Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?

Benoit R Gauthier,Petra I Lorenzo,Valentine Comaills

doi:10.3390/cancers14010083

Abstract

Simple SummaryMetastasis is the process that allows the seeding of tumor cells in a new organ. The migration and invasion of cancer cells involves the pulling, pushing, and squeezing of cells through narrow spaces and pores. Tumor cells need to cross several physical barriers, such as layers of basement membranes as well as the endothelium wall during the way in and out of the blood stream, to reach the new organ. The aim of this review is to highlight the role of physical compression in the success of metastasis. We will especially focus on nuclear squeezing and nuclear envelope rupture and explain how they can actively participate in the creation of genomic heterogeneity as well as supporting metastasis growth.During metastasis, invading tumor cells and circulating tumor cells (CTC) face multiple mechanical challenges during migration through narrow pores and cell squeezing. However, little is known on the importance and consequences of mechanical stress for tumor progression and success in invading a new organ. Recently, several studies have shown that cell constriction can lead to nuclear envelope rupture (NER) during interphase. This loss of proper nuclear compartmentalization has a profound effect on the genome, being a key driver for the genome evolution needed for tumor progression. More than just being a source of genomic alterations, the transient nuclear envelope collapse can also support metastatic growth by several mechanisms involving the innate immune response cGAS/STING pathway. In this review we will describe the importance of the underestimated role of cellular squeezing in the progression of tumorigenesis. We will describe the complexity and difficulty for tumor cells to reach the metastatic site, detail the genomic aberration diversity due to NER, and highlight the importance of the activation of the innate immune pathway on cell survival. Cellular adaptation and nuclear deformation can be the key to the metastasis success in many unsuspected aspects.

Highlights

In order to seed and create new metastasis in invading organs, tumor cells must travel in and out of the blood stream, defying several mechanical cues during their 2joouf r1-6 ney
In order to shuttle in and out of the blood stream, invading tumor cells need to cross the endothelial walls of blood vessels and as such are confronted by several mechanical challenges
Technological advances have allowed the isolation and study of circulating tumor cells (CTC) from patients, contributing to the detection of subpopulations that comprise intra-tumor heterogeneity. It permitted the detection of acquired mutations from metastatic sites that could be used as a diagnostic tool toward personalized medicine during the progression of the disease [95,96]

Summary

Introduction

In order to seed and create new metastasis in invading organs, tumor cells must travel in and out of the blood stream, defying several mechanical cues during their 2joouf r1-6 ney. In order to shuttle in (denoted as intravasation) and out (denoted as extravasation) of the blood stream, invading tumor cells need to cross the endothelial walls of blood vessels and as such are confronted by several mechanical challenges. These steps rely on the intrinsic properties of cancer cells such as the epigenetic state, the composition of the microenvironment, and the mechanical cues associated with this process (reviewed in [7]). These tumor capillary abnormalities might facilitate the entrance of tumor cells into the blood stream

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