通过高含量筛选发现的细胞外基质内化的新型激酶调节器可调节浸润性癌细胞的迁移。

IF 9.8 1区 生物学 Q1 Agricultural and Biological Sciences
PLoS Biology Pub Date : 2024-12-12 eCollection Date: 2024-12-01 DOI:10.1371/journal.pbio.3002930
Montserrat Llanses Martinez, Keqian Nan, Zhe Bao, Rachele Bacchetti, Shengnan Yuan, Joe Tyler, Xavier Le Guezennec, Frederic A Bard, Elena Rainero
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引用次数: 0

摘要

本文章由计算机程序翻译,如有差异,请以英文原文为准。
Novel kinase regulators of extracellular matrix internalisation identified by high-content screening modulate invasive carcinoma cell migration.

The interaction between cancer cells and the extracellular matrix (ECM) plays a pivotal role in tumour progression. While the extracellular degradation of ECM proteins has been well characterised, ECM endocytosis and its impact on cancer cell progression, migration, and metastasis is poorly understood. ECM internalisation is increased in invasive breast cancer cells, suggesting it may support invasiveness. However, current high-throughput approaches mainly focus on cells grown on plastic in 2D, making it difficult to apply these to the study of ECM dynamics. Here, we developed a high-content screening assay to study ECM uptake, based on the of use automated ECM coating for the generation of highly homogeneous ECM a pH-sensitive dye to image ECM trafficking in live cells. We identified that mitogen-activated protein kinase (MAPK) family members, MAP3K1 and MAPK11 (p38β), and the protein phosphatase 2 (PP2) subunit PPP2R1A were required for the internalisation of ECM-bound α2β1 integrin. Mechanistically, we show that down-regulation of the sodium/proton exchanger 1 (NHE1), an established macropinocytosis regulator and a target of p38, mediated ECM macropinocytosis. Moreover, disruption of α2 integrin, MAP3K1, MAPK11, PPP2R1A, and NHE1-mediated ECM internalisation significantly impaired cancer cell migration and invasion in 2D and 3D culture systems. Of note, integrin-bound ECM was targeted for lysosomal degradation, which was required for cell migration on cell-derived matrices. Finally, α2β1 integrin and MAP3K1 expression were significantly up-regulated in pancreatic tumours and correlated with poor prognosis in pancreatic cancer patients. Strikingly, MAP3K1, MAPK11, PPP2R1A, and α2 integrin expression were higher in chemotherapy-resistant tumours in breast cancer patients. Our results identified the α2β1 integrin/p38 signalling axis as a novel regulator of ECM endocytosis, which drives invasive migration and tumour progression, demonstrating that our high-content screening approach has the capability of identifying novel regulators of cancer cell invasion.

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来源期刊
PLoS Biology
PLoS Biology BIOCHEMISTRY & MOLECULAR BIOLOGY-BIOLOGY
CiteScore
15.40
自引率
2.00%
发文量
359
审稿时长
3-8 weeks
期刊介绍: PLOS Biology is the flagship journal of the Public Library of Science (PLOS) and focuses on publishing groundbreaking and relevant research in all areas of biological science. The journal features works at various scales, ranging from molecules to ecosystems, and also encourages interdisciplinary studies. PLOS Biology publishes articles that demonstrate exceptional significance, originality, and relevance, with a high standard of scientific rigor in methodology, reporting, and conclusions. The journal aims to advance science and serve the research community by transforming research communication to align with the research process. It offers evolving article types and policies that empower authors to share the complete story behind their scientific findings with a diverse global audience of researchers, educators, policymakers, patient advocacy groups, and the general public. PLOS Biology, along with other PLOS journals, is widely indexed by major services such as Crossref, Dimensions, DOAJ, Google Scholar, PubMed, PubMed Central, Scopus, and Web of Science. Additionally, PLOS Biology is indexed by various other services including AGRICOLA, Biological Abstracts, BIOSYS Previews, CABI CAB Abstracts, CABI Global Health, CAPES, CAS, CNKI, Embase, Journal Guide, MEDLINE, and Zoological Record, ensuring that the research content is easily accessible and discoverable by a wide range of audiences.
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