Abstract 3829: Dissecting the role of chemotherapy-induced host responses in post-therapy metastatic relapse of breast cancer

Abstract Chemotherapy-elicited host responses are regarded as a primary mechanism compromising therapeutic efficacy. Clinical evidence indicates that chemotherapy can elevate the risk of distant metastasis in certain breast cancer patients, which was also extensively observed and studied in preclinical models. In a neoadjuvant chemotherapy model, non-labeled mouse and human breast cancer cells were injected into the mouse mammary fat pad, followed by the administration of three doses of doxorubicin to mimic chemotherapy treatment. Luciferase-labeled breast cancer cells were injected into the left ventricle of the mice to establish a systemic metastasis model. In vivo bioluminescence-imaging revealed a striking increase in metastasis to the lung and liver after chemotherapy in all breast cancer mouse models, without significant metastasis to other organs. This effect was even more pronounced in NSG mice (severe immunodeficiency), suggesting that non-immune components may contribute to chemotherapy-induced metastasis. To further explore the host responses post-chemotherapy in the lung and liver, we performed single-cell RNA sequencing (scRNA-seq) to analyze non-immune cell changes following chemotherapy. This analysis identified an increased Postn (Periostin) positive mesenchymal cells subcluster in chemotherapy treated group, with upregulating collagen-processing genes, such as Col1a1 and Col3a1. Spatial transcriptomic analysis further revealed that Postn, along with collagen genes Col1a1 and Col3a1, was localized to the lung interstitial space, suggesting that extracellular matrix (ECM) remodeling in this region may facilitate metastatic colonization. We are currently investigating the role of Postn in chemotherapy-induced host responses and evaluating whether therapeutic targeting of Postn could prevent chemotherapy-induced metastasis. Citation Format: Chaojia Chen, Guangwen Ren, Zheng Gong, Jiayuan Shi. Dissecting the role of chemotherapy-induced host responses in post-therapy metastatic relapse of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3829.