Collective directional migration drives the formation of heteroclonal cancer cell clusters

• Published in: Molecular oncology Vol. 17; no. 9; pp. 1699 - 1725
• Main Authors: Palmiero, Miriam, Cantarosso, Isabel, di Blasio, Laura, Monica, Valentina, Peracino, Barbara, Primo, Luca, Puliafito, Alberto
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.09.2023; John Wiley and Sons Inc; Wiley
• Subjects: 1-Phosphatidylinositol 3-kinase; 3D models; Actin; AKT protein; Cancer; Cancer and Oncology; Cell adhesion & migration; Cell culture; collective migration; Culture media; Cytoskeleton; directional migration; Growth factors; heterogeneity; imaging; Metastasis; Myosin; Penicillin; Protein Structure and Function; protrusions; Spheroids; TOR protein; United States > US; collective migration; directional migration; 3D models; imaging; heterogeneity; protrusions
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13369

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.