Dr Philip Dunne - Phenotypic Plasticity in Colorectal Cancer
Introduction
The genomic sequencing of colorectal cancer (CRC) has identified many important oncogenic drivers, leading to the establishment of the Vogelstein genetic model for colorectal tumorigenesis. However, substantial phenotypic heterogeneity exists across and within genetically identical tumours, meaning that genetics alone cannot explain the complexity of the tumour ecosystem. To characterise the transcriptional landscape in CRC, numerous studies have developed molecular classification/subtyping systems based on gene-level data that align with genetic alterations underpinning the Vogelstein paradigm.
To move beyond these established gene-level systems, we developed a CRC classification system reflecting phenotypic landscape in CRC, based on pathway-level biological signalling. These pathway-derived subtypes (PDS) are independent of KRAS and other Vogelstein features, and reveal subtle phenotypes related to epithelial differentiation and lineage maturity, reminiscent of those proposed within Waddington’s landscape. This approach reveals how individual cells contribute to the overall phenotypic landscape observe in each human tumour, and how the selective advantage of each individual phenotype evolves during tumour development.
Using these phenotypic landscapes as the basis for biological discovery in both human tumours and genetically engineered mouse models (GEMMs), our team are using a combination of bulk, single cell and spatial transcriptomics to define a more holistic phenotypic map of the tumour landscape and cellular communication networks associated with tumour development and progression in CRC. Furthermore, while data availability has increased, molecular data rarely realises its full potential due to the programming skills required for analysis. Therefore, our team complement our biological analyses with the development of “no-programming-required” publicly available data apps for mechanistic interrogation of these cohorts. This approach facilitates new discoveries and leads to the democratisation of data analysis by removing a major bottleneck in the analysis of complex molecular profiling datasets.
EmailOther funding:
Lab Report
Key Publications
Malla SB, Byrne RM, Lafarge MW, Corry SM, Fisher NC, Tsantoulis PK, Mills ML, Ridgway RA, Lannagan TRM, Najumudeen AK, Gilroy KL, Amirkhah R, Maguire SL, Mulholland EJ, Belnoue-Davis HL, Grassi E, Viviani M, Rogan E, Redmond KL, Sakhnevych S, McCooey AJ, Bull C, Hoey E, Sinevici N, Hall H, Ahmaderaghi B, Domingo E, Blake A, Richman SD, Isella C, Miller C, Bertotti A, Trusolino L, Loughrey MB, Kerr EM, Tejpar S, Maughan TS, Lawler M, Campbell AD, Leedham SJ, Koelzer VH, Sansom OJ, Dunne PD. Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer. Nature Genetics. 2024.
Flanagan DJ, Amirkhah R, Vincent DF, Gundaz N, Gentaz P, Cammareri P, McCooey AJ, McCorry AMB, Fisher NC, Davis HL, Ridgway RA, Lohuis J, Leach JDG, Jackstadt R, Gilroy K, Mariella E, Nixon C, Clark W, Hedley A, Markert EK, Strathdee D, Bartholin L, Redmond KL, Kerr EM, Longley DB, Ginty F, Cho S, Coleman HG, Loughrey MB, Bardelli A, Maughan TS, Campbell AD, Lawler M, Leedham SJ, Barry ST, Inman GJ, van Rheenen J, Dunne PD, Sansom OJ. Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features. Nat Commun. 2022;13:7551.
Vasquez EG, Nasreddin N, Valbuena GN, Mulholland EJ, Belnoue-Davis HL, Eggington HR, Schenck RO, Wouters VM, Wirapati P, Gilroy K, Lannagan TRM, Flanagan DJ, Najumudeen AK, Omwenga S, McCorry AMB, Easton A, Koelzer VH, East JE, Morton D, Trusolino L, Maughan T, Campbell AD, Loughrey MB, Dunne PD, Tsantoulis P, Huels DJ, Tejpar S, Sansom OJ, Leedham SJ. Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia. Cell Stem Cell. 2022;29:1213-1228.e1218.
Fisher NC, Byrne RM, Leslie H, Wood C, Legrini A, Cameron AJ, Ahmaderaghi B, Corry SM, Malla SB, Amirkhah R, McCooey AJ, Rogan E, Redmond KL, Sakhnevych S, Domingo E, Jackson J, Loughrey MB, Leedham S, Maughan T, Lawler M, Sansom OJ, Lamrock F, Koelzer VH, Jamieson NB, Dunne PD. Biological Misinterpretation of Transcriptional Signatures in Tumor Samples can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data. Clinical Cancer Research. 2022;10.1158/1078-0432.Ccr-22-1102:OF1-OF14.
Corry SM, McCorry AM, Lannagan TR, Leonard NA, Fisher NC, Byrne RM, Tsantoulis P, Cortes-Lavaud X, Amirkhah R, Redmond KL, McCooey AJ, Malla SB, Rogan E, Sakhnevych S, Gillespie MA, White M, Richman SD, Jackstadt RF, Campbell AD, Maguire S, McDade SS, Longley 1137–1155DB, Loughrey MB, Coleman HG, Kerr EM, Tejpar S, Maughan T, Leedham SJ, Small DM, Ryan AE, Sansom OJ, Lawler M, Dunne PD. Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer. Gut. 2022;71:2502-2517
Dunne PD, Alderdice M, O'Reilly PG, Roddy AC, McCorry AMB, Richman S, Maughan T, McDade SS, Johnston PG, Longley DB, Kay E, McArt DG, Lawler M. Cancer-cell intrinsic gene expression signatures overcome intratumoural heterogeneity bias in colorectal cancer patient classification. Nat Commun. 2017 May 31;8:15657.
Dunne PD, McArt DG, Bradley CA, O'Reilly PG, Barrett HL, Cummins R, O'Grady T, Arthur K, Loughrey MB, Allen WL, McDade SS, Waugh DJ, Hamilton PW, Longley DB, Kay EW, Johnston PG, Lawler M, Salto-Tellez M, Van Schaeybroeck S. Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer. Clin Cancer Res. 2016 Aug 15;22(16):4095-104.
Biography
Education and qualifications
2010: PhD, Ulster University. Role of MBD4, DNMT1 and MLH1 in DNA methylation and repair.
2001: BSc, Applied Biology and Biotechnology (Honours), Waterford IT.
Appointments
2022-present: Group Leader, Cancer Research UK Scotland Institute, Glasgow.
2022-present: Reader in Molecular Pathology, Queen’s University Belfast.
2016-2017: Visiting Fellow, Istituto di Candiolo, University of Torino.
2015-2016: S:CORT Fellow, Belfast-Oxford.
2010-2015: Research Fellow, Queen’s University Belfast.
Recent Publications
2024
Lafarge MW, Domingo E, Sirinukunwattana K, Wood R, Samuel L, Murray G, Richman SD, Blake A, Sebag-Montefiore D, Gollins S, Klieser E, Neureiter D, Huemer F, Greil R, Dunne P, Quirke P, Weiss L, Rittscher J, Maughan T, Koelzer VH. Image-based consensus molecular subtyping in rectal cancer biopsies and response to neoadjuvant chemoradiotherapy. npj Precision Oncology. 2024;8:89.
Mahmood U, Blake A, Rathee S, Samuel L, Murray G, Sebag-Montefiore D, Gollins S, West NP, Begum R, Bach SP, Richman SD, Quirke P, Redmond KL, Salto-Tellez M, Koelzer VH, Leedham SJ, Tomlinson I, Dunne PD, Buffa FM, Maughan TS, Domingo E, S-CORT Consortium. Stratification to neoadjuvant radiotherapy in rectal cancer by regimen and transcriptional signatures. Cancer Research Communications. 2024 Jul 1;4(7):1765-1776.
Malla SB, Byrne RM, Lafarge MW, Corry SM, Fisher NC, Tsantoulis PK, Mills ML, Ridgway RA, Lannagan TRM, Najumudeen AK, Gilroy KL, Amirkhah R, Maguire SL, Mulholland EJ, Belnoue-Davis HL, Grassi E, Viviani M, Rogan E, Redmond KL, Sakhnevych S, McCooey AJ, Bull C, Hoey E, Sinevici N, Hall H, Ahmaderaghi B, Domingo E, Blake A, Richman SD, Isella C, Miller C, Bertotti A, Trusolino L, Loughrey MB, Kerr EM, Tejpar S, Maughan TS, Lawler M, Campbell AD, Leedham SJ, Koelzer VH, Sansom OJ, Dunne PD. Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer. Nature Genetics. 2024.
Naderi-Meshkin H, Setyaningsih WAW, Yacoub A, Carney G, Cornelius VA, Nelson CA, Kelaini S, Donaghy C, Dunne PD, Amirkhah R, Zampetaki A, Zeng L, Stitt AW, Lois N, Grieve DJ, Margariti A. Unveiling impaired vascular function and cellular heterogeneity in diabetic donor-derived vascular organoids. Stem Cells. 2024 Sept;42(9):791-808.
