Collective directional migration drives the formation of heteroclonal cancer cell clusters

Author:

Palmiero Miriam12,Cantarosso Isabel12,di Blasio Laura12,Monica Valentina12,Peracino Barbara3,Primo Luca12,Puliafito Alberto12ORCID

Affiliation:

1. Candiolo Cancer Institute, FPO – IRCCS Candiolo Italy

2. Department of Oncology University of Turin Candiolo Italy

3. Department of Clinical and Biological Sciences San Luigi Hospital, University of Turin Orbassano Italy

Abstract

Metastasisation occurs through the acquisition of invasive and survival capabilities that allow tumour cells to colonise distant sites. While the role of multicellular aggregates in cancer dissemination is acknowledged, the mechanisms that drive the formation of multiclonal cell aggregates are not fully elucidated. Here, we show that cancer cells of different tissue of origins can perform collective directional migration and can actively form heteroclonal aggregates in 3D, through a proliferation‐independent mechanism. Coalescence of distant cell clusters is mediated by subcellular actin‐rich protrusions and multicellular outgrowths that extend towards neighbouring aggregates. Coherently, perturbation of cytoskeletal dynamics impairs collective migration while myosin II activation is necessary for multicellular movements. We put forward the hypothesis that cluster attraction is mediated by secreted soluble factors. Such a hypothesis is consistent with the abrogation of aggregation by inhibition of PI3K/AKT/mTOR and MEK/ERK, the chemoattracting activity of conditioned culture media and with a wide screening of secreted proteins. Our results present a novel collective migration model and shed light on the mechanisms of formation of heteroclonal aggregates in cancer.

Funder

Associazione Italiana per la Ricerca sul Cancro

Fondazione Umberto Veronesi

Università degli Studi di Torino

Publisher

Wiley

Subject

Cancer Research,Genetics,Molecular Medicine,General Medicine,Oncology

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