TGFβ Signaling Activated by Cancer-Associated Fibroblasts Determines the Histological Signature of Lung Adenocarcinoma.
TGFβ Signaling Activated by Cancer-Associated Fibroblasts Determines the Histological Signature of Lung Adenocarcinoma.
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DOI：
10.1158/0008-5472.can-20-3941
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发表时间：
2021-09-15
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影响因子：
11.2
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中科院分区：
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CAF 分泌 TGFβ 诱导肺癌细胞中实性细胞向腺泡细胞的转变，展示了肿瘤微环境如何影响肺腺癌的组织学模式和肿瘤异质性。侵袭性肺腺癌 (LADC) 在组织学上可分为鳞状、腺泡状、乳头状、微乳头状或实性。大多数 LADC 肿瘤表现出几种组织学亚型，其异质性与治疗耐药性相关。我们在此报告，在免疫缺陷小鼠中，人类 LADC 细胞形成具有不同组织学特征的肿瘤，根据发育部位，表达 MUC5AC 的实体型或表达细胞角蛋白 7 (CK7) 的腺泡型肿瘤，并且肿瘤微环境可以诱导实体到腺泡转变 (SAT)。 TGFβ-Smad 信号通路在腺泡型肿瘤的肿瘤细胞和基质细胞中均被激活。源自腺泡型肿瘤的永生化癌症相关成纤维细胞 (CAF) 在与 LADC 细胞的 3D 共培养中诱导 SAT。外源性 TGFβ1 或 TGFβ1 活性形式的过表达会增加 LADC 细胞中 CK7 的表达并减少 MUC5AC 的表达，并且 CAF 中 Tgfb1 mRNA 的敲低会减弱 SAT 的诱导。 RNA 测序分析表明血管生成和中性粒细胞募集与体内 SAT 相关。我们的数据表明，CAF 介导的旁分泌 TGFβ 信号传导诱导肿瘤组织重塑并决定 LADC 的组织学模式，从而导致肿瘤异质性。 CAF 分泌 TGFβ 诱导肺癌细胞中实性细胞向腺泡细胞的转变，展示了肿瘤微环境如何影响肺腺癌的组织学模式和肿瘤异质性。
CAFs secrete TGFβ to induce a solid-to-acinar transition in lung cancer cells, demonstrating how the tumor microenvironment influences histological patterns and tumor heterogeneity in lung adenocarcinoma. Invasive lung adenocarcinoma (LADC) can be classified histologically as lepidic, acinar, papillary, micropapillary, or solid. Most LADC tumors manifest several of these histological subtypes, with heterogeneity being related to therapeutic resistance. We report here that in immunodeficient mice, human LADC cells form tumors with distinct histological features, MUC5AC-expressing solid-type or cytokeratin 7 (CK7)-expressing acinar-type tumors, depending on the site of development, and that a solid-to-acinar transition (SAT) could be induced by the tumor microenvironment. The TGFβ-Smad signaling pathway was activated in both tumor and stromal cells of acinar-type tumors. Immortalized cancer-associated fibroblasts (CAF) derived from acinar-type tumors induced SAT in 3D cocultures with LADC cells. Exogenous TGFβ1 or overexpression of an active form of TGFβ1 increased CK7 expression and reduced MUC5AC expression in LADC cells, and knockdown of Tgfb1 mRNA in CAFs attenuated SAT induction. RNA-sequencing analysis suggested that angiogenesis and neutrophil recruitment are associated with SAT in vivo. Our data indicate that CAF-mediated paracrine TGFβ signaling induces remodeling of tumor tissue and determines the histological pattern of LADC, thereby contributing to tumor heterogeneity. CAFs secrete TGFβ to induce a solid-to-acinar transition in lung cancer cells, demonstrating how the tumor microenvironment influences histological patterns and tumor heterogeneity in lung adenocarcinoma.