Dr Toby Phesse

Uwch Ddarlithydd

Ysgol y Biowyddorau

: PhesseT@caerdydd.ac.uk
: +44 29206 88495
: Adeilad Hadyn Ellis, Heol Maendy, Caerdydd, CF24 4HQ

: Ar gael fel goruchwyliwr ôl-raddedig

Mae diddordeb gan fy ymchwil yn y modd y mae signalau celloedd yn rheoleiddio swyddogaeth celloedd mewn meinwe arferol, bôn-gelloedd a thiwmorau i gael mewnwelediad i sut mae canser yn cychwyn, yn tyfu ac yn metastasises. Yna byddwn yn defnyddio'r wybodaeth hon i nodi targedau a strategaethau newydd i drin gwahanol ganserau, gan ganolbwyntio ar lwybr signalau Wnt a gastroberfeddol a brostad.

Ein nod yw defnyddio dull mainc wrth ochr y gwely lle mae ymchwil gymhwysol mewn modelau preclinical gan ddefnyddio technegau genetig a moleciwlaidd yn cael ei ategu â strategaethau ffarmacolegol gyda'n cydweithredwyr diwydiannol a chlinigol gan alluogi cyfieithu i gymwysiadau clinigol posibl ac yn y pen draw gwella iechyd cleifion.

Aelodau presennol y Lab:

Dr Valerie Meniel (Post Doc)

Dr Hector Arredondo (Post Doc)

Kieran Hodson (myfyriwr PhD)

Date
Type

2020

Jardé, T. et al. 2020. Mesenchymal niche-derived neuregulin-1 drives intestinal stem cell proliferation and regeneration of damaged epithelium. Cell Stem Cell 27(4), pp. 646-662.E7., article number: VOLUME 27, ISSUE 4, P646-662.E7, OCTOBER 01, 2020. (10.1016/j.stem.2020.06.021)
Tran, B. M. et al. 2020. The hepatitis B virus pre-core protein p22 activates Wnt sgnaling. Cancers 12(6), article number: 1435. (10.3390/cancers12061435)
Koushyar, S., Powell, A. G., Vincan, E. and Phesse, T. J. 2020. Targeting Wnt signaling for the treatment of gastric cancer. International Journal of Molecular Sciences 21(11), article number: 3927. (10.3390/ijms21113927)

2019

Flanagan, D. J., Vincan, E. and Phesse, T. J. 2019. Wnt signaling in cancer: not a binary ON:OFF switch. Cancer Research (10.1158/0008-5472.CAN-19-1362)
Parry, L. and Phesse, T. J. 2019. FXR regulates intestinal stem cells response to bile acids in a high fat diet. Biotarget 3(12) (10.21037/biotarget.2019.07.01)
Flanagan, D., Barker, N., Ernst, M., Vincan, E. and Phesse, T. 2019. The function of Lgr5+ cells in the gastric antrum does not require Fzd7 or Myc in vivo. Biomedicines 7(3), article number: 50. (10.3390/biomedicines7030050)
Flanagan, D. J. et al. 2019. Frizzled-7 is required for Wnt signaling in gastric tumours with and without Apc mutations. Cancer Research 79(5), pp. 970-981. (10.1158/0008-5472.CAN-18-2095)
Eissman, M. F. et al. 2019. IL-33 mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nature Communications 10, article number: 2735. (10.1038/s41467-019-10676-1)

2018

Greenow, K. R., Zverev, M., May, S., Kendrick, H., Williams, G. T., Phesse, T. and Parry, L. 2018. Lect2 deficiency is characterised by altered cytokine levels and promotion of intestinal tumourigenesis. Oncotarget 9(92), pp. 36430-36443. (10.18632/oncotarget.26335)
May, S. et al. 2018. Mbd2 enables tumourigenesis within the intestine while preventing tumour-promoting inflammation. Journal of Pathology 245(3), pp. 270-282. (10.1002/path.5074)
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)
Flanagan, D., Austin, C., Vincan, E. and Phesse, T. 2018. Wnt Signalling in gastrointestinal epithelial stem cells. Genes 9(4), article number: 178. (10.3390/genes9040178)
Vincan, E., Schwab, R. H., Flanagan, D. J., Moselen, J. M., Tran, B. M., Barker, N. and Phesse, T. 2018. The central role of Wnt signaling and organoid technology in personalizing anticancer therapy. Progress in Molecular Biology and Translational Science 153, pp. 299-319. (10.1016/bs.pmbts.2017.11.009)

