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Colorectal cancer-derived osteopontin rewires macrophages into a pro-metastatic M2 state via the PI3K/AKT/CSF1-CSF1R axis

ABSTRACT: Metastasis remains the primary cause of mortality in colorectal cancer (CRC), with a 5-year survival rate of approximately 14%, despite advancements in treatment. SPP1+ tumor-associated macrophages (TAMs) are implicated in promoting tumor growth, angiogenesis, and immune evasion. Osteopontin (OPN), encoded by the SPP1 gene, is a critical regulator of TAMs M2 polarization and CRC metastasis. However, the mechanisms by which CRC-derived OPN interacts with M2-TAMs to promote metastasis remain unclear. Here, We found that OPN is highly expressed in metastatic CRC and is associated with poor prognosis. However, knockdown or overexpression of OPN in CRC cells did not directly affect tumor cell invasion and metastasis, which is inconsistent with previously reported trends. Additionally, OPN expression levels were positively correlated with M2-like TAMs infiltration. Using an in vitro co-culture system, we found that CRC-derived OPN induces M2-like polarization of TAMs, and the two mutually promote chemotactic migration. Mechanistically, high OPN expression activates the PI3K/AKT signaling pathway in macrophages, promoting the secretion of CSF1, which induces M2-like polarization of macrophages to facilitate tumor metastasis. Finally, in a mouse metastasis model, blocking the CSF1/CSF1R axis with a CSF1R inhibitor reduced the recruitment of M2-TAMs and CRC tumor metastasis.Our study demonstrates that the OPN/CSF1/CSF1R/PI3K/AKT axis plays a crucial role in CRC metastasis. Blocking CSF1/CSF1R reduces M2-TAM infiltration and tumor metastasis, thereby enhancing the therapeutic efficacy for metastatic CRC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290045 | GEO | 2026/01/30

REPOSITORIES: GEO

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Project description:Background: Esophageal squamous cell carcinoma (ESCC) has become an important global health issue. The M2 polarization of tumor-associated macrophages (TAMs) plays a key role in the occurrence and development of ESCC. It is reported that exosome circRNAs are involved in the regulation of the polarization state of TAMs, but the underlying mechanism remains unclear. In this study, we aim to identify novel exosome circrnas that regulate the progression of ESCC and explore their biological functions and regulatory mechanisms in ESCC. Method: The highly expressed circRNAs in ESCC tissues and plasma were identified by circRNA microarray analysis. Transmission electron microscopy, differential centrifugation and Western blotting were used for the presence of exosome circAP2B, and the uptake of circAP2B1 by macrophages was determined by exosome tracing. The effects of exosome circAP2B1 on tumor proliferation and metastasis were investigated in vitro and in vivo. The role and molecular mechanism of exosome circAP2B1 in enhancing mitochondrial homeostasis of macrophages to induce M2 polarization were investigated by means of flow cytometry analysis, IP, LC-MS/MS, RIP, Pull down, CHIP, CHRIP and dual-luciferase reporter gene. Result: We demonstrated that the upregulation of exosome circAP2B1 expression was positively correlated with lymph node metastasis and poor prognosis in patients with ESCC. Functionally, exosome circAP2B1 promotes the growth and metastasis of ESCC both in vitro and in vivo by inducing TMS-M2 polarization. Mechanism speaking, the tumor-derived exosome circAP2B1 enters macrophages to promote the nuclear translocation of the circAP2B1/ESRRA/KPNA1 ternary complex and mediate the transcriptional regulation of MFN2 to enhance the mitochondrial homeostasis of TAMs. Conclusion: The exosome circAP2B1 derived from ESCC cells induces TMS-M2 polarization and tumor progression by regulating mitochondrial metabolic reprogramming in macrophages. Therefore, circAP2B1 targeting exosome packaging may provide potential diagnostic and therapeutic strategies for ESCC.

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Colorectal cancer-derived osteopontin rewires macrophages into a pro-metastatic M2 state via the PI3K/AKT/CSF1-CSF1R axis

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