Spatially resolved analysis of TGF/BMP signalling in pancreatic ductal adenocarcinoma by digital pathology identifies patient subgroups with adverse outcome

BMC Cancer. 2025 Aug 18;25(1):1327. doi: 10.1186/s12885-025-14751-3.

Abstract

Background: Transforming Growth Factor (TGF) and Bone Morphogenetic Protein (BMP) signalling critically influence pancreatic ductal adenocarcinoma (PDAC) progression, with TGF-B paradoxically exerting both tumour-promoting and -suppressive effects. Parallel to this observation, the specific context-dependent, spatial dynamics of these pathways and their interaction with the tumour microenvironment (TME) remain poorly understood.

Methods: We performed a spatially resolved analysis of PDAC on a multi-region tissue microarray cohort of 117 curatively resected PDAC specimens consisting of tumour centre (TC), tumour front (TF), and stromal(-predominant) tissue cores each. Protein (ID1, pSMAD2) and mRNA (TGF-A, TGF-B1/2, BMP4, GREM1) expression were assessed in each tissue compartment by immunohistochemistry and in situ hybridization, respectively, quantified by digital image analysis, and correlated with clinicopathologic features.

Results: ID1 was significantly overexpressed in PDAC cells compared to associated stroma (p < 0.01), while pSMAD2 was largely absent in PDAC cells, but preserved among associated stroma compartments, particularly in TF cores (p = 0.04). Higher stromal GREM1 signal correlated with reduced overall tumoural ID1 protein expression (p = 0.02), and TGF-B2high/TGF-Alow stroma was significantly associated with worse survival (p < 0.01). Intratumoural TGF-B2 was inversely correlated with stromal pSMAD2 expression (p = 0.03) and was associated with lymph node involvement (p = 0.02). FOXP3+ regulatory T-cells were significantly reduced in TGF-B2high tumours (p = 0.04), while higher tumoural TGF-B1 exhibited a trend towards increased FOXP3+ cells (p = 0.08).

Conclusions: Our spatial analysis reveals intratumoural heterogeneity of TGF/BMP signalling and its significance for PDAC progression. Notably, stromal TGF-B2 emerges as a prognostic biomarker, while TGF-B1 and ID1 are implicated in adverse clinical and pathologic features. These findings highlight the importance of TGF/BMP signalling niches in the TME with implications for PDAC biology and can inform the development of future therapeutic strategies.

Keywords: AI (Artificial intelligence); Bone morphogenetic proteins; GREM1 protein; Inhibitor of differentiation protein 1 (ID1); Pancreatic neoplasms; Spatial analysis; Stromal cells; Transforming growth factors.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Bone Morphogenetic Proteins* / genetics
  • Bone Morphogenetic Proteins* / metabolism
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / metabolism
  • Carcinoma, Pancreatic Ductal* / mortality
  • Carcinoma, Pancreatic Ductal* / pathology
  • Female
  • Humans
  • Immunohistochemistry
  • Inhibitor of Differentiation Protein 1 / genetics
  • Inhibitor of Differentiation Protein 1 / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Middle Aged
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / metabolism
  • Pancreatic Neoplasms* / mortality
  • Pancreatic Neoplasms* / pathology
  • Prognosis
  • Signal Transduction
  • Smad2 Protein / metabolism
  • Tissue Array Analysis
  • Tumor Microenvironment

Substances

  • Bone Morphogenetic Proteins
  • Inhibitor of Differentiation Protein 1
  • GREM1 protein, human
  • ID1 protein, human
  • SMAD2 protein, human
  • Smad2 Protein
  • Intercellular Signaling Peptides and Proteins