2017

Phesse, T., Marsh Durban, V. and Sansom, O. J. 2017. Defining key concepts of intestinal and epithelial cancer biology through the use of mouse models. Carcinogenesis 38(10), pp. 953-965. (10.1093/carcin/bgx080)
Flanagan, D. J., Barker, N., Nowell, C., Clevers, H., Ernst, M., Phesse, T. J. and Vincan, E. 2017. Loss of the Wnt receptor frizzled 7 in the mouse gastric epithelium is deleterious and triggers rapid repopulation in vivo. Disease Models and Mechanisms 10(8), pp. 971-980. (10.1242/dmm.029876)
Phesse, T. J. and Sansom, O. J. 2017. Lgr5 joins the club of gastric stem cell markers in the corpus. Nature Cell Biology 19(7), pp. 752-754. (10.1038/ncb3567)
Flanagan, D. J., Vincan, E. and Phesse, T. J. 2017. Winding back Wnt signalling: potential therapeutic targets for treating gastric cancers. British Journal of Pharmacology 174(24), pp. 4666-4683. (10.1111/bph.13890)
Schwab, R. . H., Amin, N., Flanagan, D. J., Johanson, T. M., Phesse, T. and Vincan, E. 2017. Wnt is necessary for mesenchymal to epithelial transition in colorectal cancer cells. Developmental Dynamics 247(3), pp. 521-530. (10.1002/dvdy.24527)

2016

Flanagan, D. J., Schwab, R. H. M., Tran, B. M., Phesse, T. J. and Vincan, E. 2016. Isolation and culture of adult intestinal, gastric, and lver organoids for cre-recombinase-mediated gene deletion. In: Methods in Molecular Biology. Humana Press, pp. 1-11., (10.1007/7651_2016_14)
Togel, L. et al. 2016. Dual targeting of Bromodomain and Extraterminal Domain Proteins, and WNT or MAPK Signaling, Inhibits c-MYC Expression and Proliferation of Colorectal Cancer Cells. Molecular Cancer Therapeutics 15(6), pp. 1217-1226. (10.1158/1535-7163.MCT-15-0724)
Phesse, T., Flanagan, D. and Vincan, E. 2016. Frizzled7: a promising achilles' heel for targeting the Wnt receptor complex to treat cancer. Cancers 8(5), pp. 50. (10.3390/cancers8050050)

2015

Pearson, H. B. et al. 2015. The polarity protein Scrib mediates epidermal development and exerts a tumor suppressive function during skin carcinogenesis. Molecular Cancer 14, article number: 169. (10.1186/s12943-015-0440-z)
Flanagan, D. et al. 2015. Frizzled7 functions as a Wnt receptor in intestinal epithelial Lgr5+ stem cells. Stem Cell Reports 4(5), pp. 759-767. (10.1016/j.stemcr.2015.03.003)

2014

Elsum, I. A. et al. 2014. Scrib heterozygosity predisposes to lung cancer and cooperates with KRas hyperactivation to accelerate lung cancer progression in vivo. Oncogene 33(48), pp. 5523-5533. (10.1038/onc.2013.498)
Phesse, T. J. et al. 2014. Partial inhibition of gp130-Jak-Stat3 signaling prevents Wnt–β-catenin–mediated intestinal tumor growth and regeneration. Science Signaling 7(345), article number: ra92. (10.1126/scisignal.2005411)
Infantino, S. et al. 2014. The tyrosine kinase Lyn limits the cytokine responsiveness of plasma cells to restrict their accumulation in mice. Science Signaling 7(338), pp. ra77. (10.1126/scisignal.2005105)
Phesse, T. J. et al. 2014. Endogenous c-Myc is essential for p53-induced apoptosis in response to DNA damage in vivo. Cell Death and Differentiation 21(6), pp. 956-966. (10.1038/cdd.2014.15)
Rickard, J. et al. 2014. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157(5), pp. 1175-1188. (10.1016/j.cell.2014.04.019)
Hare, L. et al. 2014. Physiological expression of the PI3K-activating mutationPik3caH1047Rcombines withApcloss to promote development of invasive intestinal adenocarcinomas in mice. Biochemical Journal 458(2), pp. 251-258. (10.1042/BJ20131412)
Stuart, E. et al. 2014. Therapeutic inhibition of jak activity inhibits progression of gastrointestinal tumors in mice. Molecular Cancer Therapeutics 13(2), pp. 468. (10.1158/1535-7163.MCT-13-0583-T)

