mammary epithelial cell fate by determining mitotic spindle orientation in a Notch-dependent manner. Cell Reports 4(1), pp. 110-123. (10.1016/j.celrep.2013.05.044)
- Gastaldi, S. et al. 2013. Met signaling regulates growth, repopulating potential and basal cell-fate commitment of mammary luminal progenitors: implications for basal-like breast cancer. Oncogene 32, pp. 1428-1440. (10.1038/onc.2012.154)
- Smalley, M. J., Piggott, L. and Clarkson, R. W. E. 2013. Breast cancer stem cells: obstacles to therapy. Cancer Letters 338(1), pp. 57-62. (10.1016/j.canlet.2012.04.023)
- Zvelebil, M. et al. 2013. Embryonic mammary signature subsets are activated in Brca1-/- and basal-like breast cancers. Breast Cancer Research 15(2), article number: R25. (10.1186/bcr3403)
- Eccles, S. A. et al. 2013. Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer. Breast Cancer Research 15(5), pp. R92. (10.1186/bcr3493)
- Ordonez, L. and Smalley, M. J. 2012. Who do they think they are? Wnt-responsive cells reveal their family trees. Breast Cancer Research 14(6), article number: 327. (10.1186/bcr3351)
- Soady, K. and Smalley, M. J. 2012. Slugging their way to immortality: Driving mammary epithelial cells into a stem cell-like state. Breast Cancer Research 14(5), article number: 319. (10.1186/bcr3188)
- Hopkins, S. et al. 2012. Mig6 is a sensor of EGF receptor inactivation that directly activates c-Abl to induce apoptosis during epithelial homeostasis. Developmental Cell 23(3), pp. 547-559. (10.1016/j.devcel.2012.08.001)
- Smalley, M. J. et al. 2012. Isolation of mouse mammary epithelial subpopulations: a comparison of leading methods. Journal of Mammary Gland Biology and Neoplasia 17(2), pp. 91-97. (10.1007/s10911-012-9257-1)
- Regan, J. L., Kendrick, H., Magnay, F., Vafaizadeh, V., Groner, B. and Smalley, M. 2012. c-Kit is required for growth and survival of the cells of origin of Brca1-mutation-associated breast cancer. Oncogene 31(7), pp. 869-883. (10.1038/onc.2011.289)
- Milani, E. S. et al. 2012. Protein tyrosine phosphatase 1B restrains mammary alveologenesis and secretory differentiation. Development 140(1), pp. 117-125. (10.1242/dev.082941)
- Wansbury, O. et al. 2011. Transcriptome analysis of embryonic mammary cells reveals insights into mammary lineage establishment. Breast Cancer Research 13(4), article number: R79. (10.1186/bcr2928)
- Molyneux, G. and Smalley, M. J. 2011. The cell of origin of BRCA1 mutation-associated breast cancer: a cautionary tale of gene expression profiling. Journal of Mammary Gland Biology and Neoplasia 16(1), pp. 51-55. (10.1007/s10911-011-9202-8)
- Molyneux, G. et al. 2010. BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells. Cell Stem Cell 7(3), pp. 403-417. (10.1016/j.stem.2010.07.010)
- Evers, B. et al. 2010. A tissue reconstitution model to study cancer cell-intrinsic and -extrinsic factors in mammary tumourigenesis. Journal of Pathology 220(1), pp. 34-44. (10.1002/path.2655)
- Bentires-Alj, M., Clarke, R. B., Jonkers, J., Smalley, M. J. and Stein, T. 2009. It's all in the details: methods in breast development and cancer [Meeting Report]. Breast Cancer Research 11(4), article number: 305. (10.1186/bcr2346)
- Grigoriadis, A., Oliver, G., Tanney, A., Kendrick, H., Smalley, M. J., Jat, P. and Neville, A. M. 2009. Identification of differentially expressed sense and antisense transcript pairs in breast epithelial tissues. BMC Genomics 10(1), article number: 324. (10.1186/1471-2164-10-324)
- Alexander, C. M. et al. 2009. Separating stem cells by flow cytometry: reducing variability for solid tissues. Cell Stem Cell 5(6), pp. 579-583. (10.1016/j.stem.2009.11.008)
- Huser, C. A. et al. 2009. TSC-22D1 isoforms have opposing roles in mammary epithelial cell survival. Cell Death and Differentiation 17(2), pp. 304-315. (10.1038/cdd.2009.126)
- Britt, K. L., Kendrick, H., Regan, J. L., Molyneux, G., Magnay, F., Ashworth, A. and Smalley, M. J. 2009. Pregnancy in the mature adult mouse does not alter the proportion of mammary epithelial stem/progenitor cells. Breast Cancer Research 11(2), article number: R20. (10.1186/bcr2245)
