Intercellular Transfer of Mitochondria at the Nerve-Cancer Interface - Title: Intercellular Transfer of Mitochondria at the Nerve-Cancer Interface Project Summary/Abstract Breast cancer, particularly triple-negative breast cancer (TNBC), poses a significant global health challenge, with metastasis being a major cause of breast cancer-related deaths. Despite advances in surgical treatment, there remains an urgent need for effective therapeutic strategies to combat the aggressive nature of TNBC. Recent studies have shown that cancer neurogenesis (CNG), characterized by the de novo generation of nerves within primary tumors, is associated with aggressive disease and poor patient outcomes across various cancers, including breast carcinomas. However, the functional role of CNG in tumor biology remains unclear, and the characteristics of the nerve-cancer interface during tumor innervation require further investigation. We have developed in vitro and in vivo coculture models of CNG, demonstrating its association with breast cancer metastasis. Microscopy imaging at the neuroepithelial interface has revealed significant metabolic reprogramming of neuronal cells exposed to breast cancer cells, followed by the intercellular transfer of mitochondria from nerves to cancer cells. Our preliminary data suggest that these mitochondrial transfers enhance the metabolic plasticity of recipient cancer cells, promoting their metastatic potential. The primary objective of this research is to investigate the functional role of nerve-cancer mitochondrial transfer in cancer metastasis, identify the key mediators involved in these transfers, and assess the impact of inhibiting this process on cancer progression. To achieve these goals, we developed MitoTRACER, an innovative lineage- tracing genetic strategy that enables the permanent labeling of cancer cells that have acquired mitochondria from neurons. In Specific Aim 1, we will use MitoTRACER to determine the precise contribution of nerve-to-cancer mitochondrial transfer to the breast cancer metastasis cascade in vivo. In Specific Aim 2, we will evaluate how these mitochondrial transfers contribute to the generation of cancer stem cells (CSCs) in vitro and in vivo, cancer resistance to therapy, and identify unique characteristics of nerve-mediated CSCs that could be targeted clinically to prevent TNBC recurrence. This project builds on our recently published findings and preliminary data, focusing on the mechanisms associated with CNG, intercellular communication at the nerve-cancer interface, and their impact on cancer cell metabolism and metastasis. Successful completion of this research will elucidate how cancer cells acquire metabolic plasticity to enhance their metastatic potential, paving the way for new therapeutic strategies against highly innervated cancers and providing innovative tools for studying mitochondrial exchange.
