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SIPA1 expression in breast cancer patient

ABSTRACT: To study the expression of SIPA1 in patients with metastatic triple-negative breast cancer, we obtained a subcutaneous metastatic sample from a patient with stage III triple-negative breast cancer and performed single-cell transcriptome sequencing

ORGANISM(S): Homo sapiens

PROVIDER: GSE221731 | GEO | 2022/12/31

REPOSITORIES: GEO

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Project description:Signal-induced proliferation-associated gene 1 (Sipa1) is known as a specific Rap1 GTPase-activating protein that negatively regulates Rap1 signaling. Although Sipa1 has been extensively studied in cancer research, its role in the wound healing response after myocardial infarction (MI) remains unexplored. To investigate the role of endogenous Sipa1 in MI, we performed permanent left anterior descending artery ligation in both Sipa1 knockout mice and their control littermates. Bone marrow transplantation, flow cytometry, cell sorting, and transcriptomic analysis were conducted to identify the cellular source of Sipa1 in the infarcted heart. The role of cardiac fibroblast-derived Sipa1 during MI was examined using Sipa1 deletion approaches, specifically in cardiac fibroblasts, in vivo and in vitro. Mice deficient in Sipa1 exhibited improved post-MI survival and cardiac function, along with attenuated expression of inflammatory mediators and diminished accumulation of Ly6Chigh monocytes and CCR2+ macrophages in the infarcted heart. Although Sipa1 was broadly expressed in the heart, cardiac fibroblasts were responsible for the Sipa1-induced deleterious phenotype as demonstrated by cardiac fibroblast-specific Sipa1 conditional knockout mice, which averted excessive inflammation and adverse cardiac remodeling following MI. Mechanistically, Sipa1 promotes the production of CCL2, CCL7 and granulocyte/macrophage colony-stimulating factor in the cardiac fibroblasts early after MI via a non-canonical RasGRP2-Ras-JNK signaling pathway, irrespective of canonical Rap1, thereby facilitating the accumulation and activation of inflammatory monocytes and macrophages. These results identify a previously unknown fibroblast-immune axis characterized by Sipa1, which initiates excessive inflammation and leads to poor outcomes after MI. Targeting Sipa1 offers a potential novel therapeutic strategy to optimize post-MI wound healing response, thereby preventing the development of chronic ischemic heart failure.

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SIPA1 expression in breast cancer patient

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