Mitochondria play an important role in numerous cellular processes and their function is maintained through a balance of fusion and fission. Disruptions in mitochondrial maintenance are associated with several pathologies including cancer. In tumor cells from patients with pancreatic cancer that harbor mutations in the KRAS gene, the mitochondria exhibit a short, fragmented phenotype, characteristic of increased fission. The goal of this study is to investigate how the induction of mitochondrial fission downstream of Ras leads to physiological changes in cells that result in tumor growth. The research component of this project proposes to use an in vitro and tissue culture approach to investigate the cellular processes that are regulated upon activation or inhibition of mitochondrial fission in the context of activated Ras in pancreatic cancer. Furthermore, we aim to utilize both a genetic and a pharmacological approach to confirm the specificity of this regulation. We will test the hypothesis that Ras-induced mitochondrial fission causes changes in cell growth and survival (Aim 1), and metabolism and mitophagy (Aim 2) in order to drive tumor growth. Ultimately, this research project sets out to delineate novel therapeutic targets from a critical up-and-coming node of regulation in Ras-driven tumorigenesis. The research project proposed will be carried out in conjunction with a rigorous training plan composed of the following: 1) integrative coursework and interactive training 2) participation in research meetings and seminars 3) participation in scientific conferences 4) professional development and 5) community outreach. The combination of proposed research along with an active training plan will yield meaningful contributions to the field as well as a sound basis on which to excel as a versatile and productive cancer researcher.
Mitochondria are highly dynamic, and the fusion and fission of mitochondria represent an increasingly important, but poorly understood node of cellular regulation. Recent studies have shown that defects in the fusion-fission balance have detrimental effects on human health including an involvement in diabetes and cancer. Further, many of the processes regulated by mitochondrial dynamics overlap with those that are induced by oncogenic Ras signaling. We have recently published that activated Ras signals through the MAPK pathway to promote mitochondrial fission. This mitochondrial fission is in turn required for MAPK-driven tumor growth. However, why mitochondrial fission is important for tumor growth remains to be understood. This proposal sets out to determine how mitochondrial fragmentation impacts the physiological processes necessary for tumor growth. If successful, these studies will reveal novel, physiologically-relevant and mechanistic insights into how activation of the Ras-MAPK pathway promotes tumor growth. Furthermore, these studies will elucidate novel regulatory mechanisms of mitochondrial dynamics and potentially provide novel therapeutic targets for the treatment of Ras-driven cancers.
|Nascimento, Aldo; Lannigan, Joanne; Kashatus, David (2016) High-throughput detection and quantification of mitochondrial fusion through imaging flow cytometry. Cytometry A 89:708-19|