Hippo pathway in cancer cells induces NCAM1+αSMA+ fibroblasts to modulate tumor microenvironment

IF 5.2 1区生物学 Q1 BIOLOGY

Communications Biology Pub Date : 2024-10-17 DOI:10.1038/s42003-024-07041-4

Chanida Thinyakul, Yasuhisa Sakamoto, Mayuko Shimoda, Yanliang Liu, Suyanee Thongchot, Omnia Reda, Akihiro Nita, Romgase Sakamula, Somponnat Sampattavanich, Ayato Maeda, Paweenapon Chunthaboon, David Nduru, Mayumi Niimura, Yohei Kanamori, Peti Thuwajit, Keiichi I. Nakayama, Kun-Liang Guan, Yorifumi Satou, Chanitra Thuwajit, Toshiro Moroishi

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引用次数: 0

Abstract

Cancer cells adeptly manipulate the tumor microenvironment (TME) to evade host antitumor immunity. However, the role of cancer cell-intrinsic signaling in shaping the immunosuppressive TME remains unclear. Here, we found that the Hippo pathway in cancer cells orchestrates the TME by influencing the composition of cancer-associated fibroblasts (CAFs). In a 4T1 mouse breast cancer model, Hippo pathway kinases, large tumor suppressor 1 and 2 (LATS1/2), promoted the formation of neural cell adhesion molecule 1 (NCAM1)+alpha-smooth muscle actin (αSMA)+ CAFs expressing the transforming growth factor-β, which is associated with T cell inactivation and dysfunction. Depletion of LATS1/2 in cancer cells resulted in a less immunosuppressive TME, indicated by the reduced proportions of NCAM1+αSMA+ CAFs and dysfunctional T cells. Notably, similar Hippo pathway-induced NCAM1+αSMA+ CAFs were observed in human breast cancer, highlighting the potential of TME-manipulating strategies to reduce immunosuppression in cancer immunotherapy. Single-cell RNA sequencing reveals that the Hippo pathway in cancer cells influences the composition of cancer-associated fibroblasts and modulates the tumor microenvironment, thereby promoting cancer growth.

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癌细胞中的 Hippo 通路诱导 NCAM1+αSMA+ 成纤维细胞调节肿瘤微环境

癌细胞善于操纵肿瘤微环境（TME）来逃避宿主的抗肿瘤免疫。然而，癌细胞内在信号在形成免疫抑制性肿瘤微环境中的作用仍不清楚。在这里，我们发现癌细胞中的Hippo通路通过影响癌相关成纤维细胞（CAFs）的组成来协调TME。在4T1小鼠乳腺癌模型中，Hippo通路激酶、大肿瘤抑制因子1和2（LATS1/2）促进了表达转化生长因子-β的神经细胞粘附分子1（NCAM1）+α-平滑肌肌动蛋白（αSMA）+CAFs的形成，这与T细胞失活和功能障碍有关。消耗癌细胞中的LATS1/2可减少TME的免疫抑制作用，这表现在NCAM1+αSMA+ CAFs和功能障碍T细胞的比例降低。值得注意的是，在人类乳腺癌中也观察到了类似的Hippo通路诱导的NCAM1+αSMA+ CAFs，这突显了在癌症免疫疗法中利用TME调节策略减少免疫抑制的潜力。单细胞RNA测序显示，癌细胞中的Hippo通路会影响癌症相关成纤维细胞的组成，并调节肿瘤微环境，从而促进癌症生长。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Communications Biology Medicine-Medicine (miscellaneous)

CiteScore

8.60

自引率

1.70%

发文量

1233

审稿时长

13 weeks

期刊介绍： Communications Biology is an open access journal from Nature Research publishing high-quality research, reviews and commentary in all areas of the biological sciences. Research papers published by the journal represent significant advances bringing new biological insight to a specialized area of research.