Prof. Roberto Cerbino, Università degli Studi di Milano

Cells in a tissue are densely packed, normally with little or no possibility of mutual rearrangements between neighbours. Nevertheless, notable biological processes involve cellular rearrangements and collective migration, typical examples being wound healing, morphogenesis, and cancer invasion [1]. One of the emerging frameworks to account for this increased collective motility of cells is the so-called unjamming transition, according to which a solid-like tissue can locally "liquefy”, with cells being able to move in small groups across the tissue without losing adhesion with their neighbours [2]. We recently discovered that over-expression of the GTPase RAB5A, a master regulator of endocytosis that is normally associated to mesenchymal invasion, has a dramatic effect also on the collective motility of multicellular, normal and tumorigenic, two-dimensional cell assemblies [3]: in particular, otherwise kinetically arrested epithelial monolayers, acquire a flocking mode of locomotion which is similar to what is observed in other classes of organisms such as birds or fish. Combining experiments and simulations we find that RAB5A does so by increasing cell stiffness, cell adhesion and junctional tension, while concurrently accelerating the turnover of junctional E-cadherin [3-5]. These changes lead to an increased capability of each individual cell to align its velocity to the one of the surrounding cells and, in turn, to cellular flocking. More recently, we investigated cases with stronger connection to physiological/clinical settings, by performing experiments with a variety of three-dimensional (3D) cell collectives, including cysts, spheroids and ex-vivo slices of breast ductal carcinoma in situ [6]. Our experiments show that unjamming by flocking in 3D is accompanied by impressive coherent rotations of the collectives that eventually lead to the remodelling of the extra-cellular matrix and its subsequent invasion, providing a very powerful and general mechanism for cancer invasion and metastasis.   References   [1] V. Hakim, P. Silberzan, Rep Prog Phys 80: 076601, 2017 [2] J. A. Park, et al, Nat. Mater. 14: 1040–1048, 2015 [3] C. Malinverno, S. Corallino et al., Nat. Mater. 16: 587-596, 2017 [4] F. Giavazzi et al., J. Phys. D 50: 384003, 2017 [5] F. Giavazzi et al., Soft matter 14: 3471-3477, 2018 [6] A. Palamidessi et al, Nat. Mater. 18: 1252–1263, 2019