- Kendrick, H., Regan, J., Magnay, F., Grigoriadis, A., Mitsopoulos, C., Zvelebil, M. and Smalley, M. J. 2008. Transcriptome analysis of mammary epithelial subpopulations identifies novel determinants of lineage commitment and cell fate. BMC Genomics 9(1), article number: 591. (10.1186/1471-2164-9-591)
- Melchor, L. and Smalley, M. J. 2008. Highway to heaven: mammary gland development and differentiation. Breast Cancer Research 10(5), pp. 305-307. (10.1186/bcr2147)
- Lindeman, G., Visvader, J., Smalley, M. J. and Eaves, C. 2008. The future of mammary stem cell biology: the power of in vivo transplants [Letter]. Breast Cancer Research 10(3), pp. 402. (10.1186/bcr1986)
- Cariati, M., Naderi, A., Brown, J. P., Smalley, M. J., Pinder, S. E., Caldas, C. and Purushotham, A. D. 2008. Alpha-6 integrin is necessary for the tumourigenicity of a stem cell-like subpopulation within the MCF7 breast cancer cell line. International Journal of Cancer 122(2), pp. 298-304. (10.1002/ijc.23103)
- Smalley, M. J., Reis-Filho, J. and Ashworth, A. 2008. BRCA1 and stem cells: tumour typecasting. Nature Cell Biology 10(4), pp. 377-379. (10.1038/ncb0408-377)
- Smalley, M. J. et al. 2007. Regulator of G-protein signalling 2 (RGS2) mRNA is differentially expressed in mammary epithelial subpopulations and overexpressed in the majority of breast cancers. Breast Cancer Research 9(6), article number: R85. (10.1186/bcr1834)
- Molyneux, G., Regan, J. and Smalley, M. J. 2007. Common molecular mechanisms of mammary gland development and breast cancer. Cellular and Molecular Life Sciences 64(24), pp. 3248-3260. (10.1007/s00018-007-7391-5)
- Britt, K., Ashworth, A. and Smalley, M. J. 2007. Pregnancy and the risk of breast cancer. Endocrine-Related Cancer 14(4), pp. 907-933. (10.1677/ERC-07-0137)
- Sleeman, K. E., Kendrick, H., Robertson, D., Isacke, C. M., Ashworth, A. and Smalley, M. J. 2007. Dissociation of estrogen receptor expression and in vivo stem cell activity in the mammary gland. Journal of cell biology 176(1), pp. 19-26. (10.1083/jcb.200604065)
- Regan, J. and Smalley, M. J. 2007. Prospective isolation and functional analysis of stem and differentiated cells from the mouse mammary gland. Stem Cell Reviews 3(2), pp. 124-136. (10.1007/s12015-007-0017-3)
- Sleeman, K. E., Kendrick, H., Ashworth, A., Isacke, C. M. and Smalley, M. J. 2006. CD24 staining of mouse mammary gland cells defines luminal epithelial, myoepithelial/basal and non-epithelial cells. Breast Cancer Research 8(R7) (10.1186/bcr1371)
- Smalley, M. J. et al. 2005. Dishevelled (Dvl-2) activates canonical Wnt signalling in the absence of cytoplasmic puncta. Journal of Cell Science 118(22), pp. 5279-5289. (10.1242/jcs.02647)
- Smalley, M. J., Titley, I. and Ashworth, A. 2005. An improved definition of mouse mammary epithelial side population cells. Cytotherapy 7(6), pp. 497-508. (10.1080/14653240500361145)
- Smalley, M. J. and Clarke, R. B. 2005. The mammary gland “side population”: a putative stem/progenitor cell marker?. Journal of Mammary Gland Biology and Neoplasia 10(1), pp. 37-47. (10.1007/s10911-005-2539-0)
- Ciani, L., Krylova, O., Smalley, M. J., Dale, T. C. and Salinas, P. 2004. A divergent canonical WNT-signaling pathway regulates microtubule dynamics: Dishevelled signals locally to stabilize microtubules. Journal of Cell Biology 164(2), pp. 243-253. (10.1083/jcb.200309096)
- Alvi, A. J. et al. 2003. Functional and molecular characterisation of mammary side population cells. Breast Cancer Research 5(1), pp. R1-R8. (10.1186/bcr547)
- Smalley, M. J. and Ashworth, A. 2003. Stem cells and breast cancer: A field in transit. Nature Reviews Cancer 3, pp. 832-844. (10.1038/nrc1212)
- Fraser, E. et al. 2002. Identification of the Axin and Frat binding region of glycogen synthase kinase-3. Journal of Biological Chemistry 277(3), pp. 2176-2185. (10.1074/jbc.M109462200)
- Smalley, M. J. and Dale, T. C. 2001. Wnt signaling and mammary tumorigenesis. Journal of Mammary Gland Biology and Neoplasia 6(1), pp. 37-52.
