Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer
Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer
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DOI：
10.1101/2023.10.30.564752
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发表时间：
2023-11
期刊：
影响因子：
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通讯作者：
L. Veghini;Davide Pasini;P. Delfino;Rui Fang;D. Filippini;Christian Neander;C. Vicentini;Elena Fior
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文献类型：
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作者：
L. Veghini;Davide Pasini;P. Delfino;Rui Fang;D. Filippini;Christian Neander;C. Vicentini;Elena Fior
成纤维细胞异质性越来越多地在癌症条件下被认识到。鉴于成纤维细胞对疾病进展的重要贡献，绘制成纤维细胞的异质性对于设计有效的抗癌疗法至关重要。癌相关成纤维细胞（CAFs）是胰腺导管腺癌（PDAC）中最丰富的细胞群。CAF表型是否在PDAC细胞系中有不同的特异性仍有待阐明。在这里，我们揭示了MAPK信号通路在PDAC CAF表型定义中的重要作用。我们确定myCAF转录表型是唯一依赖于熟练的MAPK信号传导。此外，显示MAPK活性升高的CAFs特异性地锚定在基底样/鳞状PDAC细胞上，并以CD8+ T细胞的频率降低来定义肿瘤亚域。我们表征了小鼠PDAC肿瘤对MAPK抑制的单细胞转录组，并鉴定了MAPKhigh CAFs的基因表达特征，这表明其具有免疫调节功能。因此，MAPKhigh CAFs的基因表达特征与几种人类癌症的不良预后相关，包括PDAC，以及免疫反应性实体肿瘤对免疫检查点抑制的反应降低。总之，我们的数据扩展了我们对CAF表型异质性的认识，并揭示了一种针对体内肌成纤维细胞CAF的新策略。
Fibroblast heterogeneity is increasingly recognised across cancer conditions. Given their important contribution to disease progression, mapping out fibroblasts’ heterogeneity is critical to devise effective anti-cancer therapies. Cancer-associated fibroblasts (CAFs) represent the most abundant cell population in pancreatic ductal adenocarcinoma (PDAC). Whether CAF phenotypes are differently specified by PDAC cell lineages remains to be elucidated. Here, we reveal an important role for the MAPK signalling pathway in the definition of PDAC CAF phenotypes. We identify the myCAF transcriptional phenotype as uniquely dependent on proficient MAPK signalling. In addition, CAFs displaying elevated MAPK activity are specifically anchored to basal-like/squamous PDAC cells and define tumour subdomains with reduced frequency of CD8+ T cells. We characterize the single-cell transcriptome of mouse PDAC tumours in response to MAPK inhibition and identify gene expression signatures of MAPKhigh CAFs, which suggest immunoregulatory functions. Accordingly, a gene expression signature of MAPKhigh CAFs correlates with poor prognosis in several human cancer conditions, including PDAC, and with reduced response to immune checkpoint inhibition in immune-reactive solid tumours. Altogether, our data expand our knowledge on CAF phenotype heterogeneity and reveal a new strategy for targeting of myofibroblastic CAFs in vivo.