Is cell migration a selectable trait in the natural evolution of cancer development?

Abstract

Selective evolutionary pressure shapes the processes and genes that enable cancer survival and expansion in a tumour-suppressive environment. A distinguishing lethal feature of malignant cancer is its dissemination and seeding of metastatic foci. A key requirement for this process is the acquisition of a migratory/invasive ability. However, how the migratory phenotype is selected for during the natural evolution of cancer and what advantage, if any, it might provide to the growing malignant cells remain open issues. In this opinion piece, we discuss three possible answers to these issues. We will examine lines of evidence from mathematical modelling of cancer evolution that indicate that migration is an intrinsic selectable property of malignant cells that directly impacts on growth dynamics and cancer geometry. Second, we will argue that migratory phenotypes can emerge as an adaptive response to unfavourable growth conditions and endow cells not only with the ability to move/invade, but also with specific metastatic traits, including drug resistance, self-renewal and survival. Finally, we will discuss the possibility that migratory phenotypes are coincidental events that emerge by happenstance in the natural evolution of cancer. This article is part of a discussion meeting issue 'Forces in cancer: interdisciplinary approaches in tumour mechanobiology'.

Keywords: cancer evolution; cell migration; collective motility; endocytosis.

Figure 1.

Cell motility impact on 3D tumour growth dynamics. (a) Shape evolution of a tumour mass composed of n = 1 × 10⁷ cells as a function of the individual cell movement probability, where M = 0 indicates low or no probability of movement. The colours reflect the degree of genetic similarity. The three-dimensional tumour with M = 0 becomes spherical and small (tumour size not to scale, as tumours with M = 1 × 10⁵ are much larger than those with M = 0). As the individual cell movement probability increases, tumours lose their spherical shape and become an ensemble of small clonal balls. (b) Emergence of drug resistant clones in tumours composed of moving cells. Simulation of the growth dynamics of tumours with a higher probability of movement M = 10⁶ performed before and after administration of a typical targeted therapy at time t = 0, at t = 1 month and at t = 6 months. Drug treatments cause the loss of most of the tumour cells, and the few (probably pre-existing) resistant clones remain after one month of drug exposure. Intrinsic cell motion facilitates regrowth of the lesions to their original size six months after the treatment. Both cartoons are adapted from [13], copyright (2018), with permission from Elsevier.

Figure 2.

The ‘nuts and bolts’ of endocytic-mediated jamming transition, and its biological consequences. (1) Global perturbations of endosomal function through elevation of the master regulator of early endosomes, RAB5A, alter endosomal numbers and macropinocytic internalization [61]. (2a–c) These alterations, in turn, can cause: increased turnover of junctional proteins (e.g. E-cadherin) and junctional tension (2a); greater volume and density fluctuations, as hallmarks of liquid-to-solid-like transition (2b); and increased formation of RAC1-dependent, polarized protrusions that can extend beneath neighbouring cells (also called cryptic lamellipodia), which promotes cell self-propulsion (2c). (3) The combination of these cellular and mechanical alterations influences the kinematics of epithelial monolayers, which can be understood through mathematical modelling. The simulation is based on a self-propelled Voronoi model with two main components: the target shape of each individual cell (p₀, ratio between perimeter and square-root of the area), which is the result of competition between intracellular adhesion and cortical tension [61]; and the inverse of the reorientation time that each individual cell takes to align to the local direction of motion, τ⁻¹. These components generate a phase diagram (bottom left) that explains endocytic re-awakening of movement in jammed epithelia, in terms of a combination of large-scale directed migration in the presence of local cell re-arrangement, which lead to a ‘flocking’ (or flowing) liquid mode of migration. (4) This transition in the mode of movement enables RAB5A-expressing epithelial monolayers to flow through micro-fabricated narrow slits that mimic the confined channels encountered during interstitial migration. (5) This might promote mechanosensitive programmes, such as the YAP1/TAZ axis [65], for the acquisition of metastatic traits. Adapted from [66], copyright (2018), with permission from Elsevier.