- Smalley, M. J., Leiper, K., Tootle, R., McCloskey, P., O'Hare, M. J. and Hodgson, H. 2001. Immortalisation of human hepatocytes by temperature-sensitive SV40 large-T antigen. In Vitro Cellular and Developmental Biology - Animal 37(3), pp. 166-168. (10.1290/1071-2690(2001)037<0166:IOHHBT>2.0.CO;2)
- Webster, M. T. et al. 2000. Sequence variants of the Axin gene in breast, colon, and other cancers: an analysis of mutations that interfere with GSK3 binding. Genes Chromosomes and Cancer 28(4), pp. 443-453. (10.1002/1098-2264(200008)28:4<443::AID-GCC10>3.0.CO;2-D)
- Naylor, S., Smalley, M. J., Robertson, D., Gusterson, B. A., Edwards, P. A. and Dale, T. C. 2000. Retroviral expression of Wnt-1 and Wnt-7b produces different effects in mouse mammary epithelium. Journal of Cell Science 113(12), pp. 2129-2138.
- Sarkar, L., Cobourne, M., Naylor, S., Smalley, M. J., Dale, T. C. and Sharpe, P. T. 2000. Wnt/Shh interactions regulate ectodermal boundary formation during mammalian tooth development. Proceedings of the National Academy of Sciences of the United States of America 97(9), pp. 4520-4524. (10.1073/pnas.97.9.4520)
- Smalley, M. J., Titley, J., Paterson, H., Perusinghe, N., Clarke, C. and O'Hare, M. J. 1999. Differentiation of separated mouse mammary luminal epithelial and myoepithelial cells cultured on EHS matrix analyzed by indirect immunofluorescence of cytoskeletal antigens. Journal of Histochemistry & Cytochemistry 47(12), pp. 1513-1524. (10.1177/002215549904701203)
- Smalley, M. J. and Dale, T. C. 1999. Wnt signalling in mammalian development and cancer. Cancer and Metastasis Reviews 18(2), pp. 215-230. (10.1023/A:1006369223282)
- Smalley, M. J. et al. 1999. Interaction of Axin and Dvl-2 proteins regulates Dvl-2-stimulated TCF-dependent transcription. EMBO Journal 18(10), pp. 2823-2835. (10.1093/emboj/18.10.2823)
- Smalley, M. J. et al. 1999. Behavior of a cell line derived from normal human hepatocytes on non-physiological and physiological-type substrates: Evidence for enhancement of secretion of liver-specific proteins by a three-dimensional growth pattern. In Vitro Cellular and Developmental Biology - Animal 35(1), pp. 22-32. (10.1007/s11626-999-0040-6)
- Smalley, M. J., Titley, J. and O'Hare, M. J. 1998. Clonal characterization of mouse mammary luminal epithelial and myoepithelial cells separated by fluorescence-activated cell sorting. In Vitro Cellular and Developmental Biology - Animal 34(9), pp. 711-721. (10.1007/s11626-998-0067-0)
Book sections
- Smalley, M. J. 2010. Isolation, culture and analysis of mouse mammary epithelial cells. In: Ward, A. and Tosh, D. eds. Mouse cell culture : methods and protocols. Methods in Molecular Biology Vol. 633. New York: Springer-Verlag, pp. 139-170., (10.1007/978-1-59745-019-5_11)
Conferences
- Dimitriou, P., Li, J., Tornillo, G., Smalley, M. and Barrow, D. 2022. Droplet incubator: a new droplet-based model to investigate living cell-synthetic cell interactions. Presented at: MicroTAS 2022, Hangzhou, China, 23-27 October 2022.
