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During normal development of the vasculature, endothelial progenitor cells coalesce to form a primitive plexus that then undergoes sprouting angiogenesis to expand additional vessel sprouts to support circulation into avascular tissue. Subsequent remodeling of this vascular plexus drives reorganization into a hierarchal network structure with specialized arteries, capillaries, and veins. My lab is interested in understanding the signaling mechanisms that control healthy vessel growth and remodeling, and how these processes go awry under pathological conditions – such as cancer – that leads to aberrant and malformed blood vessels.
A major project in my lab is focused on comparing healthy and tumor-associated angiogenesis, with the goal of understanding the underlying mechanisms that support angiogenic activation of endothelial cells (EC). Healthy sprouting angiogenesis involves transition of EC from a quiescent, epithelial-like morphology into an invasive, proliferative, mesenchymal-like morphology while retaining certain hallmarks of EC. Specifically, some EC become activated in response to angiogenic cues to partially detach from existing blood vessels, and to proliferate and migrate to form a nascent angiogenic sprout. In brief, each sprout is capped at its leading end by a “tip” cell with numerous filopodia that appear to guide the cell’s migration into target tissue. Trailing the tip cell are “stalk” cells that proliferate to support expansion of the nascent sprout. Although both tip and stalk cells are transcriptionally and morphologically distinct from non-angiogenic EC, they fully recover endothelial gene expression and other hallmarks of EC once the new sprout is established. We recently noted that this process is reminiscent of epithelial-to-mesenchymal transition (EMT),suggesting that a related process – endothelial-to-mesenchymal transition(EndoMT) – may support healthy angiogenesis, and may be dysregulated in diseases such as cancer in which angiogenic signaling is over-activated, sprouting angiogenesis is overaggressive and uncontrolled, and resulting vessels are disorganized and heterogeneously perfused.
In previous data, we and others have shown that master EMT transcription are also expressed in EC (eg. Slug, Snail) where Slug is necessary and sufficient in in vitro 3D and organ-on-a-chip models of healthy and tumor angiogenesis. We further found that global Slug knockout (SlugKO) significantly delays healthy developmental angiogenesis; and strikingly, tumor angiogenesis is completely abolished when tumor xenografts are injected into SlugKO mice. Currently, our lab is interested in better understanding how transient changes in Slug and Snail levels during angiogenesis might lead to a partial and reversible endothelial-to-mesenchymal transition during healthy angiogenesis, and whether dysregulation of this process drives cancer angiogenesis in tumor.
Separately, my lab uses vessel-on-a-chip technology to model both vessel remodeling and vessel-stroma interactions. One application for this technology is relevant to the study of vascularized tumor-on-a-chip, which enables in vitro, real-time quantification of microtumor growth, tumor-vascular interactions, and drug screening. Our lab is currently developing collaborations with several members of the Cancer Center and other School of Medicine faculty to pursue a broad array of studies in the vascularized microtumor-on-a-chip platform, which we believe will provide important insights into both vascular and cancer biology.
Education: B.A. from Cornell University; Ph.D. from The University of Arizona
ORCID ID: 0000-0001-5703-2239
MyNCBI link: https://www.ncbi.nlm.nih.gov/sites/myncbi/1P7B8XD8hxkocw/bibliography/57089327/public/
Selected Publications:
