Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan.
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, England, United Kingdom.
Clin Cancer Res. 2021 Apr 1;27(7):2023-2037. doi: 10.1158/1078-0432.CCR-20-3715. Epub 2021 Jan 25.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment.
We used a combination of pharmacologic inhibition, gain- and loss-of-function genetic experiments, cytometry by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC.
We found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression.
Hedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.
胰腺导管腺癌 (PDAC) 是一种致命性疾病，其特征是广泛的纤维炎症基质，其中包括丰富的癌相关成纤维细胞 (CAF) 群体。PDAC CAF 具有异质性，但这种异质性的性质尚不完全清楚。Hedgehog 途径在 PDAC 中以旁分泌的方式发挥作用，癌细胞分泌的配体向微环境中的基质细胞发出信号。先前研究 Hedgehog 信号在 PDAC 中的作用的报告相互矛盾，Hedgehog 信号交替被提出促进或限制肿瘤生长。鉴于新发现的 CAF 异质性，我们研究了 Hedgehog 信号通路抑制如何重新编程 PDAC 微环境。
我们使用药理学抑制、功能获得和功能丧失遗传实验、飞行时间细胞术和单细胞 RNA 测序的组合来研究 Hedgehog 信号在 PDAC 中的作用。
我们发现 Hedgehog 信号在成纤维细胞中被独特地激活，并在肌成纤维 CAF (myCAF) 中与炎症性 CAF (iCAF) 相比被差异化上调。Sonic Hedgehog 过表达促进肿瘤生长，而用 smoothened 拮抗剂 LDE225 抑制 Hedgehog 信号通路则会损害肿瘤生长。此外，Hedgehog 信号通路抑制减少了 myCAF 的数量并增加了 iCAF 的数量，这与细胞毒性 T 细胞减少和调节性 T 细胞扩增相关，表明免疫抑制增强。
Hedgehog 信号通路抑制改变了胰腺癌细胞微环境中成纤维细胞的组成和免疫浸润。