Ymchwil
Mae canser yn glefyd heterogenaidd iawn ac mae canser y fron yn enghraifft glasurol o hyn. Mae'r heterogenedd hwnnw i'w gael fel heterogenedd rhyng-tiwmor a mewnol. Gellir dosbarthu heterogenedd rhyng-tiwmor yng nghancr y fron ar sail paramedrau clinigol (ee gradd, mynegiant o dderbynyddion hormonau), proffilio mynegiant genynnau a / neu ddisgrifiad histolegol (mae mwy nag 20 o is-fathau histolegol gwahanol o ganser y fron mewn pobl). Mae heterogenedd mewn-tiwmor, mewn cyferbyniad, yn cael ei ddangos gan y llu o wahanol fathau o gelloedd a geir o fewn tiwmor. Gellir disgrifio'r rhain o ran eu hymddangosiad, ee epithelioid, celloedd gwerthyd (tebyg i EMT), squamoid, ond hefyd yn swyddogaethol. Gall celloedd heterogenaidd swyddogaethol fod yn gyfrifol am gynnal y tiwmor sylfaenol yn ogystal ag ar gyfer hadu metastases a rhoi ymwrthedd tiwmor i ymyriadau therapiwtig (er na all pob cell ddangos yr holl eiddo hyn). Yn bwysig, nid oes gan y poblogaethau swyddogaethol hyn hunaniaethau sefydlog, ond gallant godi de novo yn y tiwmor a hefyd esblygu mewn ymateb i bwysau dethol, sy'n cynrychioli targed symudol ar gyfer therapi.
Mewn gwaith blaenorol, gwnaethom ddefnyddio modelau llygoden o ganser y fron i ymchwilio i sut y gall yr un briwiau genetig sy'n digwydd mewn gwahanol gelloedd tarddiad coesyn/progenitor effeithio ar heterogenedd canser y fron. Rydym hefyd wedi astudio sut mae gwneud briwiau gwahanol yn yr un gell wreiddiol yn actifadu gwahanol rwydweithiau signalau i gynhyrchu gwahanol ffenoteipiau tiwmor. Rydym wedi dangos bod colli'r genyn atal tiwmor Brca1 mewn coesyn / progenitors epithelial negatif derbynnydd estrogen luminal yn y chwarren mammari, ac nid mewn bôn-gelloedd sylfaenol, yn arwain at diwmorau sy'n ffenogopi o ganserau'r fron BRCA1 dynol a'r mwyafrif o ganserau sylfaenol nad ydynt yn familial tebyg i'r fron (Molyneux et al, Cell Cell Bôn-gelloedd, 2010). Yn wir, rydym hefyd wedi dangos bod yr un boblogaeth hon yn debygol o fod yn gelloedd tarddiad ar gyfer y rhan fwyaf o ganser y fron isel / negyddol derbynnydd estrogen (Melchor et al, J Pathology, 2014).
Ein harbenigedd ar wahân i is-boblogaethau celloedd mammari (Sleeman et al, Ymchwil Canser y Fron, 2006; Sleeman et al, J Cell Biol, 2007; Britt et al, Ymchwil Canser y Fron, 2009; Roedd Regan et al, Oncogene, 2012) yn ein galluogi i buro bôn-gelloedd mammari i ffwrdd o boblogaethau celloedd mammari eraill, gan gynnwys mathau eraill o gelloedd sylfaenol, a chynnal proffilio moleciwlaidd. Fe wnaethom nodi nifer o enynnau a fynegwyd yn benodol yn y bôn-gelloedd mamari a dangos bod proffil mynegiant genynnau bôn-gelloedd mammari yn prognostig iawn ar gyfer goroesi heb metastasis mewn cleifion canser y fron triphlyg-negyddol (Sleeman et al, Ymchwil Canser y Fron, 2015).
