Development and Cancer

Identification of noncoding RNAs that contribute to cancer pathogenesis

Cellular senescence is an irreversible state of cell-cycle arrest induced by oncogene activation, telomere shortening, or DNA damage. This anti-proliferative response is an important tumor suppressor mechanism. While the proteins that mediate senescence, such as p53 and RB, have been highly studied, the role of noncoding RNAs in senescence remains poorly understood. To address this knowledge gap, Joshua Mendell's, Ph.D., laboratory conducted a genome-wide CRISPRi screen in human cells, revealing an unexpected and essential role for the small nucleolar RNA (snoRNA) SNORA13 in senescence. Mendell discovered that SNORA13 promotes senescence by increasing the abundance of non-ribosome associated ribosomal proteins, which activates p53 in the presence of senescence-inducing stress. These findings suggest that delivery of SNORA13 could therapeutically induce senescence in cancer cells. 

Understanding how fat cells modulate cancer risk

How fat promotes cancer is a central question in cancer biology. Philipp Scherer's, Ph.D., laboratory recently reported that adipocytes from tumor-invasive mammary fat undergo de-differentiation to fibroblast-like precursor cells that integrate into the tumor microenvironment. This showed that the metabolic interplay between tumor cells and adipocytes induces an adipocyte mesenchymal transition that contributes to a tumor-promoting microenvironment. These insights introduce new ways of manipulating cells in the tumor microenvironment in patients with obesity-associated cancers, a research priority in the SCCC catchment area. 

Understanding how the gut microbiome influences antitumor immunity​

While the gut microbiome influences most aspects of human health, how it impacts cancer treatment is unclear. Andrew Koh's, M.D., laboratory demonstrated that immune checkpoint blockade induces the relocation of gut microbiota to lymphoid organs and melanomas. This microbiota promoted stronger immune responses against cancer, and antibiotic treatment that depletes gut microbiota reduced T cell responses and limited the effectiveness of immune checkpoint inhibitors for cancer. These findings revealed a key mechanism by which gut microbiota promote anticancer immunity outside of the gut and led to a multicenter Phase I/II trial testing immunotherapy combinations in children with solid tumors. 

Understanding the genetic basis of immunotherapy responses in cancer

One of the critical shortcomings of genetically engineered mouse models of cancer is that they do not generate abundant somatic mutations, which are thought to induce antigen production and stimulate immune responses. Esra Akbay's, Ph.D., laboratory developed novel murine cancer models with extremely high mutation levels. These cancers were highly sensitive to immune checkpoint blockade and led to the insight that specific cancer genes such as TP53 can dramatically influence immunogenicity. This work allowed for the identification of critical factors that explain immunotherapy’s effectiveness in the clinic. Using these approaches, the Akbay lab showed that STING agonists and telomerase inhibitors are small molecules that can enhance immunotherapy in lung cancer, two strategies that are being tested in clinical trials.