ORCID Profile
0000-0003-2914-4932
Current Organisations
University of Oxford
,
Karolinska Institutet
,
Karolinska Universitetssjukhuset
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Publisher: Oxford University Press (OUP)
Date: 21-06-2016
DOI: 10.1093/HMG/DDW181
Publisher: Elsevier BV
Date: 03-2016
Publisher: Public Library of Science (PLoS)
Date: 19-06-2013
Publisher: Springer Science and Business Media LLC
Date: 31-01-2023
Publisher: Frontiers Media SA
Date: 31-05-2018
Publisher: American Medical Association (AMA)
Date: 09-11-2017
Publisher: Springer Science and Business Media LLC
Date: 07-12-2022
DOI: 10.1038/S41467-022-35134-3
Abstract: The pro-tumourigenic role of epithelial TGFβ signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFβ signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFβ signalling r antly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFβ signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFβ signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC’s with born to be bad traits.
Publisher: BMJ
Date: 28-09-2019
DOI: 10.1136/GUTJNL-2019-319126
Abstract: Pathological Wnt pathway activation is a conserved hallmark of colorectal cancer. Wnt-activating mutations can be ided into: i) ligand-independent (LI) alterations in intracellular signal transduction proteins ( Adenomatous polyposis coli , β-catenin), causing constitutive pathway activation and ii) ligand-dependent (LD) mutations affecting the synergistic R-Spondin axis ( RNF43 , RSPO -fusions) acting through lification of endogenous Wnt signal transmembrane transduction. Our aim was to exploit differential Wnt target gene expression to generate a mutation-agnostic biomarker for LD tumours. We undertook harmonised multi-omic analysis of discovery (n=684) and validation cohorts (n=578) of colorectal tumours collated from publicly available data and the Stratification in Colorectal Cancer Consortium. We used mutation data to establish molecular ground truth and sub ide lesions into LI/LD tumour subsets. We contrasted transcriptional, methylation, morphological and clinical characteristics between groups. Wnt disrupting mutations were mutually exclusive. Desmoplastic stromal upregulation of RSPO may compensate for absence of epithelial mutation in a subset of stromal-rich tumours. Key Wnt negative regulator genes were differentially expressed between LD/LI tumours, with targeted hypermethylation of some genes ( AXIN2 , NKD1 ) occurring even in CIMP-negative LD cancers. AXIN2 mRNA expression was used as a discriminatory molecular biomarker to distinguish LD/LI tumours (area under the curve .93). Epigenetic suppression of appropriate Wnt negative feedback loops is selectively advantageous in LD tumours and differential AXIN2 expression in LD/LI lesions can be exploited as a molecular biomarker. Distinguishing between LD/LI tumour types is important patients with LD tumours retain sensitivity to Wnt ligand inhibition and may be stratified at diagnosis to clinical trials of Porcupine inhibitors.
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Hayley L. Belnoue-Davis.