Gan weithio'n fwy mecanyddol, gwnaethom nodi prosesau allweddol sy'n ymwneud â rheoleiddio ymddygiad celloedd coesyn / progenitor mammari arferol. Yn dilyn ein dadansoddiad moleciwlaidd manwl o is-boblogaethau celloedd epithelial mammari (Kendrick et al, 2008), gwnaethom nodi'r rhwydwaith signalau c-KIT fel rheoleiddiwr goroesiad a gormodedd progenitor mammary (Regan et al, Oncogene, 2012). Canfuom hefyd fod y kinase teulu SRC LYN, transducer i lawr yr afon o signalau c-KIT, yn cael ei fynegi mewn progenitors mammari arferol a'u gor-fynegi mewn canserau sylfaenol tebyg i'r fron (Molyneux et al, Cell Bôn-gell, 2010; Regan et al, Oncogene, 2012). Rydym wedi dangos, yng nghancr y fron sy'n gysylltiedig â cholli swyddogaeth BRCA1, bod gweithgaredd LYN heb ei gysylltu o actifadu gan c-KIT. Yn hytrach, mae colled BRCA1 yn arwain at uwchreoleiddio isomerase prolyl, PIN1, sy'n rhyngweithio â ac yn actifadu LYN, yn fwyaf tebygol trwy newid ei gydffurfiad yn wladwriaeth weithredol (Tornillo et al, Cell Reports, 2018). Rydym hefyd wedi dangos bod cydbwysedd isofformau splice o LYN yn cael ei newid mewn canserau ymosodol y fron, a bod yr isoform hirach, LYN-A, yn hyrwyddo mudo celloedd canser y fron ac ymosodiad (Tornillo et al, Cell Reports, 2018). Fodd bynnag, nid oedd gan ddileu genetig LYN mewn celloedd tiwmor o ganser y fron sy'n gysylltiedig â cholli swyddogaeth BRCA1 lawer o wahaniaeth ar ymddygiad tiwmor. Yn hytrach, roedd maint ymdreiddiad celloedd imiwnedd i'r tiwmor yn well rhagfynegydd ymddygiad tiwmor (Tornillo et al, Mecanweithiau Modelau Clefydau 2024).
Rydym bellach wedi ehangu ein diddordebau i geisio deall beth yw'r ffactorau genetig sy'n rhagflaenu unigolion i gael un math o ganser ac nid un arall, gan ddefnyddio geneteg bridiau cŵn domestig fel system enghreifftiol. Fel cam cyntaf, rydym wedi gweithio gydag oncolegwyr milfeddygol, patholegwyr ac epidemiolegwyr i ddeall y ffenoteipiau brîd sy'n gysylltiedig â gwahanol fathau o ganser, yn enwedig canser y fam genedigol (sy'n fodel ardderchog ar gyfer canser y fron dynol, er gyda rhai cafeatau) ac osteosarcoma.
Rydym wedi dangos bod risg osteosarcoma yn cynyddu gyda màs y corff yn cynyddu, ond hefyd bod cŵn penglog hir (dolichocephalic) mewn mwy o berygl na chŵn sy'n wynebu fflat (brachycephalig) (Edmunds et al, Meddygaeth Canine a Geneteg, 2021) (gweler y ffigur isod).
Ffigur Legend: Siâp penglog brîd a NEU ar gyfer risg osteosarcoma wedi'i plotio yn erbyn màs corff cymedrig. Cyfrifwyd màs y corff fel cymedr amcangyfrifon VetCompass o fàs cyfartalog ar gyfer dynion a menywod o bob brîd. Ak(u), Akita (amhenodol); AC, Malamute Alaskan; AB, American Bulldog; Be, Beagle; BF, Bichon Frise; BC, Border Collie; BT, Tiriogaeth y Ffin; Bo, Boxer; Bu(u), Bulldog (amhenodol); CT, Cairn Terrier; CKCS, Cavalier Brenin Charles Spaniel; CS, Cocker Spaniel; Co(u), Collie (Unspecified); Da, Dalmatian; DdB, Dogue de Bordeaux; ESS, Saesneg Springer Spaniel; FT, Fox Terrier; FB, Bulldog Ffrengig; GP(u), Pointer Almaeneg; GSD, ci bugail Almaenig; GR, Golden Retriever; GD, Y Daniaid Mawr; Gr(u), milgwn (amhenodol); HV, Hwngari Vizsla; Hu, Husky; JRT, Jack Russell Terrier; La, Labradoodle; LR, Labrador Retriever; Lu, Lurcher; Ma(u), Mastiff (Amhenodol); Pi(u), Pinscher (Unspecified); Po(u), Poodle (amhenodol); RR, Rhodesian Ridgeback; Ro, Rottweiler; ST, Daeargi yr Alban; SBT, Terrier Bull Swydd Stafford; SP, Poodle Safonol; TT, daeargi Tibetaidd; We, Weimaraner; WHWT, Daeargi Gwyn Gorllewin yr Ucheldir; Wh, Whippet (o fridiau cŵn a chydffurfiadau corff gyda rhagdybiaeth i osteosarcoma yn y DU: astudiaeth rheoli achosion. Grace L Edmunds, Matthew J Smalley, Sam Beck, Rachel J Errington, Sara Gould, Helen Winter, Dave C Brodbelt, Dan G O'Neill. Canine Med Geneteg, 2021, 8(1): 2).
