Biomechanical activation of pro-metastatic programs in circulating tumour cells by vasculature constriction forces
File(s)
Author(s)
Perea Paizal, Julia
Type
Thesis
Abstract
Metastasis is the leading cause of cancer-related deaths, presenting a significant challenge due to the limited understanding of its mechanisms. During metastatic dissemination, circulating tumour cells (CTCs) encounter capillary beds, where they get lodged before extravasation and experience mechanical constriction forces. Despite evidence suggesting capillary transit may promote adaptations in CTCs, potentially driving more invasive phenotypes and selecting tumoral cells to successfully metastasise, the role of constriction forces on cell behaviour and fate remains elusive.
This research evaluated the effects of capillary constriction forces on cells transiting capillaries under fluid forces akin to those within capillary beds. A high-throughput microfluidic platform recapitulating human capillary constrictions was developed to characterise the immediate and persistent response of a panel of breast cells with different genetic signatures representative of breast cancer heterogeneity. All cell lines experienced nuclear envelope rupture when transiting narrow constrictions, but only the non-malignant cell line showed a transient increase in proliferation. Constriction forces transiently activated the cGAS/STING pathway, a key inflammation mediator, across all cell lines, with a more pronounced inflammatory response in the non-malignant cell line. This response included persistent changes in cell morphology and dysregulation of markers involved in epithelial-to-mesenchymal transition (EMT). Furthermore, constriction forces altered gene expression, especially in the non-malignant cell line, leading to persistent changes in protein expression compatible with EMT, metabolic reprogramming, and cancer progression.
These findings elucidate the critical role of mechanical constriction forces within capillary beds in shaping CTC behaviour. These promoted differential effects across cell lines, with changes towards a more malignant phenotype in non-malignant/more epithelial cell lines, while metastatic cell lines showed minimal alterations. These results suggest capillary transit may increase the malignancy of a subset of CTCs with a more epithelial phenotype, offering a potential avenue for identifying novel vulnerabilities in certain CTC populations to prevent metastatic dissemination.
This research evaluated the effects of capillary constriction forces on cells transiting capillaries under fluid forces akin to those within capillary beds. A high-throughput microfluidic platform recapitulating human capillary constrictions was developed to characterise the immediate and persistent response of a panel of breast cells with different genetic signatures representative of breast cancer heterogeneity. All cell lines experienced nuclear envelope rupture when transiting narrow constrictions, but only the non-malignant cell line showed a transient increase in proliferation. Constriction forces transiently activated the cGAS/STING pathway, a key inflammation mediator, across all cell lines, with a more pronounced inflammatory response in the non-malignant cell line. This response included persistent changes in cell morphology and dysregulation of markers involved in epithelial-to-mesenchymal transition (EMT). Furthermore, constriction forces altered gene expression, especially in the non-malignant cell line, leading to persistent changes in protein expression compatible with EMT, metabolic reprogramming, and cancer progression.
These findings elucidate the critical role of mechanical constriction forces within capillary beds in shaping CTC behaviour. These promoted differential effects across cell lines, with changes towards a more malignant phenotype in non-malignant/more epithelial cell lines, while metastatic cell lines showed minimal alterations. These results suggest capillary transit may increase the malignancy of a subset of CTCs with a more epithelial phenotype, offering a potential avenue for identifying novel vulnerabilities in certain CTC populations to prevent metastatic dissemination.
Version
Open Access
Date Issued
2024-04-06
Date Awarded
2024-07-01
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Au, Sam H.
Bakal, Chris
Sponsor
Cancer Research UK
Publisher Department
Department of Bioengineering
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)