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pERK转换诱导的方向性模式转换促进上皮肿瘤细胞迁移。

pERK transition-induced directional mode switching promotes epithelial tumor cell migration.

作者信息

Yu Huijing, Xiao Guanli, Gu Mingyao, Zhang Liting, Xia Ming, Mo Shimin, Zhao Yuying, Wei Chaoliang

机构信息

Shenzhen Key Laboratory of Metabolism and Cardiovascular Homeostasis, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518055, China.

School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen, Guangdong 518060, China.

出版信息

Proc Natl Acad Sci U S A. 2024 Dec 17;121(51):e2318871121. doi: 10.1073/pnas.2318871121. Epub 2024 Dec 13.

DOI:10.1073/pnas.2318871121
PMID:39671185
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11665884/
Abstract

Increasing evidence suggests that tumor cells exhibit extreme plasticity in migration modes in order to adapt to microenvironments. However, the underlying mechanism for governing the migration mode switching is still unclear. Here, we revealed that epithelial tumor cells could develop a stable directional mode driven by hyperactivated ERK activity. This highly activated and dynamically changing ERK activity, called pERK transition, is crucial for inducing the switch from pauses state to directional movement and is also necessary for maintaining epithelial tumor cells in the directional mode. PERK transition integrated pERK surf, the dynamic and localized ERK activity at the leading edge. The sequential activation of RhoA and Rac1 by pERK transition played critical roles in generation of pERK surf activity through a movement feedback mechanism. PERK transition activity converted the orderly collective migration into the disordered dispersal movement, enhanced the invasiveness of epithelial tumor cells, and promoted their metastasis in immune-deficient mice. These findings revealed that the exquisite spatiotemporal organization of ERK activity orchestrates migration and invasion of tumor cells and provide evidence for the mechanism underlying migration mode switching in epithelial tumor cells.

摘要

越来越多的证据表明，肿瘤细胞在迁移模式上表现出极强的可塑性，以适应微环境。然而，控制迁移模式转换的潜在机制仍不清楚。在这里，我们发现上皮肿瘤细胞可以形成由过度激活的ERK活性驱动的稳定定向模式。这种高度激活且动态变化的ERK活性，称为pERK转换，对于诱导从暂停状态到定向运动的转变至关重要，也是使上皮肿瘤细胞维持在定向模式所必需的。PERK转换整合了pERK surf，即前沿动态且局部化的ERK活性。pERK转换对RhoA和Rac1的顺序激活通过运动反馈机制在pERK surf活性的产生中起关键作用。PERK转换活性将有序的集体迁移转变为无序的分散运动，增强了上皮肿瘤细胞的侵袭性，并促进了它们在免疫缺陷小鼠中的转移。这些发现揭示了ERK活性精确的时空组织协调肿瘤细胞的迁移和侵袭，并为上皮肿瘤细胞迁移模式转换的潜在机制提供了证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/c85234dc03ec/pnas.2318871121fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/4b9c1ebecc3b/pnas.2318871121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/3251c2b10b9f/pnas.2318871121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/f40d80676b56/pnas.2318871121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/d4bdff8fd2c9/pnas.2318871121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/d6a17a0b9bd2/pnas.2318871121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/1945dd141b66/pnas.2318871121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/c85234dc03ec/pnas.2318871121fig07.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/4b9c1ebecc3b/pnas.2318871121fig01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/3251c2b10b9f/pnas.2318871121fig02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/f40d80676b56/pnas.2318871121fig03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/d4bdff8fd2c9/pnas.2318871121fig04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/d6a17a0b9bd2/pnas.2318871121fig05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/1945dd141b66/pnas.2318871121fig06.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7e9d/11665884/c85234dc03ec/pnas.2318871121fig07.jpg

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