Mesenchymal Lineage Heterogeneity Underlies Nonredundant Functions of Pancreatic Cancer-Associated Fibroblasts.
Mesenchymal Lineage Heterogeneity Underlies Nonredundant Functions of Pancreatic Cancer-Associated Fibroblasts.
复制标题
间充质谱系异质性是胰腺癌相关的成纤维细胞的非冗余功能。
DOI：
10.1158/2159-8290.cd-21-0601
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发表时间：
2022-03
期刊：
影响因子：
28.2
通讯作者：
Sherman MH
中科院分区：
文献类型：
--
作者：
Helms EJ;Berry MW;Chaw RC;DuFort CC;Sun D;Onate MK;Oon C;Bhattacharyya S;Sanford-Crane H;Horton W;Finan JM;Sattler A;Makar R;Dawson DW;Xia Z;Hingorani SR;Sherman MH
对特定CAF群体的追踪和消融显示，来自特定起源细胞的数量较小的CAF亚型在建立胰腺肿瘤微环境方面发挥着独特的作用。癌症相关成纤维细胞(CAF)的异质性越来越受到重视，但不同的CAF亚型的起源和功能仍然知之甚少。在胰腺导管腺癌(PDAC)中，丰富且转录多样性的CAF细胞群被认为起源于一种常见的起源细胞，即胰腺星状细胞(PSC)，其多样性是由于肿瘤微环境中细胞因子和生长因子的梯度造成的。在此，我们分析了PSCs在体内肿瘤进展过程中的分化和功能。与预期相反，我们发现PSC产生了PDAC CAF的一个数字子集。在宿主组织内靶向消融PSC来源的CAF揭示了这种已定义的CAF群体在塑造PDAC微环境中的非冗余功能，包括产生特定的细胞外基质成分和组织硬度调节。总之，这些发现将不同来源细胞的间质进化与PDAC CAF之间的转录异质性联系在一起，并展示了明确细胞来源的CAF的独特功能。通过跟踪和消融特定的CAF群体，我们发现来自特定起源细胞的数量较小的CAF亚型在建立胰腺肿瘤微环境中发挥着独特的作用。结合以前的研究，这项工作表明，间充质谱系的异质性和信号梯度使PDAC CAF多样化。见Cukierman的相关评论，第296页。本文在本期特写中重点介绍，第275页
Tracking and ablation of a specific CAF population reveals that a numerically minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor microenvironment. Cancer-associated fibroblast (CAF) heterogeneity is increasingly appreciated, but the origins and functions of distinct CAF subtypes remain poorly understood. The abundant and transcriptionally diverse CAF population in pancreatic ductal adenocarcinoma (PDAC) is thought to arise from a common cell of origin, pancreatic stellate cells (PSC), with diversification resulting from cytokine and growth factor gradients within the tumor microenvironment. Here we analyzed the differentiation and function of PSCs during tumor progression in vivo. Contrary to expectations, we found that PSCs give rise to a numerically minor subset of PDAC CAFs. Targeted ablation of PSC-derived CAFs within their host tissue revealed nonredundant functions for this defined CAF population in shaping the PDAC microenvironment, including production of specific extracellular matrix components and tissue stiffness regulation. Together, these findings link stromal evolution from distinct cells of origin to transcriptional heterogeneity among PDAC CAFs and demonstrate unique functions for CAFs of a defined cellular origin. By tracking and ablating a specific CAF population, we find that a numerically minor CAF subtype from a defined cell of origin plays unique roles in establishing the pancreatic tumor microenvironment. Together with prior studies, this work suggests that mesenchymal lineage heterogeneity and signaling gradients diversify PDAC CAFs. See related commentary by Cukierman, p. 296. This article is highlighted in the In This Issue feature, p. 275