Dr Philip Dunne - Phenotypic Plasticity in Colorectal Cancer

Introduction

LeQuesne John

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.

Other funding:

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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.