Rydym hefyd wedi nodi bridiau sydd â risg uwch o ganser mammari (Varney et al, Cofnod Milfeddygol, 2023) yn ogystal â darganfod bod brîd nid yn unig yn effeithio ar risg o gael canser ond hefyd sut y gall y canser hwnnw ymddwyn, o leiaf ar gyfer tiwmorau mammari (Edmunds et al, Journal of Mammary Gland Biology and Neoplasia, 2023). Gan adeiladu ar ein gwaith blaenorol ar c-KIT, rydym bellach yn astudio a yw haploteipiau brid-benodol etifeddu haploteipiau o'r genyn KIT yn sail i'r rhagdybiaethau brîd adnabyddus i tiwmorau celloedd mast canin, math tiwmor sy'n cael ei yrru gan actifadu signalau c-KIT aberrant.
Mae ein ffocws presennol hefyd wedi rhoi cyfleoedd i weithio gyda chydweithwyr clinigol i nodi a dilysu marcwyr prognostig a rhagfynegol newydd posibl mewn ystod o fathau o diwmor o anifeiliaid cydymaith.
Cymorth grant cyfredol
- Breast Cancer Now (2023-2026) - Targedu ymatebion tymor hir i gemotherapi trwy fregusrwydd coesyn/imiwnedd newydd yn Triple Canser y Fron Negyddol (cyd-ymgeisydd gyda'r Athro Richard Clarkson)
Cydweithredwyr
- Yr Athro Richard Clarkson (Prifysgol Caerdydd)
- Dr Grace Edmunds (Bristol Veterinary School, Prifysgol Bryste)
- Dr Melanie Dobromylskyj (Patholegwyr Finn)
- Dr Sam Beck (Independent Anatomic Ltd)
- Dr Anita Grigoriadis (Coleg y Brenin Llundain)
- Yr Athro David Brodbelt (Coleg Milfeddygol Brenhinol)
- Dr Dan O'Neill (Coleg Milfeddygol Brenhinol)
Addysgu
Tiwtor personol ar gyfer Israddedigion Gwyddoniaeth Biofeddygol (1af - 4ydd blwyddyn)
Goruchwyliwr Prosiect ar gyfer Prosiectau'r Flwyddyn Olaf Dangradute 3edd Blwyddyn Olaf
Goruchwyliwr Prosiect ar gyfer myfyrwyr Meistr a Meistr Ymchwil Integredig
Goruchwyliwr PhD
Darlithydd - Bioleg Cell (Modiwl 2il Flwyddyn)
Darlithydd - Pynciau Cyfoes mewn Clefydau (Modiwl 3edd Flwyddyn)
Darlithydd - Canser: Mecanweithiau Cellog a Moleciwlaidd a Therapiwteg (Modiwl 3edd Flwyddyn)
Bywgraffiad
Cynhaliais fy ymchwil PhD a hyfforddiant ôl-ddoethurol cynnar yn y Sefydliad Ymchwil Canser, ar safleoedd Sutton a Chelsea, gan weithio ar fioleg ddatblygiadol mammari. Yn dilyn Cymrodoriaeth EMBO blwyddyn yn Sefydliad Canser yr Iseldiroedd gan weithio gyda'r Athro Anton Berns a'r Athro Jos Jonkers ar fodelau canser y llygoden a addaswyd yn enetig, dychwelais i'r ICR fel uwch gymrawd ôl-ddoethurol ac yna arweinydd grŵp iau. Bryd hynny dechreuais fy rhaglen ymchwil i ddefnyddio modelau llygoden i ddeall gwreiddiau cellog moleciwlaidd a (coesyn) heterogenedd canser y fron, a defnyddio'r wybodaeth honno i nodi targedau therapiwtig moleciwlaidd penodol i isdeip canser y fron. Symudais i Ysgol y Biowyddorau Caerdydd yn 2012 fel Uwch-ddarlithydd gyda'r Sefydliad Ymchwil Bôn-gelloedd Canser Ewropeaidd (ECSCRI) newydd. Cefais fy nyrchafu yn Ddarllenydd ac yn Ddirprwy Gyfarwyddwr ac yna fe wnes i Athro yn 2017. Roeddwn yn Gyfarwyddwr ECSCRI rhwng 2018 a 2022. Ar hyn o bryd rwy'n gweithio ar ddeall gyrwyr genetig rhagdybiaeth canser gan ddefnyddio samplau clinigol milfeddygol fel systemau enghreifftiol yn ogystal â datblygu dulliau diagnostig prognositig a rhagfynegol newydd ar gyfer patholeg moleciwlaidd filfeddygol.
