Abstract 798: Epithelial-mesenchymal transition directs stem cell polarity via regulation of mitofusin

Mitochondria are dynamic organelles that have been linked to stem cell homeostasis. However, the mechanism involved in mitochondrial regulation of stem cell fate determination remain elusive. Here we discover that epithelial-mesenchymal transition (EMT), a key process in cancer progression, induces mitochondrial fusion through regulation of miR200c-PGC1a-MFN1 pathway. EMT-activated MFN1 forms a complex with PKCz and is required for PKCz-mediated NUMB phosphorylation and dissociation from the cortical membrane to direct asymmetric division of mammary stem cells, where fused mitochondria are tethered by MFN1-PKCz to the cortical membrane and asymmetrically segregated to the stem cell-like progeny with enhanced glutathione synthesis and reactive oxygen species scavenging capacities, allowing sustaining of a self-renewing stem cell pool. Suppression of MFN1 expression leads to equal distribution of the fragmented mitochondria in both progenies that undergo symmetric luminal cell differentiation. Together, this study elucidates a novel role of mitofusin in stem cell fate determination to mediate EMT-associated stemness and provides therapeutic implications for targeting EMT-induced tumor stem cell populations. Citation Format: Meng-Ju Wu, Mi Ran Kim, Silpa Gampala, Yingsheng Zhang, Yueyang Wang, Jer-Yen Yang, Chun-Ju Chang. Epithelial-mesenchymal transition directs stem cell polarity via regulation of mitofusin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 798.