Jeong, H. H. | Search bioRxiv

bioRxiv2020

Phenotypic plasticity of ER+ breast cancer in the bone microenvironment

ER+ breast cancer exhibits a strong bone-tropism in metastasis. How the bone microenvironment impacts the ER signaling and endocrine therapies remains poorly understood. Here, we discover that the osteogenic niche transiently reduces ER expression and activities specifically in bone micrometastases (BMMs), leading to endocrine resistance. This is mediated by gap junctions and paracrine FGF/PDGF signaling, which together generate a stable "memory": cancer cells extracted from bone remain resistant to endocrine therapies for several generations. Using single cell-derived populations (SCPs), we demonstrated that this process is independent of clonal selection, and represents an EZH2-mediated epigenomic reprogramming. EZH2 drives ER+ BMMs toward a basal and stem-like state. EZH2 inhibition reverses endocrine resistance. Our data demonstrates how epigenomic adaptation to the bone microenvironment drives phenotypic plasticity of metastatic seeds and alters their therapeutic responses together with clonal selection, and provides insights into the clinical enigma of ER+ metastatic recurrences despite endocrine therapies.

cancer biology↗

bioRxiv2020

Transplantation of muscle stem cell mitochondria rejuvenates the bioenergetic function of dystrophic muscle

Mitochondrial dysfunction has been implicated in various pathologies, including muscular dystrophies. During muscle regeneration, resident stem cells, also known as muscle satellite cells (MuSCs), undergo myogenic differentiation to form de novo myofibers or fuse to existing syncytia. Leveraging this cell-cell fusion process, we postulated that mitochondria stemming from MuSCs could be transferred to myofibers during muscle regeneration to remodel the mitochondrial network and restore bioenergetic function. Here, we report that dystrophic MuSCs manifest significant mitochondrial dysfunction and fuse with existing dystrophic myofibers to propagate mitochondrial dysfunction during muscle repair. We demonstrate that by transplanting healthy donor MuSCs into dystrophic host muscle, the mitochondrial network (reticulum) and bioenergetic function can be rejuvenated. Conversely, when bioenergetically-compromised donor MuSCs are transplanted, improvements in mitochondrial organization and bioenergetic function were ablated in the dystrophic recipient. Overall, these data reveal a unique role of muscle stem cells as an essential regulator of myofiber mitochondrial homeostasis and a potential therapeutic target against mitochondrial myopathies.

cell biology↗