Abstract IA007: Regulation of metastasis efficiency via mitochondrial genetics

Abstract

Abstract While there has been increasing appreciation for the roles of mitochondria in cancer, most efforts investigating the genetics of cellular functions study only the nuclear genome. To overcome technical complications of studying the specific contributions of mitochondrial genetics, we created mitochondrial nuclear exchange (MNX) mice by transferring an oocyte nucleus from strain-x into an enucleated oocyte from strain-y. Using MNX mice, we made the following discoveries demonstrating the profound role(s) of mtDNA on several complex phenotypes. - Crossing nuclear genome-matched female mice with male transgenic mice bearing oncogenes, tumorigenicity and metastasis were up- or down-regulated depending upon mtDNA. - MNX mice exhibit different autochthonous tumor formation. - When syngeneic (i.e., histocompatible) mammary and melanoma cells were injected into MNX mice, metastasis changed 3-5X, depending on mtDNA SNP. C57BL/6J mtDNA inhibited metastasis while C3H/HeN mtDNA increased metastasis. - MNX mice have selectively altered epigenetic marks (DNA methylation and histone marks) in the nuclear genome. - MNX mice with higher ROS form more metastases. Scavenging ROS reduced metastasis. - Baseline immune profiles differ in MNX mice compared to nDNA-matched counterparts and polarization states of myeloid populations infiltrating lung metastases were also significantly different. - Metabolomic profiling of >5000 metabolites showed minor differences, none of which appear to correlate with the above-referenced phenotypic changes. - MNX mice have distinct gut microbiota than matched wild-type strains, suggesting mitochondrial-bacterial communication. Together, these results demonstrate that mitochondrial genes are among metastatic quantitative trait loci by intrinsic and extrinsic mechanisms. Candidate signals from mitochondria to the nucleus or bacteria will be reported. And since mitochondrial SNP are markers of genetic ancestry, our findings also suggest that mtDNA SNP could serve as prognostic biomarkers and partially explain racial disparities in disease severity. Support: Susan G. Komen for the Cure (SAC11037), METAvivor Research & Support Inc., National Foundation for Cancer Research, National Cancer Institute P30-CA168524. Citation Format: Danny R. Welch. Regulation of metastasis efficiency via mitochondrial genetics [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA007.