Raul Mostoslavsky, MD, PhD, is the senior author of the Cell paper SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b, which identifies a molecular signal found in 30 percent of pancreatic ductal adenocarcinoma, a highly fatal form of pancreatic cancer.

Dr. Mostoslavsky is an investigator in the Mass General Cancer Center, an Associate Professor of Medicine at Harvard Medical School, and the Kristine and Bob Higgins MGH Research Scholar.

What question were you trying to answer with this study?

Well, there was genetics data from human datasets suggesting that SIRT6 could be deleted/downregulated in pancreatic cancer. We decided to generate a mouse model to directly determine whether SIRT6, as a chromatin factor, indeed works as a tumor suppressor in pancreatic cancer.

Our results demonstrated that SIRT6, indeed, is a potent tumor suppressor in pancreatic cancer.

Furthermore, we identified a novel pathway regulated by SIRT6, one that appears to be deregulated in up to ~30% of human patients.

For a cancer where there is no current efficient therapy, these results are highly encouraging given its potential to design novel therapies to tackle this pathway.

What methods did you use?

Genetically engineered mouse models, biochemical assays, chromatin assays, human cancer lines, and human patients samples. What was unique about your approach? When we identified SIRT6 as a clear tumor suppressor, we were caught at a step where determining why lack of SIRT6 causes such aggressive tumors was not upfront and straightforward to understand.

We had to use an unbiased, genome-wide approach, using the known chromatin marks that SIRT6 regulate, to identify potential targets that were driving the phenotype.

This was possible thanks to unique cancer cell lines we developed, some carrying SIRT6, some deleted for SIRT6 and some where we re-introduced SIRT6. Using this comparative approach, we identified a unique RNA-binding protein, called Lin28b, as the main target for SIRT6. Lin28b is only expressed during development, so up regulation of this protein causes these tumors to de-differentiate, explaining their aggressive behavior.

Did anything surprise you about the results?

Indeed. In previous studies (Sebastian et al., Cell 2012), we found that SIRT6 functions as a tumor suppressor in colon cancer by modulating glycolytic metabolism (a phenomenon called Warburg effect). So, when we found SIRT6 as a tumor suppressor in pancreatic cancer, we were sure it will work by modulating metabolism as well.

To our surprise, these tumors were already highly glycolytic, and deletion of SIRT6 did not influence metabolism at all. Instead, the tumors that manage to delete SIRT6 acquired a unique advantage by de-repressing Lin28b.

These results taught us that different tumors get rid of chromatin factors to acquire “plasticity" in a way that will benefit each tumor in a manner that suits the needs of that particular tumor.

What (if anything) will be the next step in the process?

First, we would like to understand the SIRT6/Lin28b downstream mechanisms that can explain the increased aggressiveness of these tumors. And of course, we would love to develop inhibitors against Lin28b, which we believe could specifically target an important fraction of pancreatic cancer patients – when we genetically inhibit Lin28b, the SIRT6-deleted cancer cells die in less than 24 hours.