An epithelial-to-mesenchymal transition model recovers and predicts critical mutations underlying hepatic cancer stem cells emergence

Abstract

Abstract Background: Cancer stem cells (CSCs) have the ability to form tumors, induce metastasis and resistance to chemotherapy. These cells are generated by the epithelium-mesenchymal transition, and its presence has been linked to a poor prognosis. In the case of hepatocellular carcinoma (HCC), it has been seen that the increase in stemness markers portends the death of the patient. Thus, it is essential to understand how CSCs are formed in order to improve treatments against HCC. Results: In the present work we carry out an exhaustive documentary investigation to create a gene regulatory network (GRN) in which a total number of 240 bibliographic references are integrated to model the epithelial-to-mesenchymal transition in hepatocytes (hEMT). From this network, we constructed a discrete Boolean model able to reproduce several apparently unconnected behaviors of the hEMT reported in the literature. We found that stem-like cells are formed by the action of hEMT only from proliferating hepatocytes in the WT model. Under normal conditions, stem-like cells are unstable and easily differentiate into other phenotypes. However, somatic mutations in tumor suppressors such as p53 or aberrant overexpression of oncogenes such as YAP1 stabilize proliferation conditions in hepatocytes and favor the appearance of CSCs. In addition, we found that these mutations have different effects on hEMT-mediated cell fates. Finally, our data suggest that this process is common to other epithelial cancers, but in HCC, inhibition of p53 is particularly important. Conclusions: In this work we found the mechanism by which somatic mutations generate the emergence of CSCs. These mechanisms may be used to understand the formation of CSCs in other epithelial cancers.