Abstract P5-06-01: Spatiotemporal gene expression analysis to identify novel tumor-neural crosstalk in TNBC brain metastases

Abstract

Abstract Brain metastasis (BrM) occurs in 25-40% of TNBC metastatic patients while one-year survival remains a single digit. In contrast to other primary subtypes, TNBC usually spreads to the brain rapidly at early stages or even before the diagnosis of primary cancer. The shorter development time of BrM in TNBC and shorter survival time after BrM diagnosis may indicate a certain innate ability of TNBC cells in adapting to the brain. Recent seminal findings and our studies identified enriched and diverse expressions of neurotransmitters receptors, transporters, and key synthesis enzymes in brain metastatic TNBC cells. Since neurotransmitters, gliotransmitters, neurotrophic factors, and neural cytokines, called neuroactive substances (NSs), are the most abundant and key intercellular communication signals in the brain, we hypothesize that tumor cells leverage NSs to assimilate into the neural circuitry via communicating with various types of neural cells, including astrocytes, microglia/macrophages, oligodendrocytes and so on, to reinforce tumor-neural crosstalk in the development of BrM. By performing spatial transcriptomics experiments on mouse brain tissue sections bearing TNBC metastatic tumors, we found that brain regions, tumor lesions at different locations, and even tumor-surrounding areas were well separated into different clusters based on the spatial gene expressions and further predicted several novel paracrine and autocrine signalings between/within tumors and tumor-surrounding neural niches under different conditions, including tumor locations, tumor sizes, tumor center vs. edges, and stages of tumor development using the Cell-Cell Communication Explorer (CCCExplorer), a computational modeling tool for multi-cellular crosstalk and intracellular signaling developed by our lab. We conducted functional experiments to demonstrate that cell type-specific depletion of the secreted NSs deactivated the activities of corresponding receptor and downstream signaling using a cellular co-culture BrM system. The presented study indicates that the characterization and identification of spatiotemporal tumor-neural crosstalk in the BrM metastatic niche would open up a new vista for discovering novel therapeutics targets for devastating metastatic brain tumor. Citation Format: Hong Zhao, Xin Wang, Jianting Sheng, Shan Xu, Dongbing Gao, Stephen Wong. Spatiotemporal gene expression analysis to identify novel tumor-neural crosstalk in TNBC brain metastases [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-06-01.