Mechanical stress during confined migration causes aberrant mitoses and c-MYC amplification

• 成果类型: Article
• 署名作者: Bastianello, Giulia; Kidiyoor, Gururaj Rao; Lowndes, Conor; Li, Qingsen; Bonnal, Raoul; Godwin, Jeffrey; Iannelli, Fabio; Drufuca, Lorenzo; Bason, Ramona; Orsenigo, Fabrizio; Parazzoli, Dario; Pavani, Mattia; Cancila, Valeria; Piccolo, Stefano; Scita, Giorgio; Ciliberto, Andrea; Tripodo, Claudio; Pagani, Massimiliano; Foiani, Marco
• 署名单位: IFOM - FIRC Institute of Molecular Oncology; University of Milan; University of Palermo; University of Padua; Consiglio Nazionale delle Ricerche (CNR); Istituto di Genetica Molecolare (IGM-CNR); National University of Singapore
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9524
• DOI: 10.1073/pnas.2404551121
• 发表日期: 2024-07-16
• 关键词: chromosomal instability; dna-damage; nuclear-envelope; cell-migration; cancer-cell; oncogene amplification; gene-expression; tumor-cells; progression; deformation

摘要

Confined cell migration hampers genome integrity and activates the ATR and ATM mechano-- transduction pathways. We investigated whether the mechanical stress generated by metastatic interstitial migration contributes to the enhanced chromosomal instability observed in metastatic tumor cells. We employed live cell imaging, micro-- fluidic approaches, and scRNA-seq- seq to follow the fate of tumor cells experiencing confined migration. We found that, despite functional ATR, ATM, and spindle assembly checkpoint (SAC) pathways, tumor cells dividing across constriction frequently exhibited altered spindle pole organization, chromosome mis-- segregations, micronuclei formation, chromosome fragility, high gene copy number variation, and transcriptional de-- regulation and up-- regulation of c-MYC- MYC oncogenic transcriptional signature via c-MYC- MYC locus amplifications. In vivo tumor settings showed that malignant cells populating metastatic foci or infiltrating the interstitial stroma gave rise to cells expressing high levels of c-MYC.- MYC. Altogether, our data suggest that mechanical stress during metastatic migration contributes to override the checkpoint controls and boosts genotoxic and oncogenic events. Our findings may explain why cancer aneuploidy often does not correlate with mutations in SAC genes and why c-MYC- MYC amplification is strongly linked to metastatic tumors.