Abstract 4831: Mitochondrial plasticity enables metabolic reprogramming and metastatic latency

Abstract

Abstract Introduction: Metastatic relapses are common in epidermal growth factor receptor 2 (HER2) amplified breast cancer patients considered disease-free after primary diagnosis and treatment. Stem-like disseminated tumor cells with specialized metastatic traits adapt and survive as latent metastases in distal organs by overcoming oxidative stress, nutrient limitation, microenvironmental and immune defenses. These latent subclinical metastatic cells are responsible for late recurrences. Understanding the traits and vulnerabilities of these cells is critical for developing strategies to prevent metastatic relapse. Method: Here, we employed mouse models and patient samples along with RNA sequencing, Steady-state metabolite analysis, Lipid profiling, C13-isotope tracing, C12-BODIPY pulse chase, Lentiviral shRNA Knockdown, Transmission electron microscopy etc. to investigate how disseminated latent metastatic cells meet their cellular energetic demands and initiate overt metastasis in the lipid-rich brain microenvironment. Result: The ability to utilize available nutrients in distal organs and rewire metabolism is critical for survival of disseminated tumor cells. We report that latent metastatic cells in the brain uptake, store, and utilize fatty acids secreted by tumor-associated reactive astrocytes to meet their cellular energetic needs. Fatty acid oxidation (FAO) and dynamin-related protein 1(DRP1) driven punctate mitochondria enabled utilization of fatty acids and promote survival of latent cells by maintaining cellular bioenergetics and redox homeostasis. Attenuating fatty acid oxidation by genetic and pharmacological inhibition disrupted mitochondrial dynamics and limits metastatic incidence. Likewise, depleting DRP1 altered mitochondrial dynamics that results in reduced FAO, increased reactive oxygen species and attenuated metastatic latency and relapse in HER2+ breast cancer brain metastatic models. Furthermore, comparison with patient-matched primary tumor and brain metastasis identified increased pDRP1 expression in brain metastatic lesions. Moreover, pharmacological inhibition of DRP1 reduced brain metastatic burden in these preclinical models. Conclusion: Despite significant advances in targeted therapies, HER2+ breast cancer patients often develop brain metastasis and their prevention and management remain an unmet need. Our findings in latent HER2+ breast cancer brain metastatic models demonstrate mitochondrial plasticity and altered fatty acid metabolism are key determinants of metastatic adaptation to the brain and establish DRP1 as a promising therapeutic target for treating brain metastasis. Key Words: Breast Cancer Brain Metastasis, Mitochondrial Plasticity, DRP1, Metastatic Latency, Redox Homeostasis. Citation Format: Pravat Kumar Parida, Srinivas Malladi. Mitochondrial plasticity enables metabolic reprogramming and metastatic latency. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4831.