Aelodaethau proffesiynol
Aelod o'r Gymdeithas Brydeinig ar gyfer Patholeg Filfeddygol
Safleoedd academaidd blaenorol
Apwyntiadau presennol a blaenorol
2018 – 2022 Cyfarwyddwr, Sefydliad Ymchwil Bôn-gelloedd Canser Ewrop, Prifysgol Caerdydd.
2017 – Athro parhaus , Sefydliad Ymchwil Bôn-gelloedd Canser Ewrop / Ysgol y Biowyddorau, Prifysgol Caerdydd.
2016 – 2017 Cyd-gyfarwyddwr, Cancer Research UK Canolfan Ymchwil Caerdydd.
2015 – 2022 Dirprwy Bennaeth Adran Biofeddygaeth, Ysgol y Biowyddorau, Prifysgol Caerdydd.
2014 – 2017 Darllenydd, Sefydliad Ymchwil Bôn-gelloedd Canser Ewrop / Ysgol y Biowyddorau, Prifysgol Caerdydd.
2013 – 2017 Dirprwy Gyfarwyddwr, Sefydliad Ymchwil Bôn-gelloedd Canser Ewropeaidd.
2012 – 2014 Uwch Ddarlithydd, Sefydliad Ymchwil Bôn-gelloedd Canser Ewrop / Ysgol y Biowyddorau, Prifysgol Caerdydd.
2006 – 2011 Arweinydd Tîm (Cyfadran Ymchwil Datblygu Gyrfa), Canolfan Ymchwil Canser y Fron Breakthrough , Sefydliad Ymchwil Canser, Llundain.
2003 – 2005 Cymrawd Ymchwil Ôl-ddoethurol, Canolfan Ymchwil Canser y Fron Breakthrough , Sefydliad Ymchwil Canser, Llundain.
2002 – 2003 EMBO Cymrodoriaeth Ôl-ddoethurol, Adran Geneteg Moleciwlaidd, Sefydliad Canser yr Iseldiroedd, Amsterdam, Yr Iseldiroedd, Yr Iseldiroedd.
1997 – 2002 Cymrawd Ymchwil Ôl-ddoethurol, Adran Bioleg Celloedd a Moleciwlaidd, Sefydliad Ymchwil Canser, Llundain.
1994 – 1997 Swyddog Ymchwil Ôl-ddoethurol, Ysgol Feddygol Ôl-raddedig Frenhinol, Ysbyty Hammersmith, Llundain.
Cymwysterau
1994 PhD, Bioleg Celloedd, Sefydliad Ymchwil Canser, Llundain.
1990 BA (Anrh, Uwch Ail Ddosbarth), Sŵoleg, Prifysgol Rhydychen.
Pwyllgorau ac adolygu
Cyd-drefnydd Gweithdai EMBO 2017, 2018 a 2020 ar Bioleg Mammary Gland (a gynhaliwyd yn EMBL Heidelberg)
Sefydlydd Rhwydwaith Ewropeaidd Labordai Datblygu Canser a Datblygu Canser (http://www.enbdc.org/)
Aelod o Ymgyrch Canser y Fron/Bwrdd Cynghori Gwyddonol Canser y Fron Nawr (Mai 2012 – Mehefin 2017)
Cyd-gadeirydd Tîm Hunanasesu BIOSI Athena SWAN (hyd at Ebrill 2016; prif awdur ar gais a enillodd Wobr Arian Athena SWAN).
