Abstract IA30: Intrinsic and extrinsic contributions of mitochondrial DNA to metastatic efficiency: A genetic explanation for disparities in metastasis efficiency?
Authors: Welch Danny R. 
Published: August 2020

Single-nucleotide polymorphisms (SNP) in nuclear and mitochondrial DNA are used to define clades (or races) in people, as well as different strains in mice (PMID: 27383787). Previous studies showed that nuclear SNP determine metastasis efficiency; we hypothesized that mtDNA SNP could also play roles in tumorigenicity and metastasis. Mitochondrial Nuclear Exchange (MNX) mice, created by transferring an oocyte nucleus from strainx into an enucleated oocyte from strainy (PMID: 27840835), show that mammary tumor formation and metastasis are regulated by inherited mitochondrial polymorphisms when MNX mice were bred to MMTV-PyMT or MMTV-HER2 mice (PMID: 26471915; 29070615). Since stromal compartments also possess changed mitochondria in MNX mice, we hypothesized that mitochondrial SNP in noncancer compartments could exert effects on tumor formation or metastasis in addition to genetic (cell autonomous) changes. Syngeneic tumor cells were injected into MNX mice with the same nuclear (and, therefore, same histocompatibility) background. Experimental metastasis was compared between wild-type and MNX mice (i.e., with same or different mtDNA backgrounds, respectively). E0771 mammary carcinoma and B16-F10 melanoma cells (both syngeneic to C57BL/6J), formed significantly (P&lt;0.01) more lung metastases in C57BL/6J-mtMNX(C3H/HeN). K1735-M2 melanoma cells (syngeneic to C3H/HeN) formed significantly (P&lt;0.05) fewer lung metastases in C3H/HeNmtMNX(C57BL/6J) mice. These results have been replicated ≥3 times using &gt;10 mice per experiment. C57BL/6J mitochondria confer resistance to metastasis in both cell autonomous and non-cell autonomous experiments. Basal metabolic and ROS differences comparing mouse embryonic fibroblasts isolated from wild-type and MNX mice exist and may be responsible for the stromal effects. Likewise, significant and statistically significant differences in MNX mice for nuclear DNA methylation (PMID: 28663334) and epigenetic marks (J. McGuire & D.R. Welch, in preparation), immune (T.C. Beadnell & D.R. Welch, in preparation) and microbota (S.J. Manley & D.R. Welch, in preparation) profiles are observed. Together, our findings highlight the striking influences that mitochondrial haplotypes can exert on tumorigenicity and metastasis via both intrinsic and extrinsic mechanisms. These findings also suggest that mitochondrial SNP could serve, in part, as a genetic basis to explain racial disparities with regard to cancer aggressiveness.

Support: Susan G. Komen for the Cure (SAC11037), Natl. Fndn. Cancer Res., CA168524, W81XWH-18-1-0450, GM103418.

Citation Format: Danny R. Welch. Intrinsic and extrinsic contributions of mitochondrial DNA to metastatic efficiency: A genetic explanation for disparities in metastasis efficiency? [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr IA30.