| First Author | Cammareri P | Year | 2017 |
| Journal | Cell Death Differ | Volume | 24 |
| Issue | 10 | Pages | 1681-1693 |
| PubMed ID | 28622298 | Mgi Jnum | J:261205 |
| Mgi Id | MGI:6151377 | Doi | 10.1038/cdd.2017.92 |
| Citation | Cammareri P, et al. (2017) TGFbeta pathway limits dedifferentiation following WNT and MAPK pathway activation to suppress intestinal tumourigenesis. Cell Death Differ 24(10):1681-1693 |
| abstractText | Recent studies have suggested increased plasticity of differentiated cells within the intestine to act both as intestinal stem cells (ISCs) and tumour-initiating cells. However, little is known of the processes that regulate this plasticity. Our previous work has shown that activating mutations of Kras or the NF-kappaB pathway can drive dedifferentiation of intestinal cells lacking Apc. To investigate this process further, we profiled both cells undergoing dedifferentiation in vitro and tumours generated from these cells in vivo by gene expression analysis. Remarkably, no clear differences were observed in the tumours; however, during dedifferentiation in vitro we found a marked upregulation of TGFbeta signalling, a pathway commonly mutated in colorectal cancer (CRC). Genetic inactivation of TGFbeta type 1 receptor (Tgfbr1/Alk5) enhanced the ability of Kras(G12D/+) mutation to drive dedifferentiation and markedly accelerated tumourigenesis. Mechanistically this is associated with a marked activation of MAPK signalling. Tumourigenesis from differentiated compartments is potently inhibited by MEK inhibition. Taken together, we show that tumours arising in differentiated compartments will be exposed to different suppressive signals, for example, TGFbeta and blockade of these makes tumourigenesis more efficient from this compartment. |
