Understanding lactate catabolism by BACH1 in triple negative breast cancer - PROJECT SUMMARY Primary metabolic pathways in cancer are useful targets for therapeutic intervention. However, intratumoral heterogeneity in cancer metabolism is a major challenge for anti-cancer therapy. Reducing metabolic variance by reprogramming cancer metabolism is essential to enhance efficacy of inhibitors targeting metabolism. Our long-term goal is to overcome metabolic heterogeneity through reprogramming metabolic networks to increase the number of cancer cells vulnerable to metabolic inhibitors. To reach this goal, our novel strategy is to reduce metabolic variance among cancer cells by targeting BACH1, a master regulator of metabolism-related transcription in triple negative breast cancer (TNBC), to obtain maximal response of drugs targeting metabolic pathways. Our previous molecular and metabolomic profiling of breast tumors revealed that BACH1 suppresses mitochondrial metabolism. Thus, BACH1 depletion made TNBC cells more sensitive to mitochondrial inhibitors. These findings led to the novel concept that BACH1 depletion increases the proportion of cancer cells with higher dependency on mitochondrial respiration and restricted tumor metabolic plasticity. Our preliminary studies indicate that BACH1 also suppresses lactate catabolism, which is a primary pathway for lactate oxidation in mitochondria of cancer cells. In support of this finding, recent clinical studies showed that lactate catabolism depends on lactate transporter (MCT1). In TNBC cells, BACH1 represses transcription of genes that encode enzymes involved in lactate catabolism, including lactate transporter (MCT1), lactate dehydrogenase B (LDHB), and mitochondrial pyruvate carriers. Specifically, BACH1 depletion sensitized cancer cells to blockade of MCT1 or LDHB. Based on our preliminary data, we hypothesize that BACH1 is the key determinant of whether cancer cells produce lactate or consume lactate. The primary objective of this proposed study is to link BACH1 contribution to lactate catabolic variance, and to better understand regulation of lactate oxidation in TNBC. Using multiple innovative approaches, including in vitro and in vivo breast tumor models and a combination of transcriptomics and metabolomics, we will interrogate BACH1 regulation of lactate catabolism and define the underlying molecular regulatory mechanism in breast cancer cells. Furthermore, using patient-derived xenograft and syngeneic mouse models, we will investigate whether BACH1 inhibition (through the repurposed non-toxic FDA-approved drug, panhematin) increases breast tumor vulnerability to drugs targeting the lactate transporter MCT1. By combining cell biology and in vivo assays, this study will provide comprehensive insights into how cancer cells use lactate as a substrate, whether metabolic variances are reduced by targeting BACH1, and how to achieve better therapeutic strategies using lactate catabolism inhibitors.