2013

Phesse, T. and Sansom, O. J. 2013. Responding to R-spondin: slit2 potentiates intestinal regeneration. Cell Stem Cell 13, pp. 512-514. (10.1016/j.stem.2013.10.006)
Meniel, V. et al. 2013. Cited1 deficiency suppresses intestinal tumorigenesis. PLoS Genetics 9(8), article number: e1003638. (10.1371/journal.pgen.1003638)

2011

Sakthianandeswaren, A. et al. 2011. PHLDA1 expression marks the putative epithelial stem cells and contributes to intestinal tumorigenesis. Cancer Research 71(10), pp. 3709-3719. (10.1158/0008-5472.CAN-10-2342)

2010

Ashton, G. H. et al. 2010. Focal adhesion kinase is required for intestinal regeneration and tumorigenesis downstream of Wnt/c-Myc signaling. Developmental Cell 19(2), pp. 259-269. (10.1016/j.devcel.2010.07.015)

2009

Burke, Z. D., Reed, K. R., Phesse, T., Sansom, O. J., Clarke, A. R. and Tosh, D. 2009. Liver zonation occurs through a β-catenin–dependent, c-Myc–independent mechanism. Gastroenterology 136(7), pp. 2316-2324. (10.1053/j.gastro.2009.02.063)
Pearson, H. B., Phesse, T. and Clarke, A. R. 2009. K-ras and Wnt signaling synergize to accelerate prostate tumorigenesis in the mouse. Cancer Research 69(1), pp. 94-101., article number: http://dx.doi.org/10.1158/0008-5472.CAN-08-2895. (10.1158/0008-5472.CAN-08-2895)
Phesse, T. and Clarke, A. R. 2009. Normal stem cells in cancer prone epithelial tissues. British Journal of Cancer 100(2), pp. 221-227. (10.1038/sj.bjc.6604850)
Bollrath, J. et al. 2009. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15(2), pp. 91-102. (10.1016/j.ccr.2009.01.002)

2008

Phesse, T., Parry, L., Reed, K. R., Ewan, K. B. R., Dale, T. C., Sansom, O. J. and Clarke, A. R. 2008. Deficiency of Mbd2 attenuates Wnt induced tumourigenesis via deregulation of a novel Wnt inhibitor, Lect.2. Molecular and Cellular Biology 28(19), pp. 6094-6103. (10.1128/MCB.00539-08)

2007

Sansom, O. J. et al. 2007. Myc deletion rescues Apc deficiency in the small intestine. Nature 446(7136), pp. 676-679. (10.1038/nature05674)

2006

Muncan, V. et al. 2006. Rapid loss of intestinal crypts upon conditional deletion of the Wnt/Tcf-4 target gene c-Myc. Molecular and Cellular Biology 26(22), pp. 8418-8426. (10.1128/MCB.00821-06)

My primary research interest is in understanding how cell signalling controls homeostasis, regeneration, stem cell function and disease, with a focus on Wnt signalling in the gastrointestinal tract. Many of the cell signalling pathways that are critical for embryonic development, homeostasis and regeneration of epithelial tissues are deregulated during disease, and in particular cancer. Thus, by understanding the molecular events that regulate cell signalling during these biological processes, and the aberrations that result in deregulation and disease, we aim to identify novel therapeutic strategies.

My lab uses a combination of advanced in vitro techniques, such as organoid cultures (Fig. 1), together with sophisticated mouse models (Fig. 2), to gain new insights into the requirement for cell signalling during the biology of the adult gastrointestinal epithelium, and thus understand how deregulated signalling results in disease.

Stem cells are intimately associated with cancer, as they have frequently been demonstrated to be the cell of origin for several different cancers including the intestine. The discovery of Lgr5 as a marker of intestinal stem cells has provided a powerful research tool to enable further insight into the biology of the intestine and the role of stem cells in cancer. Indeed, Lgr5 also marks a population of cancer stem cells which is able to provide the proliferative and self-renewal properties of intestinal tumours. Thus, understanding what regulates stem cells is a major interest in the field and our lab is particularly interested in the role of Wnt signalling.

