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Development Project 1: Force Propagation in Melanoma Cancer Progression, Steven An, Ph.D.
Melanoma is the leading cause of death from skin cancer worldwide. Although gene-environment interactions play a critical role in melanoma development, cancer morbidity and mortality are attributable to the metastatic spread of primary tumors to distant organs, culminating in multiple organ failure. In the metastatic cascade, the abilities of cancer cells to invade the extracellular matrix (ECM), to withstand shear stresses imposed by blood circulation, and to migrate through the surrounding tissue microenvironment all comprise mechanical processes that are enabled, in large part, by material properties of the underlying cytoskeleton (CSK). CSK is the network of biopolymers that confers mechanical structure, as well as transmits physical forces to and from the ECM in the surrounding tissue microenvironment. However, mechanisms by which a cancer cell senses, integrates, and initiates its network of physical forces during its pilgrimage from adhesion to migration and invasion of the tissue remain unexplained. We intend to integrate two fundamental ideas in the biological sciences (i.e. CSK) and the material sciences (i.e. glasses) in order to make a paradigm shift in tumor metastasis. Based on our preliminary studies, here we consider the CSK of the living human melanocyte as a phase of soft glassy material (described below) and, employing an entirely new experimental approach, explore the mechanism of force propagation in melanoma cancer progression. Our central hypothesis is that the malignant transformation of melanoma cells exists along a continuous spectrum of ‘solid-like’ and ‘fluid-like’ states of their CSK lattice. We will test this hypothesis with the following two experimental aims.
Aim 1. We will test the prediction that the metastatic potential of melanoma is explicitly linked to the effective matrix temperature x(defined below)and that a shift in this empirical parameter x initiates force propagation and drives melanoma cell migration (glassy cytoskeleton transition in melanoma).
Aim 2. We will measure the spatiotemporal changes in cell traction forces exerted by melanoma cell lines derived from ‘minimally invasive’, ‘more aggressive’, and ‘metastatic’ melanomas in response to a transient stretch of duration and magnitude corresponding to the physiological range (physical regulation of melanoma force propagation).