ORIGINAL RESEARCH article
Front. Oncol.
Sec. Cancer Cell Signaling
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1595523
FN1 from Cancer-Associated Fibroblasts Orchestrates Pancreatic Cancer Metastasis via Integrin-PI3K/AKT Signaling
Provisionally accepted
- 1Henan Provincial People's Hospital, Zhengzhou, China
- 2Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
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Pancreatic ductal adenocarcinoma (PDAC) metastasis is linked to cancer-associated fibroblast (CAF) remodeling in the tumor microenvironment (TME), but the molecular mechanisms are unclear. This study investigates the role of CAF-derived fibronectin 1 (FN1) in pancreatic cancer metastasis, focusing on its molecular mechanism and immune regulatory functions via the integrin-PI3K/AKT signaling axis. Transcriptome (GSE183795) and single-cell sequencing (GSE156405) data were integrated with in vitro coculture models, functional assays (Transwell, Western blot, qRT-PCR), and clinical cohort analysis. Differential gene analysis, functional enrichment, and CytoHubba identified FN1 as a core hub gene in the PI3K pathway. Single-cell sequencing localized FN1 expression to CAF subsets. In vitro experiments validated FN1's activation of PI3K/AKT through integrin receptors and its impact on invasion and the immune microenvironment. FN1 was highly expressed in metastatic CAF subsets and identified as a core hub gene in the PI3K/AKT pathway. Functional experiments confirmed FN1 activates PI3K/AKT via integrin receptors. Combined PI3K/AKT and integrin inhibition synergistically blocked invasion. Clinical data linked high FN1 expression to shorter survival and an immunosuppressive 2 microenvironment (M2 macrophage/Treg infiltration). This study reveals FN1 drives pancreatic cancer metastasis through the integrin-PI3K/AKT axis and indirectly by recruiting immunosuppressive cells, shaping a "cold tumor" microenvironment. FN1's dual mechanism deepens understanding of CAF heterogeneity and offers new therapeutic strategies. Targeting both PI3K/AKT and integrins may overcome PI3K inhibitor resistance, with significant clinical potential.
Keywords: fibronectin 1, Pancreatic Cancer, metastasis, integrin-PI3K/AKT signaling axis, cancer-associated fibroblasts
Received: 18 Mar 2025; Accepted: 17 Jun 2025.
Copyright: © 2025 Zhu, Li, Liu and Xiao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zheng Xiao, Henan Provincial People's Hospital, Zhengzhou, China
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