Cynrychiolydd SWAN ar Bwyllgor Staff ac Amgylchedd Gwaith BIOSI (hyd at Ebrill 2016)
Cynrychiolydd ECSCRI ar bwyllgor diogelwch BIOSI (hyd at Ionawr 2016)
Arweinydd academaidd ar y cyd yn Rhwydwaith Bôn-gelloedd Caerdydd (hyd at Ionawr 2016)
Cynrychiolydd BIOSI ar Bwyllgor Lles Anifeiliaid a Gweithdrefnau a Reoleiddir y Coleg Gwyddorau Biolegol a Bywyd (hyd at Ionawr 2016)
Aelod o Fwrdd Golygyddol Ymchwil Canser y Fron (Mawrth 2015 – parhaus)
Aelod o Fwrdd Ymchwil Iechyd Iwerddon – Panel sy'n Canolbwyntio ar Gleifion (Mehefin 2013)
Aelod o Fwrdd Golygyddol y Journal of Mammary Gland Biology and Neoplasia (Mai 2011 - parhaus).
Dirprwy Arweinydd Grŵp 7 (Goresgyniad, Metastasis, Angiogenesis, Hypoxia, Bôn-gelloedd, Celloedd Cylchredeg) o Ddadansoddi Bwlch Ymgyrch Canser y Fron 2012, Hydref 2012.
Gwahodd cyfranogwr (Bioleg – Cychwyn gweithdy arbenigol Canser y Fron), Cyfarfod dadansoddi bwlch Ymgyrch Cancr y Fron, 2 Tachwedd 2006 (Cyhoeddwyd fel A. Thompson, K. Brennan, A. Cox, J. Gee, D. Harcourt, A. Harris, M. Harvie, I. Holen, A. Howell, R. Nicholson, M. Steel a C. Streuli ar ran Cyfarfod Dadansoddi Bwlch Ymgyrch Cancr y Fron, 2 Tachwedd 2006, Llundain, Lloegr (2008). Gwerthusiad o'r cyfyngiadau gwybodaeth cyfredol mewn ymchwil canser y fron: dadansoddiad bwlch. Ymchwil Canser y Fron 10:R36).
Adolygydd llawysgrif ar gyfer Ymchwil Canser y Fron, Ymchwil Cancr, Carcinogenesis, Cell Bôn-gell, Metastasis Clinigol ac Arbrofol, Adolygiadau Arbenigol mewn Meddygaeth Moleciwlaidd, Genes a Datblygu, International Journal of Cancer, Journal of Cell Science, Nature, Nature Reviews Cancer, Oncogene a Bôn-gelloedd
Meysydd goruchwyliaeth
I am interested in supervising PhD students in the areas of:
- Non-DNA repair functions of BRCA1 in breast cancer
- SRC-family kinases in breast cancer
- Veterinary oncology
Note self-funded PhD students must also come with bench fees to support experimental costs
Past projects
Current Students
2019 - 2022 Alex Gibbs (KESS PhD; second supervisor) Cancer stem cells in squamous cell carcinoma
2019 - 2022 Gemma Davies (KESS PhD; second supervisor) CD200 signalling in renal cancer
2018 – 2020 Manisha Das (KESS PhD; second supervisor) PI3K and PTEN signalling in prostate cancer
Previous Students
2016 – 2019 Ana Jiminez Pascual (PhD, second supervisor) FGRF signalling in glioma
2015 – 2017 Maria Konstantinou (PhD, submitted Jan 2018) Theranostic targeting of DNA damage in colo-rectal cancer
2014 – 2017 Noha Mohamed (PhD, awarded 2017) WNT signalling in ovarian cancer
2013 – 2016 Mairian Thomas (PhD, awarded 2016; second supervisor) Novel in vitro mammary cell culture models
2013 – 2014 Huw Morgan (MRes) Novel models of ER+ breast cancer
2009 – 2013 Kelly Soady (PhD, awarded 2013) Identification, purification and molecular characterisation of mammary epithelial stem cells
2006 – 2010 Joseph Regan (PhD, awarded 2010) c-KIT signalling in mammary stem cells
2005 – 2007 Katherine Sleeman (PhD, awarded 2007) Identification of mammary stem and progenitor cell populations
Contact Details
Themâu ymchwil
Arbenigeddau
- Bioleg celloedd canser
- Geneteg canser
- Patholeg filfeddygol
