Searching for key players in the ‘cellular amnesia’ of pancreatic cancer
Researchers have identified the protein MED12 as a contributor to a ‘cellular amnesia’ mechanism that conveys chemotherapy resistance to some pancreatic cancers.
Researchers at Cold Spring Harbor Laboratory (NY, USA) have recently identified a protein implicated in the loss of pancreatic identity in pancreatic cancer cells. This was achieved using genomic screening of these cancer cells and subsequent binding analysis of the protein encoded by the gene highlighted in these screens. As loss of pancreatic identity amongst pancreatic cancer cells is associated with increased resistance to chemotherapy, it is hoped that this protein could be targeted by future pancreatic cancer therapies.
Pancreatic cancer is notorious for its poor prognosis compared to other malignancies. One factor that contributes to this is the ability of pancreatic cancer cells to lose their identity and begin to behave like other cell types. These instances, known as basal-like pancreatic cancer, occur in up to one in ten pancreatic cancer cases and are associated with increased resistance to treatments such as chemotherapy.
Identifying factors involved in the loss of pancreatic identity and maintenance of alternative identities in these malignancies could be key the development of more effective therapeutics. However, until recently only the protein p63 has been implicated in the development of these characteristics, which is difficult to target.
To address this challenge, researchers sought to determine other factors implicated in this process through full genomic screens of basal-like cancer cells. Genes were ranked by their importance in maintaining basal-like identity, with the gene MED12 identified as the most significant. The MED12 protein constitutes one subunit of a complex responsible for gene regulation, composed of dozens of other proteins; however, most of the genes that encode these other proteins did not appear significant in maintaining basal-like features. This suggested that MED12 had distinct properties that made it a key player in the maintenance of a basal-like identity.
Subsequent binding analysis revealed that MED12 binds directly with p63, suggesting these proteins work in tandem. These findings highlight MED12 has an alternative target to p63 that has the potential to be more amenable to drug targeting.
It is hoped this discovery will lay the foundation for new approaches to treat particularly resistant pancreatic tumors and improve patient outcomes. “Finding these critical partners is sort of a first step toward blocking the pathway.” Explained Diogo Maia-Silva, lead author on this study.
