Proteomic profiling identifies a stromal TGF-β1/podoplanin axis as a driver of colorectal cancer progression.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:40842027", "kind": "science-record", "revision": 2, "content_hash": "sha256:f1d94cc8107e9a324dc211a443e774007835731c290ae2bd2b0343de3a2b4b11", "created_at": "2026-11-01T20:30:56Z", "updated_at": "2026-11-01T21:35:40Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Proteomic profiling identifies a stromal TGF-β1/podoplanin axis as a driver of colorectal cancer progression.", "doi": "10.1186/s13046-025-03496-3", "pmid": "40842027", "authors": ["Silvia Di Agostino", "Davide La Padula", "Vittoria Rago", "Caterina Gabriele", "Francesco Conforti", "Elio Aprigliano", "Lidia Urlandini", "Elvira Parrotta", "Danilo Lofaro", "Francesca Vescio", "Andrea Sacconi", "Valeria Cernaro", "Giuseppe Currò", "Angela Alibrandi", "Girolamo Ranieri", "Valeria Zuccalà", "Antonio Ieni", "Marco Gaspari", "Giovanni Cuda", "Michele Ammendola", "Vittorio Abbonante"], "journal": "Journal of experimental & clinical cancer research : CR", "year": 2025, "abstract": "BACKGROUND: The 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.\nMETHODS: We 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.\nRESULTS: PDPN 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.\nCONCLUSION: This 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.", "claims": [{"id": "claim-method", "statement": "Then, significant differentially expressed proteins were identified by applying a two-sample test with a Permutation based FDR set at 0.05 (S0 was set to 0.2).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40842027", "locator": "sections[9] \"Data analysis and results reporting\" paragraph 3", "quote": "Then, significant differentially expressed proteins were identified by applying a two-sample test with a Permutation based FDR set at 0.05 (S0 was set to 0.2)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "RAW LC-MS/MS data analyzed during the current study are available from the corresponding author on request.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40842027", "locator": "sections[40] \"Data availability\" paragraph 2", "quote": "RAW LC-MS/MS data analyzed during the current study are available from the corresponding author on request."}], "state": "complete"}, {"id": "claim-target-result", "statement": "This 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.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:40842027", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "This 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."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "This 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.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:40842027"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "blocked", "blocked_on": "data:accession_absent", "description": "The GEO series accession resolves and its sample accessions are listed. 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