ArticleJournal of experimental & clinical cancer research : CR2025
Proteomic profiling identifies a stromal TGF-β1/podoplanin axis as a driver of colorectal cancer progression.
Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Development and validation of a stromal myeloid-fibrotic index and a tumor-intrinsic immune evasion index for molecular stratification in colorectal cancer.Functional & integrative genomics · 2026Article
- Integrating Tumor Budding and the Invasive-Front Microenvironment in Colorectal Carcinoma: An Exploratory Histopathological Score-Based Association Study.International journal of molecular sciences · 2026Article
- Targeting phase separation: a new strategy to disrupt the stromal-immune axis in colorectal cancer.Cell communication and signaling : CCS · 2026Review
- SFTA2 reduced colorectal cancer ferroptosis promoting metastasis through regulating EMT transition by degradation of Nrf2.Food & nutrition research · 2026Article
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Authors and funding
21 authors.
Funding
Abstract
backgroundThe tumor microenvironment (TME) plays a pivotal role in the development and progression of colorectal cancer (CRC), yet the complex crosstalk among its components remains incompletely understood. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) have emerged as key regulators of CRC progression, but their specific contributions, particularly given their heterogeneity, are not fully elucidated. This study identifies podoplanin (PDPN), a transmembrane glycoprotein enriched in CAFs, as highly expressed in the CRC TME, in particular surrounding the tumor, and associated with macrophage infiltration and cancer progression.
methodsWe performed mass spectrometry-based proteomic analysis on matched CRC and adjacent normal tissues from patients to identify altered signaling pathways and protein expression. The clinical relevance of PDPN expression was evaluated in CRC samples from two independent cohorts using immunohistochemistry and immunofluorescence analysis. Publicly available data from the Gene Expression Omnibus (GEO) database were analyzed to assess the association between PDPN expression and patient survival. Functional assays using direct and indirect co-culture systems investigated the influence of macrophage infiltration on stromal PDPN expression and its effect on colon adenocarcinoma cell growth.
resultsPDPN expression was significantly elevated in the stroma of the colorectal tumor tissues compared to normal tissues and correlated with M2-like macrophage infiltration. High PDPN expression was associated with reduced relapse-free survival in CRC patients. Stromal cells pre-conditioned with M2-like macrophages upregulated PDPN and more effectively supported the growth of three colon adenocarcinoma cell lines. PDPN depletion impaired the ability of stromal cells to promote tumor cell proliferation. Mechanistically, M2-like macrophage pre-conditioning induced a TGF-β1-dependent increase in YAP/TAZ nuclear localization, RhoA/ROCK/myosin-driven cytoskeletal contractility, and extracellular matrix (ECM) production in stromal cells. Inhibition of TGF-β1 signaling or ROCK activity reduced stromal support for cancer cell growth.
conclusionThis study reveals a novel mechanism by which the TME facilitates CRC progression and highlights PDPN as a potential prognostic biomarker and therapeutic target in CRC.
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