Mitochondrial Morphology As A Biomarker Of Cancer Phenotype And Drug Response

Mitochondria, critical organelles in quiescent and dividing cells, have been shown to vary in number, mass, and shape. While previous work has focused on understanding molecular mechanisms underlying changes in normal and immortalized cells, less is known about longer-term mitochondrial behavior such as morphological patterns in individual cells and overall populations, the heterogeneity and functional consequences of these patterns, and ultimately how potential mitochondrial heterogeneity can be exploited in the clinic. Indeed, while previous studies have been conducted illustrating mitochondrial dysfunction and morphological alterations in certain tumor types, more comprehensive analyses across tumor and cell types, as well as from cells derived from individual patients, have yet to be conducted. A primary impediment to this work is the technical challenge of consistently assaying mitochondrial morphology in diverse cell types where fixation procedures, collection techniques, and differing optical qualities between samples make potential analyses a challenging application. We have developed an image based analytical technique to phenotype mitochondrial morphology in different cancers, including in vitro cancer cell lines and patient derived cancer cells. Our methodology is based on a combination of novel, clinically relevant collection and fixation techniques, and advanced image processing and computer learning analysis methodologies. Our results demonstrate that i) cancer cells of different origins, including patient-derived xenografts, express highly diverse mitochondrial phenotypes; ii) a given phenotype is characteristic of a cell population and fairly constant over time; iii) mitochondrial patterns correlate with cell metabolomics measurements and iv) therapeutic interventions can alter mitochondrial phenotypes in drug-sensitive cancers as measured in pre- versus post-treatment fine needle aspirates in mice. These observations shed light on the role of mitochondrial dynamics in the biology and drug response of cancer cells. Citation Format: Randy J. Giedt, Paolo Fumene Fergulio, Divya Pathania, Katherine S. Yang, Aoife Kilcoyne, Claudio Vinegoni, Tim J. Mitchison, Ralph Weissleder. Mitochondrial morphology as a biomarker of cancer phenotype and drug response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 234.