Abstract 6051: Dissecting unique metabolic vulnerabilities in triple-negative breast cancer metastasis

Abstract

Abstract Introduction. Triple-negative breast cancer (TNBC) exhibits the worst outcome due to an aggressive clinical course, high rates of metastasis, and therapeutic resistance. Lack of effective FDA approved anti-metastatic targeted therapies has generated an unmet medical need for developing effective novel treatments. Targeting metastatic seeding and colonization remains a therapeutic challenge. Only recently, attention has been drawn to the idea that cancer cells selectively and dynamically adapt their metabolism along the changing microenvironments of the metastatic cascade. However, the precise nature of the metabolic reprograming in vivo is poorly understood and constitutes a major barrier in formulating a rationally designed therapeutic approach. Using a genetic lineage tracing approach, we identified a discrete subpopulation of highly metastatic SOX2/OCT4+ cells within primary tumors that exhibit enhanced invasion and metastasis, increased self-renewal, higher chromosomal instability, and marked resistance to chemotherapy. We posited that this lineage tracing system may allow assessment of precise metabolic alterations as a function of tumor progression directly in vivo. Methods and data. Transcriptomic analysis of sorted cellular fractions from progressing primary TNBC tumor identified metabolic heterogeneities between metastatic SOX2/OCT4+ and the SOX2/OCT4- counterparts. SOX2/OCT4+ metastatic cells exhibited elevated levels of mitochondrial respiration (OXPHOS) and fatty acid (FA) metabolism; a finding supported by proteomic analysis. Using a combination of CRISPR knockout of key pathway genes, seahorse metabolic flux analysis, metabolomics, and stable isotope tracing, we provide evidence for increased dependence of the metastatic SOX2/OCT4+ population on these unique metabolic adaptions. Importantly, we have identified upstream regulators of these pathways and demonstrate impact of both genetic and pharmacological inhibition of the metabolic regulatory networks on metastasis in vivo. Conclusion. By identifying metabolic adaptations unique to the metastatic compartment of the primary tumor, we provide evidence for using clinical grade pharmacological inhibitors including metformin, tetrathiomolybdate and FA pathway inhibitors like TVB-2640 and BMS-303141, as an anti-metastatic approach in TNBC. This knowledge of metabolic remodeling could therefore be employed as a next-generation therapeutic approach for high-risk TNBC patients. Citation Format: Divya Ramchandani, Liron Yoffe, Arshdeep Singh, Linda Vahdat, Vivek Mittal. Dissecting unique metabolic vulnerabilities in triple-negative breast cancer metastasis [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 6051.