Abstract 3262: Mitochondrial haplotype effects on tumor formation and metastasis are both cell autonomous and non-cell autonomous

Abstract

Abstract Increasing data support roles for mitochondrial genomes in complex diseases, including cancer. We hypothesize that primary tumor formation and metastasis can arise from inherited mitochondrial differences. To test directly the role of mitochondrial DNA (mtDNA) in mammary cancer tumorigenicity and metastasis, we generated Mitochondrial Nuclear Exchange (MNX) mice. This unique animal model is created by moving the nucleus from an oocyte of one strain into an enucleated oocyte of a different strain. By exchanging the nucleus of mouse strains promoting or inhibiting metastatic efficiency, mtDNA effects can be distinguished from phenotypes which would occur due to nuclear admixing. To determine if a change in the mtDNA background impacts metastasis in a cell autonomous manner, two FVB transgenic mouse strains encoding either Her2 or PyMT oncogenes were crossed with MNX mice with FVB nuclear DNA and mtDNA from either BALB/cJ or C57BL6J strains. The mtDNA were chosen because of higher or lower metastatic efficiency, respectively (PMID9679770, PMID16491073). Latency of mammary tumor formation in MNX mice with C57BL/6 mtDNA is longer for both Her2 and PyMT. Lung metastases are smaller in C57BL6 but larger in BALB/c MNX crosses with the PyMT. Studies measuring metastasis efficiency in the MNX crosses with Her2 are still in progress. To determine whether the mitochondrial haplotype alters tumorigenicity or metastasis in a non-cell autonomous manner, syngeneic tumor cells were injected orthotopically and ectopically (i.v.). Tumor formation and metastasis differ in a tumor and mtDNA-dependent manner. For example, E0771 forms significantly more lung metastases in C57BL/6n:C3H/HeNmt mice compared to controls. To explore underlying mechanisms, metabolic differences were observed in MNX and matched wild type mouse embryonic fibroblasts using the Seahorse bioanalyzer. Conclusion: mtDNA affects mammary cancer development and progression via both genetic and non-cell autonomous mechanisms in the tumor microenvironment. Support: Susan G. Komen for the Cure (SAC11037), Natl Fndn Cancer Res, Steiner Family Fund for Metastasis Research, Kansas Bioscience Authority, CA134981, P30-CA168524 Citation Format: Amanda E. Brinker, Carolyn J. Vivian, Kyle P. Feeley, Scott W. Ballinger, Danny R. Welch. Mitochondrial haplotype effects on tumor formation and metastasis are both cell autonomous and non-cell autonomous. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3262. doi:10.1158/1538-7445.AM2015-3262