Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 12 2022
07 12 2022
Historique:
received:
03
08
2021
accepted:
18
11
2022
entrez:
8
12
2022
pubmed:
9
12
2022
medline:
15
12
2022
Statut:
epublish
Résumé
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 rampantly 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.
Identifiants
pubmed: 36477656
doi: 10.1038/s41467-022-35134-3
pii: 10.1038/s41467-022-35134-3
pmc: PMC9729215
doi:
Substances chimiques
Transforming Growth Factor beta
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7551Subventions
Organisme : Wellcome Trust
ID : 110371/Z/15/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S021205/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 24387
Pays : United Kingdom
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/T002824/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A12481
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_21042
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R017247/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 26045
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17117
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M016587/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 15333
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 29834
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA208179
Pays : United States
Organisme : Cancer Research UK
ID : A17196
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206314/Z/17/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400302
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 29802
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2022. The Author(s).
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