Nasreddin N, Jansen M, Loughrey MB, Wang LM, Koelzer VH, Rodriguez-Justo M, Novelli M, Fisher J, Brown MW, Al Bakir I, Hart AL, Dunne P, Graham TA, Leedham SJ. Poor diagnostic reproducibility in the identification of nonconventional dysplasia in colitis impacts the application of histological stratification tools. Modern Pathology. 2024 Mar;37(3):100419.
The S:CORT Consortium. Identification and validation of a machine learning model of complete response to radiation in rectal cancer reveals immune infiltrate and TGFβ as key predictors. EBioMedicine. 2024;106:105228.
Dunne PD, Arends MJ. Molecular pathological classification of colorectal cancer—an update. Virchows Arch. 2024;484, 273–285.
Hillson LVS, McCulloch AK, Edwards J, Dunne PD, O'Cathail SM, Roxburgh CS. Radiation-induced changes in gene expression in rectal cancer specimens. Clinical and Translational Oncology. 2024 Jan 19.
Pun SH, O'Neill KM, Naderi-Meshkin H, Malla S, Botezatu B, King W, Dunne PD, Brazil DP, Watson CJ, Grieve DJ. NOX4 NADPH oxidase signalling is a key determinant of angiogenic function of cord-blood endothelial colony-forming cells in hypoxia. Medical Sciences Forum. 2024 Aug 26;27(1 (2)):1.2.
2023
Amirkhah R, Gilroy K, Malla SB, Lannagan TRM, Byrne RM, Fisher NC, Corry SM, Mohamed N-E, Naderi-Meshkin H, Mills ML, Campbell AD, Ridgway RA, Ahmaderaghi B, Murray R, Llergo AB, Sanz-Pamplona R, Villanueva A, Batlle E, Salazar R, Lawler M, Sansom OJ, Dunne PD. MmCMS: mouse models’ consensus molecular subtypes of colorectal cancer. British Journal of Cancer. 2023;128: 1333–1343
Begum M, Lewison G, Wang X, Dunne PD, Maughan T, Sullivan R, Lawler M. Global colorectal cancer research, 2007‐2021: Outputs and funding. International Journal of Cancer. 2023 Feb 1;152(3):470-479.
Egan H, Treacy O, Lynch K, Leonard NA, O'Malley G, Reidy E, O'Neill A, Corry SM, De Veirman K, Vanderkerken K, Egan LJ, Ritter T, Hogan AM, Redmond K, Peng L, Che J, Gatlin W, Jayaraman P, Sheehan M, Canney A, Hynes SO, Kerr EM, Dunne PD, O'Dwyer ME, Ryan AE. Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment. Cell Reports. 2023 May 10;112475.
Naderi-Meshkin H, Eleftheriadou M, Carney G, Cornelius VA, Nelson CA, Kelaini S, Yacoub A, Dunne PD, Amirkhah R, Zampetaki A, Zeng L, Stitt AW, Lois N, Grieve DJ, Margariti A. Blood vessel organoids derived from diabetic patients revealed impaired function based on a subpopulation of endothelial cells. Heart. 2023 Jun 2;109(Suppl 3):BS16.
Pun SH, O’Neill KM, Edgar KS, Gill EK, Moez A, Naderi-Meshkin H, Malla SB, Hookham MB, Alsaggaf M, Madishetti VV, Botezatu B, King W, Brunssen C, Morawietz H, Dunne PD, Brazil DP, Medina RJ, Watson CJ, Grieve DJ. PLAC8-mediated activation of NOX4 signalling restores angiogenic function of endothelial colony-forming cells in experimental hypoxia. Cells. 2023 Sept 6;12(18):2220.
Suzuki T, Kilbey A, Casa Rodriguez N, Lawlor A, Georgakopoulou A, Hayman H, Yin Swe KL, Nordin A, Cantù C, Vantourout P, Ridgway RA, Byrne RM, Chen L, Verzi MP, Gay DM, Gil Vazquez E, Belnoue-Davis HL, Gilroy K, Kostner AH, Kersten C, Thuwajit C, Andersen DK, Wiesheu R, Jandke A, Blyth K, Roseweir AK, Leedham SJ, Dunne PD, Edwards J, Hayday A, Sansom OJ, Coffelt SB. β-catenin drives butyrophilin-like molecule loss and γδ T-cell exclusion in colon cancer. Cancer Immunology Research. 2023;11:1137–1155
Hamilton AC, Bannon FJ, Dunne PD, James J, McQuaid S, Gray RT, Salto-Tellez M, Cardwell CR, Loughrey MB, Coleman, HG. Distinct molecular profiles of sporadic early onset colorectal cancer: a population-based cohort and systematic review. Gastro Hep Advances. 2023 Mar 1;2(3):347-359.
