Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin.
Multiomic analysis reveals conservation of cancer-associated fibroblast phenotypes across species and tissue of origin.
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DOI：
10.1016/j.ccell.2022.09.015
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发表时间：
2022-11-14
期刊：
影响因子：
50.3
通讯作者：
Longaker, Michael T.
中科院分区：
文献类型：
--
作者：
Foster, Deshka S.;Januszyk, Michael;Delitto, Daniel;Yost, Kathryn E.;Griffin, Michelle;Guo, Jason;Guardino, Nicholas;Delitto, Andrea E.;Chinta, Malini;Burcham, Austin R.;Nguyen, Alan T.;Bauer-Rowe, Khristian E.;Titan, Ashley L.;Salhotra, Ankit;Jones, R. Ellen;da Silva, Oscar;Lindsay, Hunter G.;Berry, Charlotte E.;Chen, Kellen;Henn, Dominic;Mascharak, Shamik;Talbott, Heather E.;Kim, Alexia;Nosrati, Fatemeh;Sivaraj, Dharshan;Ransom, R. Chase;Matthews, Michael;Khan, Anum;Wagh, Dhananjay;Coller, John;Gurtner, Geoffrey C.;Wan, Derrick C.;Wapnir, Irene L.;Chang, Howard Y.;Norton, Jeffrey A.;Longaker, Michael T.
癌症相关成纤维细胞（CAFs）是实体肿瘤微环境不可或缺的一部分。单细胞rna测序曾被认为是相对统一的基质生成细胞群，但它揭示了CAF的多种表型。在这里，我们通过综合多组学方法进一步探讨了CAF异质性。利用配对的同细胞染色质可及性和转录组分析，我们在复杂的空间转录组学和蛋白质组学景观中对CAF亚群进行了综合分析，以确定三种超簇-稳态样（SSL），机械反应性（MR）和免疫调节（IM） CAF。这些超簇在多个组织类型和物种中被重述。选择性破坏潜在的机械力或免疫检查点抑制治疗导致CAF亚群分布的变化并影响肿瘤生长。因此，CAF超星系团之间的平衡可能具有相当大的平移意义。总的来说，这项研究扩展了我们对CAF生物学的理解，确定了CAF分化的调控途径，并以一种物种和肿瘤不可知的方式阐明了治疗靶点。Foster等人通过肿瘤发展整合了癌症相关成纤维细胞（CAFs）在空间和时间上的表观基因组、转录组和蛋白质组学变化。CAF超簇-稳态样（SSL），机械反应性（MR）和免疫调节(IM) -概括了组织类型和物种。免疫治疗或破坏机械转导会改变CAF分布，提示“推拉”动态。
Cancer associated fibroblasts (CAFs) are integral to the solid tumor microenvironment. Once thought to be a relatively uniform population of matrix-producing cells, single-cell RNA-sequencing has revealed diverse CAF phenotypes. Here, we further probed CAF heterogeneity with a comprehensive multi-omics approach. Using paired, same-cell chromatin accessibility and transcriptome analysis, we provided 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 were recapitulated across multiple tissue types and species. Selective disruption of underlying mechanical force or immune checkpoint inhibition therapy resulted in shifts in CAF subpopulation distributions and impacted 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 therapeutic targets in a species- and tumor-agnostic manner. Foster et al. integrate epigenomic, transcriptomic and proteomic changes in cancer associated fibroblasts (CAFs) both spatially and temporally through tumor development. CAF superclusters – steady state-like (SSL), mechanoresponsive (MR), and immunomodulatory (IM) – are recapitulated across tissue types and species. Immunotherapy or disruption of mechanotransduction shifts CAF distributions, suggesting a “push-pull” dynamic.
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影响因子：
6
作者：
Garcia PE;Scales MK;Allen BL;Pasca di Magliano M
通讯作者：
Pasca di Magliano M
影响因子：
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作者：
Mascharak S;Talbott HE;Januszyk M;Griffin M;Chen K;Davitt MF;Demeter J;Henn D;Bonham CA;Foster DS;Mooney N;Cheng R;Jackson PK;Wan DC;Gurtner GC;Longaker MT
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作者：
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通讯作者：
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作者：
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Eliceiri KW