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Paracrine regulation of pancreatic cancer cell response to chemotherapy by GLI2-Collagen I signaling

ABSTRACT: Despite the well described role of non-cellular components of the tumor microenvironment (TME) in regulating tumor growth, the molecular events dictating expression and biological functions of key components of the TME remain elusive. Here, using pancreatic cancer (PC) models, we describe a novel mechanism through which the zinc finger transcription factor GLI2 in cancer associated fibroblasts (CAFs) induces expression of COL1A1, which is a major component of Collagen I and the most abundant collagen variant in the tumor milieu. Bulk and single nuclei RNA-seq showed that GLI2 expression in CAF strongly correlates with COL1A1 levels, fibrosis, and CAF activation. ChIP-qPCR and expression studies of the PC matrisome identified COL1A1 as the direct target of GLI2 in CAFs. We also provide evidence that GLI2 is an effector that mediates COL1A1 induction by transforming growth factor β1 (TGFβ1). RNA-seq analysis of PC cells treated with Collagen I revealed enrichment of chemotherapeutic gene expression profiles, which includes irinotecan resistance signature. Viability studies confirmed that Collagen I promotes irinotecan resistance in PC cells. Altogether, our results uncover a novel role for the TGFβ1-GLI2 axis within CAFs to modulate Collagen I expression and promote chemoresistance in PC cells. Our findings increase our understanding of the complex molecular network operating in the TME.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283407 | GEO | 2025/07/23

REPOSITORIES: GEO

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Project description:Cancer-associated fibroblasts (CAFs) are one of the components in tumor microenvironment (TME) that can facilitate tumor progression, invasion, and metastasis directly through tumor-CAF interactions, or indirectly by crosstalking with tumor infiltrating immune cells and inducing immunosuppressive TME. Indeed, high stromal signature has been associated with reduced therapeutic efficacy and resistance to Immune Checkpoint Blockade. AEBP1 is highly expressed in myofibroblast cells whose expression is further upregulated in activated fibroblasts and the extracellular matrix (ECM)-producing CAFs. AEBP1 has two alternatively spliced isoforms that the extracellular isoform binds to collagen and promotes collagen remodeling, and the intracellular isoform modulates transcription and signaling. We observed expression of both isoforms of AEBP1 in primary human CAFs. Our data showed that combined knock out (KO) of both isoforms of AEBP1 by gene editing technology decreased CAF proliferation, collagen gel contractility and CAF-mediated tumor cell proliferation in vitro. Pan AEBP1 KO mouse fibroblasts also showed reduced activity in vitro and in vivo in the co-implantation mouse model. We found that knocking out both isoforms of AEBP1 downregulated the collagen biosynthesis and ECM organization related pathways in both mouse fibroblasts and primary human CAFs through RNA sequencing studies. In addition, loss of AEBP1 in fibroblasts impacted tumor cell phenotypes resulting in significant decrease of tumor cells with,with epithelial-mesenchymal transition signature in the co-implantation mouse model. Furthermore, AEBP1 KO in CAFs enhanced the anti-PD-1 induced effector T cell activity and the anti-PD-1 efficacy in this co-implantation model. Altogether, our results demonstrate that AEBP1 is important in regulating CAF function in the TME. Inhibiting AEBP1, therefore, may be a novel strategy in targeting CAF tumor-supporting activity and overcoming cancer resistance to anti-PD-1 immunotherapy.

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Paracrine regulation of pancreatic cancer cell response to chemotherapy by GLI2-Collagen I signaling

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