The Cancer Grand Challenges SpecifiCancer team continues to deliver breakthroughs in major unanswered questions in cancer research. The team, which was jointly funded in 2019 by The Mark Foundation for Cancer Research and Cancer Research UK, is examining why tissues respond differently to the “stop” and “go” signals which control cell growth and underlie cancer progression. While genomic data have revealed many of the mutations in oncogenes which drive tumorigenesis, their oncogenic effects are only realized in specific tissue types. For instance, the same “go” signal may cause cancer if it arises in breast tissue, while having no effect on the brain, but the reasons for this tissue specificity are not well understood. SpecifiCancer, an international and interdisciplinary group led by Stephen Elledge of Harvard University, set out to tackle this problem and enable better understanding and treatment for a diverse array of cancers.
The team has seen tremendous scientific output in the last two and a half years, which has increased our understanding of this process. Insights have been gained through numerous studies expanding upon the tissue specificity of genes implicated in cancer development and progression, such as KRAS, WNT, BRAF, and APC. Now, a new paper from SpecifiCancer investigators Stephen Elledge (Harvard Medical School) and Kevin Haigis (Dana-Farber Cancer Institute) in Science continues their work by demonstrating that the adaptive immune system is a major selective driver for mutations in tumor suppressor genes. The authors used CRISPR screening in wild-type and immunocompromised mice to determine requirements for tumorigenesis under adaptive immune system pressure. Strikingly, they found that proliferation of cancers in vivo in the presence of the adaptive immune system requires the loss of various tumor suppressor genes in a cancer- and tissue-specific manner. Paradoxically, the loss of these known tumor suppressor genes does not always increase growth in a tissue culture setting. These exciting results expand upon screening that has been done in tissue culture models that cannot recapitulate the complex interplay of tumor cells and the host microenvironment, laying the foundation for future efforts to boost the immune system’s cancer fighting capabilities.