Multiomic analysis reveals conservation of cancer associated fibroblast phenotypes across species and tissue of origin [spatial trascriptomics]

Cancer associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. Once thought to be a relatively uniform population of matrix-producing cells, the arrival of single cell RNA sequencing has revealed diverse CAF phenotypes. Here, we further probe CAF heterogeneity with a comprehensive multiome approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provide an integrated analysis of CAF subpopulations over a complex spatial transcriptomic and proteomic landscape to identify three superclusters – steady state-like (SSL), mechanoresponsive (MR) and immunomodulatory (IM) CAFs. These superclusters are recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy results in shifts in CAF subpopulation distributions and impacts tumor growth. As such, the balance among CAF superclusters may have considerable translational implications. Collectively, this research expands our understanding of CAF biology, identifying regulatory pathways in CAF differentiation and elucidating novel therapeutic targets in a species- and tumor-agnostic manner. Overall design: spatial transcriptomics data from mouse endogeneous breast tumors using the 10X Genomics Visium platform

肿瘤相关成纤维细胞（Cancer associated fibroblasts, CAFs）是实体肿瘤微环境中不可或缺的组成部分。此前学界曾认为其是一类相对均一的基质分泌细胞群，而随着单细胞RNA测序技术的应用，学界得以揭示肿瘤相关成纤维细胞存在多样的表型。本研究通过综合多组学方法进一步探究肿瘤相关成纤维细胞的异质性：采用配对的同细胞染色质开放状态与转录组分析手段，基于复杂的空间转录组与蛋白质组图谱，对肿瘤相关成纤维细胞亚群进行整合分析，最终鉴定出三类超级聚类群——稳态样（steady state-like, SSL）、机械应答型（mechanoresponsive, MR）与免疫调节型（immunomodulatory, IM）肿瘤相关成纤维细胞。这三类超级聚类群在多种组织类型与物种中均得以重现。选择性干扰潜在机械力信号或施以免疫检查点抑制治疗，可使肿瘤相关成纤维细胞亚群的分布发生改变，并对肿瘤生长产生影响。由此可见，肿瘤相关成纤维细胞三类超级聚类群间的平衡状态或具备重要的转化应用价值。综上，本研究拓展了学界对肿瘤相关成纤维细胞生物学特性的认知，明确了其分化过程中的调控通路，并以不依赖物种和肿瘤类型的方式阐明了全新的治疗靶点。研究整体设计：本研究采用10X Genomics Visium平台，获取小鼠内源性乳腺癌的空间转录组数据。