TGF-β1-mediated downregulation of L1CAM in pancreatic ductal adenocarcinoma drives upregulation of collagen 17A1 and MMP2, facilitating tumor invasiveness and metastasis

TL;DR

This study shows how a specific protein (L1CAM) loss in pancreatic cancer cells leads to increased collagen and tumor spread, and how a drug (Tranilast) might help.

Contribution

The study reveals a novel mechanism linking L1CAM downregulation to collagen remodeling and tumor aggressiveness in pancreatic cancer.

Findings

L1CAM downregulation by TGF-β1 increases COL17A1 and MMP2, promoting tumor invasiveness.

L1low cells correlate with fibrotic stroma, reduced drug sensitivity, and increased metastasis.

Tranilast reduces collagen and MMP2 levels while restoring L1CAM expression in PDAC.

Abstract

The highly fibrotic microenvironment of pancreatic ductal adenocarcinoma (PDAC) poses significant challenges for effective treatment, particularly in drug delivery and tumor progression. Our study investigates the role of collagen dynamics in PDAC, revealing that TGF-β1 negatively regulates the expression of L1 cell adhesion molecule (L1CAM), leading to a more invasive tumor phenotype. We identify a subset of PDAC cells with low L1CAM expression (L1low) that actively influences collagen deposition and remodeling, as evidenced by the upregulation of collagen 17A1 (COL17A1) and matrix metalloproteinase 2 (MMP2), both associated with poor prognosis. In vivo studies demonstrate that L1low cells correlate with increased collagen deposition, reduced sensitivity to gemcitabine, and heightened liver metastasis. The secretion of COL17A1 and MMP2 by these cells enhances their migratory capabilities and contributes to the formation of a fibrotic stroma that facilitates tumor progression. This interaction underscores the critical role of collagen in shaping the tumor microenvironment and promoting aggressive tumor behavior. Notably, treatment with Tranilast significantly reduced collagen deposition and MMP2 levels while promoting L1CAM expression, suggesting a therapeutic avenue for counteracting the aggressive characteristics of L1low cells. By modulating collagen dynamics and enhancing drug delivery, Tranilast may improve treatment outcomes for patients with low L1CAM-expressing tumors. Understanding the mechanisms by which L1low cells contribute to collagen secretion and tumor aggressiveness is essential for developing effective interventions in pancreatic cancer.

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