Abstract A051: Mitochondrial metabolism and fission as dynamic drivers of breast cancer metastasis

Abstract

Abstract Approximately 30% of women with early-stage breast cancer will develop metastatic disease, making efforts to define drivers of metastasis critical. Our group found that metastatic breast cancer cells express an oxidative phosphorylation (OXPHOS) gene signature. Further, inhibiting OXPHOS reduced metastatic seeding, thus revealing the functional role of mitochondrial metabolism in breast cancer metastasis. It is understood that mitochondria are highly dynamic organelles that are regulated by a balance of fission and fusion proteins; however, it remains poorly understood how mitochondrial metabolism and their dynamics promote cancer spreading. To interrogate mitochondrial heterogeneity within primary tumors, we sorted tumor cells from patient derived xenograft (HCI010) and murine (4T1) breast tumors stratified by low or high uptake of tetramethylrhodamine methyl ester (TMRM, a dye that accumulates in active mitochondria undergoing OXPHOS). Low or high cell fractions were re-injected intravenously in new cohorts of mice. We found greater metastatic burden in the lungs of mice injected with the TMRM high fraction. Furthermore, we uncovered that the TMRM high cells had greater mitochondria abundance than TMRM low cells. We hypothesized the differences in mitochondrial content we observed in primary tumor cells is caused by shifts in cellular expression of mitochondria fission and fusion proteins. Consistent with this hypothesis, we found that TMRM high, metastatic tumor cells had greater expression of mitochondria fission gene, DRP1, and lower expression of fusion gene, MFN2. Collectively, our results revealed heterogeneity in tumor cell mitochondrial content within a primary tumor that appears to influence the fitness of a cell to metastasize. Lastly, our data supports a role for mitochondrial fission in breast cancer metastasis. Future directions for our studies will include genetic and pharmacological modulation of mitochondrial fission and fusion to better understand why it influences metastasis and at what point during the metastatic cascade. Citation Format: Hannah Savage, Dennis Ma, Devon Lawson. Mitochondrial metabolism and fission as dynamic drivers of breast cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A051.