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Jan 16, 2014

Cancer "Driver" Genes Pop Up in Unexpected Places

  • A key focus of cancer research is the identification of “driver” mutations behind tumorogenesis/metastasis. Daniel Schramek, Ph.D., and colleagues, working at Howard Hughes Medical Institute, Rockefeller University, along with scientists at Icahn School of Medicine at Mount Sinai in New York and at University of Chicago report in the January 17 issue of Science in a paper titled “Direct in Vivo RNAi Screen Unveils Myosin IIa as a Tumor Suppressor of Squamous Cell Carcinomas” that they used a direct in vivo RNA interference (RNAi) strategy to find several genes not previously linked to tumor development that nonetheless predispose mice to cancer.

    The authors note that prior approaches to identifying driver genes to functionally test putative “driver mutations” that confer a selective advantage and contribute to tumor progression have used RNAi followed by allografting of transduced cultured cancer cells. However, they say, orthotopic transplantations necessitate use of immunocompromised animals and generate wound responses, which they say can confound physiological relevance.

    In this case, Dr. Schramek and colleagues used an in vivo RNAi strategy to shut down genes thought to initiate development of squamous cell carcinomas (SCC). The authors circumvented confounding difficulties with noninvasive, ultrasound-guided in utero lentiviral-mediated RNAi delivery, selectively transducing single-layered surface ectoderm of living mouse embryos at embryonic day 9.5.

    The method allowed the investigators to simultaneously test hundreds of candidate genes whose mutations are associated with head and neck squamous cell carcinomas (HNSCCs). Seven of their top hits including Myh9-encoding nonmuscle myosin-IIa had not been linked to tumor development, yet, on tumor-susceptible backgrounds, tissue-specific Myh9 RNAi and knockout trigger invasive SCC formation.

    After shutting down the genes, they looked at which ones, once silenced, caused cancer to progress. Many of those that were critical to human tumor development showed up, but the researchers also found seven that have not previously been linked to carcinogenesis. One of these was myosin-IIa; deficiency of this gene altered the stability of p53, a known tumor-suppressor gene.

    In human and mouse keratinocytes, myosin-IIa’s function is manifested not only in conventional actin-related processes, but also in regulating post-transcriptional p53 stabilization. Clinically, myosin protein is lost in ~20% of human SCCs examined and low myosin expression correlates with very poor survival of HNSCC patients.

    These findings establish myosin as a major SCC suppressor with prognostic and therapeutic relevance, and also highlight the utility of direct in vivo RNAi to integrate cancer genomics and mouse modeling to rapidly discover and validate potent but low-penetrance cancer driver mutations. They also highlight the utility of in vivo RNAi to integrate cancer genomics and mouse modeling for rapid discovery, validation, and functional characterization of potent but low-penetrance tumor suppressors.



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