Researchers from Rutgers Cancer Institute have discovered a mechanism to explain what drives the formation of mucinous colorectal adenocarcinoma (MAC), a rare subtype of colorectal cancer (CRC), as well as identifying the genes responsible for the regulation of this mechanism.
MAC is a distinct and aggressive form of CRC, accounting for 10 to 15 percent of patients and is characterised by the excess secretion of the protein known as mucin and has an entirely different molecular signature - or biological behaviour - than classic CRC. What drives the formation of MAC tumours is currently unknown and underexplored.
Using mouse models, investigators in this study demonstrated that loss of a tumour suppressor protein known as FILIP1L induces colonic epithelial hyperplasia and mucin secretion. They also demonstrated that FILIP1L stimulates degradation of a molecular chaperone protein known as PFDN1. This breakdown results in abnormal stabilisation of PFDN1 leading to elevated mucin secretion and defects in cell division in colon cancer cells. These defects mirror the same characteristics that are seen in the aggressive form of MAC. The authors who reported their discoveries in the paper, ‘FILIP1L loss is a driver of aggressive mucinous colorectal adenocarcinoma and mediates cytokinesis defects through PFDN1’, published in Cancer Research, noted these findings strongly implicate FILIP1L as an essential regulator of MAC tumour development.
"Decreased production of FILIP1L is associated with chemotherapy resistance and poor prognosis in ovarian and colon cancers,” explained the study's lead author, Dr Mijung Kwon, Rutgers Cancer Institute researcher and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School. “Elucidating the driver behind the development of mucinous colorectal adenocarcinoma gives researchers the ability to explore ways to target this mechanism and develop much needed therapeutics for this particular patient population.”
The authors are continuing to explore this mechanism in both human tumour samples and in evolving mouse models in the hope that their work can lead to novel treatment and diagnostic approaches.
"Our lab already has published evidence that FILIP1L plays a role in other cancer types such as pancreas, lung, breast, ovarian and prostate,” added Rutgers Cancer Institute of New Jersey Director, Dr Steven K Libutti, who is also senior vice president of oncology services at RWJBarnabas Health, vice chancellor for cancer programs for Rutgers Biomedical and Health Sciences, and senior author of the work. “Identifying an association between FILIP1L and mucinous colorectal adenocarcinoma further enhances our understanding of the role this novel tumour suppressor plays in the development of these cancers.”