Sense and Sensitivity: Physical Limits to Multicellular Sensing, Migration, and Drug Response

Abstract

Metastasis is a process of cell migration that can be collective and guided by chemical cues. Viewing metastasis in this way, as a physical phenomenon, allows one to draw upon insights from other studies of collective sensing and migration in cell biology. Here we review recent progress in the study of cell sensing and migration as collective phenomena, including in the context of metastatic cells. We describe simple physical models that yield the limits to the precision of cell sensing, and we review experimental evidence that cells operate near these limits. Models of collective migration are surveyed in order understand how collective metastatic invasion can occur. We conclude by contrasting cells' sensory abilities with their sensitivity to drugs, and suggesting potential alternatives to cell-death-based cancer therapies.Keywords: metastasis, collective behavior, gradient sensing, cell migration Metastasis is one of the most intensely studied stages of cancer progression because it is the most deadly stage of cancer. The first step of metastasis is invasion, wherein cells break away from the tumor and invade the surrounding tissue. Our understanding of metastatic invasion has benefited tremendously from genetic and biochemical approaches [25,26,36]. However, the physical aspects of metastatic invasion are still unclear [26]. We know that at a fundamental level, metastatic invasion is a physical process. Tumor cells sense and respond to chemical gradients provided by surrounding cells [4,14,51,55] or other features of the tumor environment [49,54,55] (Fig. 1A). Indeed, tumor cells are highly sensitive, able to detect a 1% difference in concentration across the cell length [55]. Sensing is ultimately a physical phenomenon. Therefore, can we build a simple physical theory to understand the sensory behavior of tumor cells, and can this physical theory inform treatment options?Metastatic invasion involves coordinated migration of tumor cells away from the tumor site. In many types of cancer, migration is collective and highly organized, involving the coherent motion of connected groups of cells [1,11,21,51] (Fig. 1B). Collective migration is ultimately a physical phenomenon, since it relies on mechanical coupling and can often be understood as emerging from simple physical interactions at the cell-to-cell level. Can we understand the collective migration of tumor cells with simple physical models?Here we review recent progress on modeling sensing and migration in cells and cell collectives. We discuss metastatic cells explicitly, and emphasize that physical insights gained from other cellular systems can inform our understanding of metastatic invasion. We focus on simple physical models and order-of-magnitude numerical estimates in order to quantitatively probe the extent of, and the limits to, cell sensory and migratory behavior. Our hope is that a more quantitative understanding of * Electronic address: amugler@purdue.edu metastatic invasion will inform treatment protocols, and to that end we conclude by discus...

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“…Chemotaxis plays a crucial role in many biological phenomena such as organism development, immune system targeting, and cancer progression [1][2][3][4]. Specifically, recent studies indicate that chemotaxis occurs during metastasis in many different types of cancer [2,[5][6][7][8][9].…”

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