2022
Ahmaderaghi B, Amirkhah R, Jackson J, Lannagan TRM, Gilroy K, Malla SB, Redmond KL, Quinn G, McDade S, Consortium A, Maughan T, Leedham S, Campbell AS, Sansom OJ, Lawler M, Dunne PD. Molecular Subtyping Resource: a user-friendly tool for rapid biological discovery from transcriptional data. Dis Model Mech. 2022;15: dmm049257.
Corry SM, McCorry AM, Lannagan TR, Leonard NA, Fisher NC, Byrne RM, Tsantoulis P, Cortes-Lavaud X, Amirkhah R, Redmond KL, McCooey AJ, Malla SB, Rogan E, Sakhnevych S, Gillespie MA, White M, Richman SD, Jackstadt RF, Campbell AD, Maguire S, McDade SS, Longley 1137–1155DB, Loughrey MB, Coleman HG, Kerr EM, Tejpar S, Maughan T, Leedham SJ, Small DM, Ryan AE, Sansom OJ, Lawler M, Dunne PD. Activation of innate-adaptive immune machinery by poly(I:C) exposes a therapeutic vulnerability to prevent relapse in stroma-rich colon cancer. Gut. 2022;71:2502-2517
Fisher NC, Byrne RM, Leslie H, Wood C, Legrini A, Cameron AJ, Ahmaderaghi B, Corry SM, Malla SB, Amirkhah R, McCooey AJ, Rogan E, Redmond KL, Sakhnevych S, Domingo E, Jackson J, Loughrey MB, Leedham S, Maughan T, Lawler M, Sansom OJ, Lamrock F, Koelzer VH, Jamieson NB, Dunne PD. Biological Misinterpretation of Transcriptional Signatures in Tumor Samples can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data. Clinical Cancer Research. 2022;10.1158/1078-0432.Ccr-22-1102:OF1-OF14.
Fisher NC, Loughrey MB, Coleman HG, Gelbard MD, Bankhead P, Dunne PD. Development of a semi-automated method for tumour budding assessment in colorectal cancer and comparison with manual methods. Histopathology. 2022 Feb;80(3):485-500. Epub 2021 Sept 28.
Flanagan DJ, Amirkhah R, Vincent DF, Gundaz N, Gentaz P, Cammareri P, McCooey AJ, McCorry AMB, Fisher NC, Davis HL, Ridgway RA, Lohuis J, Leach JDG, Jackstadt R, Gilroy K, Mariella E, Nixon C, Clark W, Hedley A, Markert EK, Strathdee D, Bartholin L, Redmond KL, Kerr EM, Longley DB, Ginty F, Cho S, Coleman HG, Loughrey MB, Bardelli A, Maughan TS, Campbell AD, Lawler M, Leedham SJ, Barry ST, Inman GJ, van Rheenen J, Dunne PD, Sansom OJ. Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features. Nat Commun. 2022;13:7551.
Henderson RH, French D, McFerran E, Adams R, Wasan H, Robert Glynne-Jones R, Fisher D, Richman S, Dunne PD, Wilde L, Maughan T, Sullivan R, Lawler M. Spend less to achieve more: economic analysis of intermittent versus continuous cetuximab in KRAS wild-type patients with metastatic colorectal cancer. Journal of Cancer Policy. 2022 Sept;33:100342.
Vasquez EG, Nasreddin N, Valbuena GN, Mulholland EJ, Belnoue-Davis HL, Eggington HR, Schenck RO, Wouters VM, Wirapati P, Gilroy K, Lannagan TRM, Flanagan DJ, Najumudeen AK, Omwenga S, McCorry AMB, Easton A, Koelzer VH, East JE, Morton D, Trusolino L, Maughan T, Campbell AD, Loughrey MB, Dunne PD, Tsantoulis P, Huels DJ, Tejpar S, Sansom OJ, Leedham SJ. Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia. Cell Stem Cell. 2022;29:1213-1228.e1218.
Lusby R, Dunne P, Tiwari VK. Tumour invasion and dissemination. Biochemical Society Transactions. 2022 Jun 17.
