Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features.
Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features.
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DOI：
10.1038/s41467-022-35134-3
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发表时间：
2022-12-07
影响因子：
16.6
通讯作者：
Sansom OJ
中科院分区：
文献类型：
--
作者：
Flanagan DJ;Amirkhah R;Vincent DF;Gunduz 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
上皮TGFβ信号传导在结直肠癌（CRC）中的促肿瘤发生作用是有争议的。在这里，我们确定了一组出生不良的早期（T1）结直肠肿瘤，具有侵袭性特征和早期扩散倾向，其特征是高上皮细胞内在TGFβ信号传导。在同时存在Apc和Kras突变的情况下，上皮TGFβ信号传导的激活猛烈地加速肿瘤发生，并与天生是坏的T1人类肿瘤的转录特征共享，并预测II期CRC的复发。在机制上，上皮TGFβ信号传导诱导促进生长的EGFR信号传导模块，其与突变型APC和KRAS协同作用以驱动MAPK信号传导，从而使肿瘤细胞对MEK和/或EGFR抑制剂重新敏感。总之，我们确定上皮TGFβ信号传导既是早期传播的决定因素，也是先天不良特征的CRC的潜在治疗脆弱性。尽早识别将扩散的结直肠癌（CRC）仍然至关重要。在这里，作者确定了具有侵袭性且易于早期传播的CRC肿瘤，其特征在于上皮TGFβ和生长因子信号传导-这可以用MEK/EGFR抑制剂靶向。
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. It remains critical to identify colorectal cancers (CRC) that will disseminate as early as possible. Here, the authors identify CRC tumours that are aggressive and prone to early dissemination, characterised by epithelial TGFβ and growth-factor signalling - which could be targeted with MEK/EGFR inhibitors.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
4.2
作者：
Fujino, Shiki;Miyoshi, Norikatsu;Mori, Masaki
通讯作者：
Mori, Masaki
影响因子：
50.3
作者：
Calon A;Espinet E;Palomo-Ponce S;Tauriello DV;Iglesias M;Céspedes MV;Sevillano M;Nadal C;Jung P;Zhang XH;Byrom D;Riera A;Rossell D;Mangues R;Massagué J;Sancho E;Batlle E
通讯作者：
Batlle E
影响因子：
--
作者：
Gao Y;Vincent DF;Davis AJ;Sansom OJ;Bartholin L;Li Q
通讯作者：
Li Q
影响因子：
11.1
作者：
Fessler E;Drost J;van Hooff SR;Linnekamp JF;Wang X;Jansen M;De Sousa E Melo F;Prasetyanti PR;IJspeert JE;Franitza M;Nürnberg P;van Noesel CJ;Dekker E;Vermeulen L;Clevers H;Medema JP
通讯作者：
Medema JP