Although the Wnt pathway is deregulated in around 85% of colon tumours it is also required, at lower levels, for the normal homeostatic function of the intestine, and during regeneration. The cytoplasmic signal transducers involved in Wnt signalling have been well characterised, and current research continues to gain new insights into its complexity and interaction with other pathways (Bollrath and Phesse et al, Cancer Cell, 2009 and Phesse et al, Science Signalling, 2014). Compared to the cytoplasmic Wnt regulators, the Wnt receptor complex is relatively poorly understood. Indeed, it is still not fully documented which of the 10 mammalian Frizzled Wnt receptors bind to which of the 19 mammalian Wnt ligands. It was only in 2015 that we demonstrated that Frizzled7 is the predominant Wnt receptor required for intestinal stem cell function (Flanagan and Phesse et al, Stem Cell Reports, 2015 and reviewed in Phesse et al, Cancers, 2016), and current projects are investigating the role of this receptor in other organs and disease settings.

The bacteria Helicobacter pylori is estimated to infect around 50% of the world’s population, and is strongly associated with the development of gastric cancer, but very little is known regarding how infection triggers this pathology. In collaboration with colleagues at the Capital Medical University in Beijing, we are also investigating the requirement for Wnt signalling in H pylori associated gastric cancer.

Key Collaborators

Professor Owen Sansom – Beatson CRUK, Scotland

Professor Elizabeth Vincan – University of Melbourne, Australia

Professor Nick Barker – AStar Institute, Singapore

Rwy'n rhoi darlithoedd, gweithdai a thiwtorialau mewn sawl pwnc gan gynnwys, bioleg foleciwlaidd, bioleg celloedd, therapi canser a bôn-gelloedd.

Ar hyn o bryd rwy'n addysgu yn y modiwlau canlynol yng Nghaerdydd: Bioleg Foleciwlaidd y Genau (BI2234), Pynciau Cyfoes mewn Clefydau (BI3351), Canser: Mecanweithiau Cellog a Moleciwlaidd a Therapeutics (BI3352), ac asesu gwaith mewn Cysyniadau Clefydau (BI2332).

Rwy'n arwain yr arweinydd asesu academaidd ar gyfer Bioleg Foleciwlaidd y genyn (BI2234).

Rwy'n Gymrawd o'r Academi Addysg Uwch (FHEA), ac yn ymdrin ag ymagwedd ddeniadol, ryngweithiol tuag at fy holl addysgu.

Dyfarnwyd ei PhD i Dr Phesse o Brifysgol Warwick lle bu'n astudio'r cydweithrediad rhwng signalau Wnt a signalau TGF-β yn ystod datblygiad embryonig. Yn ystod y prosiect hwn y dysgodd am y rôl bwysig a chwaraeodd signalau Wnt yn ystod canser, ac wedi hynny sicrhaodd swydd ôl-doc yn labordy yr Athro Alan Clarke ym Mhrifysgol Caerdydd. Yn labordy Alan y bu'n meithrin ei ddiddordeb ymchwil sylfaenol, gan astudio sut mae signalau celloedd yn rheoleiddio homeostasis, swyddogaeth bôn-gelloedd, adfywio a chanser. Mae ei waith wedi canolbwyntio'n bennaf ar lwybr signalau Wnt a'r llwybr gastroberfeddol, er ei fod hefyd wedi ymchwilio i organau eraill gan gynnwys yr afu, y prostad a'r croen, gyda'r nod sylfaenol o nodi strategaethau therapiwtig newydd ar gyfer trin canser.

Ar ôl tair blynedd lwyddiannus gydag Alan, cafodd Toby Gymrodoriaeth gan y British Council i weithio yn Sefydliad Ludwig ym Melbourne i astudio'r rhyngweithio rhwng signalau Wnt a signalau gp130/Stat3 mewn canser GI. Cyhoeddodd y gwaith hwn yn Cell Canser yn 2009 sydd bellach wedi cael ei nodi dros 700 o weithiau. Yn dilyn hynny, cynhaliodd gyllid parhaus gan y Cyngor Ymchwil Meddygol Iechyd Gwladol am y 6 blynedd ganlynol a'i galluogodd i reoli grŵp ymchwil bach mewn amrywiaeth o sefydliadau, gan gynnwys Sefydliad nodedig Walter ac Eliza Hall a Phrifysgol Melbourne, gan astudio rôl signalau celloedd mewn adfywio a chanser.

