Bräutigam Konstantin, Zens Philipp, Reinhard Stefan, Rohrbach Jessica L, Leedham Simon J, Wenning Anna S, Gloor Beat, Koelzer Viktor H, Wartenberg Martin
Centre for Evolution and Cancer, Institute of Cancer Research, London, UK.
Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland.
BMC Cancer. 2025 Aug 18;25(1):1327. doi: 10.1186/s12885-025-14751-3.
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.
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.
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-B2/TGF-A 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-B2 tumours (p = 0.04), while higher tumoural TGF-B1 exhibited a trend towards increased FOXP3 cells (p = 0.08).
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.
转化生长因子（TGF）和骨形态发生蛋白（BMP）信号传导对胰腺导管腺癌（PDAC）的进展具有关键影响，而TGF-β具有矛盾的促肿瘤和抑肿瘤作用。与此观察结果并行的是，这些信号通路的特定背景依赖性、空间动态及其与肿瘤微环境（TME）的相互作用仍知之甚少。
我们对117例经根治性切除的PDAC标本的多区域组织微阵列队列进行了PDAC的空间分辨分析，每个标本包括肿瘤中心（TC）、肿瘤前沿（TF）和基质（主要是基质）组织核心。分别通过免疫组织化学和原位杂交在每个组织区室中评估蛋白质（ID1、pSMAD2）和mRNA（TGF-α、TGF-β1/2、BMP4、GREM1）表达，通过数字图像分析进行定量，并与临床病理特征相关联。
与相关基质相比，ID1在PDAC细胞中显著过表达（p < 0.01），而pSMAD2在PDAC细胞中基本不存在，但在相关基质区室中保留，特别是在TF核心中（p = 0.04）。较高的基质GREM1信号与总体肿瘤ID1蛋白表达降低相关（p = 0.02），且TGF-β2/TGF-α基质与较差的生存率显著相关（p < 0.01）。肿瘤内TGF-β2与基质pSMAD2表达呈负相关（p = 0.03），并与淋巴结受累相关（p = 0.02）。在TGF-β2肿瘤中，FOXP3调节性T细胞显著减少（p = 0.04），而较高的肿瘤TGF-β1表现出FOXP细胞增加的趋势（p = 0.08）。
我们的空间分析揭示了TGF/BMP信号传导的肿瘤内异质性及其对PDAC进展的意义。值得注意的是，基质TGF-β2成为一种预后生物标志物，而TGF-β1和ID1与不良的临床和病理特征有关。这些发现突出了TME中TGF/BMP信号微环境的重要性，对PDAC生物学具有重要意义，并可为未来治疗策略的开发提供参考。
