TMIC-07. HIGH ALDEHYDE DEHYDROGENASE ACTIVITY IDENTIFIES BRAIN METASTASIS-INITIATING CELLS IN BREAST CANCER

Abstract

Brain metastases (BM) from breast cancer (BC) are associated with significant morbidity and mortality. However, the mechanism of how BC cells initiate and propagate BM tumors remains elusive. In this study, we established a set of patient-derived models of circulating tumor cells (CTCs) from either hormone receptor positive (HR+) or negative (HR-) cells, and subsequent BM cells in vivo. Our brain-primed BC derivative lines exhibited a trend to form metastatic tumors in the brain more frequently than in the bones or lungs. In contrast, the naive BC cells rarely formed BM tumors. Micro-MRI of mouse brains after cardiac injection of brain-primed BC derivatives detected the persistent attachment and subsequent colonization of these circuiting cells, whereas naive BC cells, when injected into arterial circulation, were quickly eradicated from the brain. Transcriptomic expression analysis showed that ALDH isoforms including ALDH1A3 are highly upregulated in BM cells in contrast to BC cells. Silencing of ALDH1A3 by lentiviral shRNA infection specifically attenuated in vivo BM formation from the BC derivatives through arterial circulation, while it did not affect formation of the metastases in the lungs and bones. RNA sequencing detected that the expression of tissue transglutaminase (TG2), constitutive activator of transcription factor-kB (NF-kB), is higher in BM but not in lung and bone metastasis and its expression was attenuated by reducing ALDH1A3. Clinically, matched pairs of human primary BC and BM tissue samples showed the elevation of ALDH1A3 expression in BM tumors. In addition, ALDH1A3 expression was significantly correlated with poor prognosis. To develop therapeutics for ALDH1A3, we designed and synthesized a small molecule ALDH1A3 inhibitor, termed GA11. Systemic treatment of the CTC-BM mouse models with GA11 yielded a prominent inhibitory effect on BM formation. Taken together, our results suggest that ALDH1A3 might be a promising therapeutic target for BM tumors.