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| Status |
Public on Aug 13, 2021 |
| Title |
Epithelial TGFβ activation engages growth-factor signalling to circumvent cell death and drive intestinal tumorigenesis with aggressive features. |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
The pro-tumourigenic role of epithelial TGFβ in colorectal cancer (CRC) has been controversial. Here we identify a cohort of aggressive ‘bad acting’ early-stage (T1) disseminating tumours characterised by high cell-intrinsic TGFβ signalling emanating from the epithelium, not stroma. To address its functional significance, we activated TGFβ signalling in the murine intestinal epithelium either alone or in concert with the common tumour suppressive and oncogenic mutations found in CRC, namely Apc and Kras. Consistent with previous studies, we found that activation of TGFβ rapidly induced apoptosis in Apc-mutant intestine and completely killed Apc-mutant organoids. However, in the presence of both Apc and Kras mutation, activation of TGFβ within the epithelium rampantly accelerates tumourigenesis. Importantly the transcriptional signatures derived from these mice overlapped with the “bad acting” T1 human tumours and this signalling could also predict recurrence in stage II CRC. Mechanistically, the activation of intrinsic TGFβ induced the expression of a growth-factor signalling module containing EGFR that synergised with Apc and Kras to drive marked activation of MAPK signalling. Importantly, inhibition of MEK and/or EGFR suppressed the acceleration conferred by TGFβ even in Kras-mutant cells, which are refractory to MEK/EGFR inhibition in the absence of epithelial TGFβ. Together, we identify both a determinant of early dissemination and a potential vulnerability for tumours with these born-to-be-bad traits.
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| Overall design |
RNA sequencing analysis of genetically engineered mouse models in the presence/absence of drug treatment
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| Contributor(s) |
Flanagan DJ, Amirkhah R, Gilroy K, Sansom OJ |
| Citation(s) |
36477656 |
| |
| Submission date |
Aug 12, 2021 |
| Last update date |
Jan 04, 2023 |
| Contact name |
Dustin Flanagan |
| E-mail(s) |
[email protected]
|
| Organization name |
Cancer Research UK Beatson Institute
|
| Street address |
Garscube Estate, Switchback Road, , Bearsden
|
| City |
Glasgow |
| State/province |
Glasgow |
| ZIP/Postal code |
G61 1BD |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (47)
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| Relations |
| BioProject |
PRJNA754185 |
| SRA |
SRP332356 |
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