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Mechanobiology of interstitial flow and "autologous chemotaxis"
Cell homing towards lymphatics: "autologous chemotaxis"
We are striving to understand how tumor cells spread via the lymphatic system and how the biophysical tumor microenvironment can influence this process. Lymphatics primarily function to maintain tissue fluid balance by collecting blood capillary filtrates via the interstitial space. This fluid flux into draining lymphatics is very slow and is referred to as interstitial flow. We have recently identified a phenomenon that we have termed autologous chemotaxis whereby a cell can receive directional cues while at the same time being the source of such cues. This phenomenon is a consequence of the subtle convective forces created in the biophysical environment. Using computer modeling and novel in vitro co-culture models we have demonstrated that slow interstitial flow is sufficient to create and amplify transcellular chemokine gradients which a cell can utilize and chemotact along; in the case of cancer, a cell can directionally chemotact along autologously generated CCL21 gradients with interstitial flow towards draining lymphatics and subsequently disseminate. The phenomenon of autologous chemotaxis is a fundamentally important mechanism in relation to cell trafficking hence we are also investigating how interstitial flow can influence immune cell transport via lymphatics and the limits of transcellular gradient detection.
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Mechanobiology of interstitial flow
We have demonstrated that fibroblasts-connective tissue cells found throughout the body-respond to interstitial flow by remodeling the extracellular matrix, resulting in both cell and collagen fiber alignment perpendicular to the direction of fluid flow. Interstitial fluid flow also induces fibroblasts to differentiate into myofibroblasts. Myofibroblasts are highly contractile and secrete a host of factors, making them important players in wound healing, but their persistent presence is also associated with pathological conditions such as fibrosis and cancer. Currently, we are tackling the question of how flow-induced myofibroblast differentiation and matrix remodeling play a significant role in the invasion and metastasis of tumors (such as breast carcinomas and melanomas). We hypothesize that changes in the interstitial flow environment around a developing tumor drive myofibroblast differentiation, and these myofibroblasts, in turn, promote cancer invasion by remodeling the stromal matrix and secreting tumor-supportive growth factors and chemokines.
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