Yn 2016 fe'i penodwyd yn Uwch Gymrawd Ymchwil a phennaeth cyd-labordy ym Mhrifysgol Melbourne, cyn derbyn cymrodoriaethau ychwanegol yn y DU (Wellcome Trust a Phrifysgol Caerdydd) i hwyluso ei symud yn ôl i Gaerdydd fel Cymrawd yn Sefydliad Ymchwil Bôn-gelloedd Canser Ewropeaidd newydd ym Mhrifysgol Caerdydd. Yn 2019 fe'i penodwyd yn Uwch Gymrawd Ymchwil, ac yn 2021 Darlithydd, ac Uwch Ddarlithydd yn 2023.

Mae ganddo swydd barhaus ym Mhrifysgol Melbourne fel Uwch Gymrawd Anrhydeddus, gan gynnal cysylltiadau agos yno gyda chydariannu a diddordebau ymchwil agos gyda chydweithwyr yno.

Aelodaethau proffesiynol

Cymrawd yr Academi Addysg Uwch

Safleoedd academaidd blaenorol

2023-presennol	Uwch Ddarlithydd, Sefydliad Ymchwil Bôn-gelloedd Canser Ewrop, Prifysgol Caerdydd.
2021- 2023	Darlithydd, Sefydliad Ymchwil Bôn-gelloedd Canser Ewrop, Prifysgol Caerdydd.
2018 – presennol	Uwch Gymrawd Tenured yn Sefydliad Ymchwil Bôn-gelloedd Canser Ewrop, Prifysgol Caerdydd.
2016 - presennol	Cymrawd Ymchwil Arweinydd Grŵp yn Sefydliad Ymchwil Bôn-gelloedd Canser Ewrop, Prifysgol Caerdydd.
2016 - presennol	Uwch Gymrawd Anrhydeddus, Sefydliad Doherty, Prifysgol Melbourne, Awstralia.
2016	Pennaeth Cyd-labordy gyda'r Athro Vincan, Sefydliad Doherty, Prifysgol Melbourne, Awstralia.
2012 – 2015	Uwch Gymrawd Ôl-ddoethurol yn Sefydliad Ymchwil Meddygol Walter ac Eliza Hall, Melbourne, Awstralia.
2008 - 2012	Uwch Gymrawd Ôl-ddoethurol yn Sefydliad Ymchwil Canser Ludwig Cyf. yn labordy yr Athro Matthias Ernst, Melbourne, Awstralia.
2008 - 2012	Cymrawd Anrhydeddus Prifysgol Melbourne, Adran Llawfeddygaeth ac Adran Bioleg Feddygol, Awstralia, Melbourne.
2004 - 2008	Postfeddyg ym Mhrifysgol Caerdydd, y DU yn labordy'r Athro Alan Clarke.

Pwyllgorau ac adolygu

Adolygydd Grant ar gyfer MRC, BBSRC, NHMRC (Aus), Ymchwil Canser Fyd-eang, Sefydliad Croen Prydain, Ymchwil Coluddyn y DU, Ymddiriedolaeth Leverhulme, a Phrifysgol Tel-Aviv.

Adolygydd Journal ar gyfer llawer o gyfnodolion gan gynnwys Nature, Nat Cell Biol, EMBO Reports, Oncogene, Carcinogenesis a DMM.

Aelod Panel REF2021 ac Adolygiad REF2028 mewnol.

Cadeirydd Pwyllgor Grantiau Sefydliad Ymchwil Bôn-gelloedd Canser Ewrop.

Aelod o'r Panel ar gyfer Bwrdd Cynghori Athena Swann ar Rieni a Gofalwyr.

Mae gen i ddiddordeb mewn goruchwylio myfyrwyr PhD ym meysydd:

Signalau Wnt
Canser gastroberfeddol
Canser y prostad
Cholangiocarcinoma
Virotherapy ar gyfer canser

Goruchwyliaeth gyfredol

Kieran Hodson

Myfyriwr ymchwil

Array

Themâu ymchwil

Arbenigeddau

Bioleg celloedd canser
Therapi canser
Celloedd bonyn

Ymchwilwyr Prifysgol Caerdydd i ymchwilio i gyffur newydd i atal canser y prostad na ellir ei wella rhag lledaenu