Extreme normality in superficial or seemingly inconsequential matters can be a sign that something is deeply wrong. This thought may have occurred to scientists at the University of Colorado (CU) Cancer Center when they began looking at a population of cancer cells that, unlike most cancer cells, avoids downregulating MHC Class I molecules. Cancer cells tend to deemphasize these molecules because they can display abnormal proteins and attract the immune system’s attention. Cancer cells that carry a normal number or a surplus of MHC Class I molecules are conspicuously, well, inconspicuous.
And that’s not all. The MHC Class I-high cells also expressed high levels of CDK1, a “normal” molecule that regulates the cell cycle. Overexpression of CDK1, the CU Cancer Center scientists found, increased the spheroid forming ability, tumorigenic potential, and tumor-initiating capacity of the curious cell type. Although the scientists could suppress these stem-cell-like characteristics by inhibiting of CDK1 with pharmacological agents, they couldn’t see how CDK1’s role as a cell cycle regulator could be relevant.
Their curiosity piqued, the CU scientists decided to look deeply into the cell type and do more than simply inquire into which drugs or genetic changes might cause the tumors initiated by the cell type to grow or shrink. Instead, the CU scientists asked which factors could cause these cells to initiate tumor growth in the first place. To answer this question, the CU scientists used patient samples, mouse models, and publicly available genetic data to search for the genetic/genomic commonalities in cells capable of initiating melanoma, pancreatic, and colon cancers.
Ultimately, the CU scientists conducted a proteomic analysis that revealed an interaction between CDK1 and the pluripotent stem cell transcription factor Sox2. This finding, the scientists indicated, could help explain how cells of different subtypes within cancers show various tumor-initiating capacities. That is, enhanced tumor-initiating capacities could come down to interactions between stem cell genes and seemingly unrelated regulatory mechanisms.
Detailed results appeared in the journal Cancer Research, in an article titled, “CDK1 interacts with Sox2 and promotes tumor initiation in human melanoma.”
“Blockade or knockdown of CDK1 resulted in reduced phosphorylation, nuclear localization, and transcriptional activity of Sox2,” the article indicated. “Knockout of Sox2 in CDK1-overexpressing cells reduced CDK1-driven tumor-initiating capacity substantially. Furthermore, GSEA analysis of CDK1-hi tumor cells identified a pathway signature common in all three cancer types, including E2F, G2M, MYC, and spermatogenesis, confirming a stem-like nature of CDK1-hi tumor cells.”
Sox2 is a transcription factor that helps embryonic and neural stem cells keep their stem-ness. It is also a known marker of cancer stem cells, implicated in the development of more than 25 forms of the disease. Despite its identification as a driver of cancer, Sox2 remains a difficult target.
“It's very difficult to control a transcription factor like Sox2. We can show Sox2 is very important for tumorigenesis, but it's difficult to have a Sox2 inhibitor,” says Mayumi Fujita, M.D., Ph.D., an investigator at the CU Cancer Center and senior author of the current study, which found that CDK1 directly interacts with Sox2 to keep cancer cells “stemmy.” And here is the important part: “If CDK1 controls Sox2 function through this interaction, probably we can someday inhibit it, maybe through some way of targeting CDK1 or perhaps some way to interfere with the interaction of CDK1 with Sox2,” notes Dr. Fujita.
Importantly, this signature of MHC Class 1, CDK1, and Sox2 was common across melanoma, colon, and pancreatic cancers, implying that cancer stem cells across cancer types may share common features.
“We can't say that all tumor types have this signature, but it's prevalent. We think probably this phenotype is very common in melanoma, pancreatic, and colon cancer,” Dr. Fujita suggests.
Moving forward, Dr. Fujita's group hopes to further define the mechanism of Sox2 regulation via CDK1 in hopes of finding essential links that might be targets for new drugs aimed, eventually, at stopping the action of Sox2.
