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核心技术专利：CN118964589B侵权必究
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发现YAP信号的非基因组驱动因素可调节结直肠癌肿瘤细胞系中的细胞可塑性。

Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines.

作者信息

Ogasawara Nobuhiko, Kano Yoshihito, Yoneyama Yosuke, Kobayashi Sakurako, Watanabe Satoshi, Kirino Sakura, Velez-Bravo Fausto D, Hong Yourae, Ostapiuk Aleksandra, Lutsik Pavlo, Onishi Iichiroh, Yamauchi Shinichi, Hiraguri Yui, Ito Go, Kinugasa Yusuke, Ohashi Kenichi, Watanabe Mamoru, Okamoto Ryuichi, Tejpar Sabine, Yui Shiro

机构信息

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.

Department of Clinical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8510, Japan.

出版信息

iScience. 2024 Feb 16;27(3):109247. doi: 10.1016/j.isci.2024.109247. eCollection 2024 Mar 15.

DOI:10.1016/j.isci.2024.109247
PMID:38439969
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10910304/
Abstract

In normal intestines, a fetal/regenerative/revival cell state can be induced upon inflammation. This plasticity in cell fate is also one of the current topics in human colorectal cancer (CRC). To dissect the underlying mechanisms, we generated human CRC organoids with naturally selected genetic mutation profiles and exposed them to two different conditions by modulating the extracellular matrix (ECM). Among tested mutation profiles, a fetal/regenerative/revival state was induced following YAP activation via a collagen type I-enriched microenvironment. Mechanistically, YAP transcription was promoted by activating AP-1 and TEAD-dependent transcription and suppressing intestinal lineage-determining transcription via mechanotransduction. The phenotypic conversion was also involved in chemoresistance, which could be potentially resolved by targeting the underlying YAP regulatory elements, a potential target of CRC treatment.

摘要

在正常肠道中，炎症可诱导胎儿/再生/复苏细胞状态。这种细胞命运的可塑性也是目前人类结直肠癌（CRC）研究的热点之一。为了剖析其潜在机制，我们构建了具有自然选择基因突变谱的人类CRC类器官，并通过调节细胞外基质（ECM）使其暴露于两种不同条件下。在测试的基因突变谱中，通过富含I型胶原蛋白的微环境激活YAP后，可诱导胎儿/再生/复苏状态。从机制上讲，通过激活AP-1和TEAD依赖的转录并通过机械转导抑制肠道谱系决定转录来促进YAP转录。表型转化也与化疗耐药有关，通过靶向潜在的YAP调控元件可能解决这一问题，这是CRC治疗的一个潜在靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/89507bb8734f/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/ee82024a5727/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/fe8dbfcace4e/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/b93fc24bddf8/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/41da65851936/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/16be7c739639/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/6cde9888fe35/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/89507bb8734f/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/ee82024a5727/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/fe8dbfcace4e/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/b93fc24bddf8/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/41da65851936/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/16be7c739639/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/6cde9888fe35/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3525/10910304/89507bb8734f/gr6.jpg

相似文献

[1]
Discovery of non-genomic drivers of YAP signaling modulating the cell plasticity in CRC tumor lines.

iScience. 2024-2-16

[2]
Collagen type I-mediated mechanotransduction controls epithelial cell fate conversion during intestinal inflammation.

Inflamm Regen. 2022-11-28

[3]
Extracellular matrix type modulates mechanotransduction of stem cells.

Acta Biomater. 2019-6-28

[4]
Type I collagen deposition via osteoinduction ameliorates YAP/TAZ activity in 3D floating culture clumps of mesenchymal stem cell/extracellular matrix complexes.

Stem Cell Res Ther. 2018-12-7

[5]
CK2-induced cooperation of HHEX with the YAP-TEAD4 complex promotes colorectal tumorigenesis.

Nat Commun. 2022-8-25

[6]
Obesity-associated leptin promotes chemoresistance in colorectal cancer through YAP-dependent AXL upregulation.

Am J Cancer Res. 2021-9-15

[7]
Loss-of-function mutations of SOX17 lead to YAP/TEAD activation-dependent malignant transformation in endometrial cancer.

Oncogene. 2023-1

[8]
Mutual dependence of the MRTF-SRF and YAP-TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics.

Genes Dev. 2017-12-1

[9]
Yap-dependent reprogramming of Lgr5(+) stem cells drives intestinal regeneration and cancer.

Nature. 2015-10-21

[10]
VASN promotes colorectal cancer progression by activating the YAP/TAZ and AKT signaling pathways via YAP.

FASEB J. 2023-1

引用本文的文献

[1]
Hippo/YAP signaling pathway in colorectal cancer: regulatory mechanisms and potential drug exploration.

Front Oncol. 2025-6-19

[2]
Phenotypic heterogeneity and plasticity in colorectal cancer metastasis.

Cell Genom. 2025-7-9

本文引用的文献

[1]
Trellis tree-based analysis reveals stromal regulation of patient-derived organoid drug responses.

Cell. 2023-12-7

[2]
Cancer cell plasticity during tumor progression, metastasis and response to therapy.

Nat Cancer. 2023-8

[3]
YAP/TAZ as master regulators in cancer: modulation, function and therapeutic approaches.

Nat Cancer. 2023-1

[4]
igv.js: an embeddable JavaScript implementation of the Integrative Genomics Viewer (IGV).

Bioinformatics. 2023-1-1

[5]
Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a vulnerability in mesenchymal colorectal cancer.

Cancer Cell. 2023-2-13

[6]
Collagen type I-mediated mechanotransduction controls epithelial cell fate conversion during intestinal inflammation.

Inflamm Regen. 2022-11-28

[7]
Metastatic recurrence in colorectal cancer arises from residual EMP1 cells.

Nature. 2022-11

[8]
Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia.

Cell Stem Cell. 2022-11-3

[9]
Phase I trial of the TNF-α inhibitor certolizumab plus chemotherapy in stage IV lung adenocarcinomas.

Nat Commun. 2022-10-15

[10]
Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus molecular classification of colorectal cancer.

Nat Genet. 2022-7

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