Mechanical stress during confined migration causes aberrant mitoses and c-MYC amplification.
Giulia BastianelloGururaj Rao KidiyoorConor LowndesQingsen LiRaoul BonnalJeffrey GodwinFabio IannelliLorenzo DrufucaRamona BasonFabrizio OrsenigoDario ParazzoliMattia PavaniValeria CancilaStefano PiccoloGiorgio ScitaAndrea CilibertoClaudio TripodoMassimiliano PaganiMarco FoianiPublished in: Proceedings of the National Academy of Sciences of the United States of America (2024)
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 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 oncogenic transcriptional signature via c-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. 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 amplification is strongly linked to metastatic tumors.
Keyphrases
- copy number
- genome wide
- squamous cell carcinoma
- small cell lung cancer
- mitochondrial dna
- dna damage
- cell migration
- induced apoptosis
- transcription factor
- dna damage response
- dna methylation
- gene expression
- cell cycle arrest
- cell cycle
- stress induced
- high resolution
- dna repair
- neuropathic pain
- spinal cord injury
- heat stress
- heat shock
- electronic health record
- big data
- oxidative stress
- endoplasmic reticulum stress
- deep learning
- spinal cord
- nucleic acid
- artificial intelligence
- squamous cell
- cell death
- single molecule
- hip fracture