Investigating the role of kras mutation in peritoneal carcinomatosis

The peritoneal carcinomatosis comprises a sequence of complex events starting from tumour detachment from its primary site, surviving in the peritoneal cavity, adherence to mesothelial surface, penetration, and invasion into submesothelial space where it can form a secondary tumour. Gastrointestinal cancers, particularly pancreatic ductal adenocarcinoma (PDAC) and colorectal carcinoma (CRC), have tendencies to metastasise to the peritoneum, so we investigated the underlying reasons of this proclivity in this project. We formed our hypothesis from a case where a patient had hepatocellular carcinoma (HCC) rupture, tumour spillage was found in the peritoneal cavity, and it was still viable. However, neither by the time of the surgery nor in three-year post-operation follow-up was any peritoneal dissemination observed. With the inspiration of this case, this project focused on the effect of KRAS mutation. Due to its frequency in PDAC and CRC, we transduced KRAS mutation to HCC cell lines, which originally held a wild-type KRAS, and investigated the molecular alterations caused by this mutation. We also examined pre-metastatic niche formation in the form of fibrotic reaction when HCC cells co-cultured with hepatic stellate cells. As a result, we found that HCC cells could proliferate, migrate, or form colonies without needing an additional mutation, which supports our clinical case. We created a screen that includes genes that have a role in peritoneal carcinomatosis, fibrosis and are related to KRAS mutation in general. We did not observe significant changes that KRAS induced in adhesion and penetration steps of peritoneal carcinomatosis. However, we gathered compelling information about gene expression patterns that differ in diverse co-culture conditions. This could help us understand tumour-stromal cell crosstalk and could be employed as the foundation for further evaluations of tumour premetastatic niche formation.