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Migration speed of captured breast cancer subpopulations correlates with metastatic fitness

ABSTRACT: The genetic alterations contributing to migration proficiency, a phenotypic hallmark of metastatic cells required for colonizing distant organs, remain poorly defined. Here, we used single-cell magneto-optical capture (scMOCa) to isolate fast cells from heterogeneous breast cancer cell populations, based on their migratory ability alone. We show that captured fast cell subpopulations retain higher migration speed and focal adhesion dynamics over many generations due to a motility-related transcriptomic profile. Upregulated genes in fast selected cells encoded integrin subunits, proto-cadherins and numerous other genes associated with cell migration. Dysregulation of several of these genes correlated with poor survival outcomes in patients, while primary tumors established from fast cells generated a higher number of circulating tumor cells and soft tissue metastases in vivo. Subpopulations of cells selected for a highly migratory phenotype demonstrated an increased fitness for metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188224 | GEO | 2023/06/16

REPOSITORIES: GEO

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Project description:Breast cancer is the first type of cancer in term of incidence in the world with only 36% of survival at 5 years. This poor prognosis is mainly due to metastasis formation. Cell migration is a key process in nature and the understanding of its complex mechanisms has a crucial importance in biomaterials, engineering, medicine, cell biology and immunology. Cells can detect chemical and physical gradients both on surface and in solution and respond to them with oriented movement. Therefore, controlling such processes could potentially result in major advances in biochemistry and biotechnology with potential breakthroughs in metastasis treatment and tissue regeneration. After a thorough investigation on current literature, but also basing our foundations on our previous results published by Marega et al, Small (2016), this research project focusses on the integrins α5β1 and αvβ3, already known to be implicated in cell migration, angiogenesis and resistance to cell death. Such transmembrane receptors can be activated indirectly by EGFR pathway or directly by IGD type I fibronectin motifs. The influence of both integrin invalidation will be studied on cell migration in usual culture plates and on IGDQ-exposing surfaces. In this work known as PACMAN (Peptide-Assisted Cellular Migration Along eNgineered surfaces) project, we have recently shown in an in vitro model migration that IGDQ-exposing (IsoLeu-Gly-Asp-Glutamine type I Fibronectin motif) monolayers (SAMs) on gold sustain the migration of MDA-MB-231 cells by triggering Focal Adhesion Kinase. In this project, such tunable scaffolds are used to mimic the extracellular environment, being able to induce and control cell migration on an anisotropic surface. The observed migratory behavior induced by the IGDQ-bearing peptide gradient along the surface suggests the presence of cell subpopulations associated with a “stationary” or a “migratory” phenotype, the latter determining a considerable cell migration at the sub-cm length scale. Those subpopulations with a “stationary” or a “migratory” phenotype obtained was characterized by a single-cell RNA-sequencing in order to identify new pathways regulating the metastasis process. The aim of this work is to highlight the pathways implied into the integrin-dependent cell migration and to find putative therapeutic, diagnostic or prognostic targets. That will permit a better molecular stratification of tumors and will improve the therapeutic personalization.

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Migration speed of captured breast cancer subpopulations correlates with metastatic fitness

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