Center for Mechanical Determinants of Organ-Selective Metastatic Colonization, Dormancy and Outgrowth (U54)
The objective of the Center for Mechanical Determinants of Organ-Selective Metastatic Colonization, Dormancy and Outgrowth is to address the key mechanisms employed by cancer tumor cells (TCs) as they are exposed to a series of physical stressors, with some small fraction surviving, entering into a remote tissue, and either proliferating or entering a dormant state thereby leading to immediate or delayed metastatic disease.
Recent data show that these metastatic tumors are implicated in over 90% of the deaths due to cancer. Through the use of first-in field in vitro, in vivo and in silico models and technologies that enable the modeling of several of the critical steps in metastatic cancer and responses to molecular intervention, we analyze, quantify and identify cellular phenotypes that facilitate the survival of TCs through the latter stages of the metastatic cascade. We focus on physical factors that continuously act on TCs and their environment and the changes in gene expression profile and chromatin dynamics that occur as a result while recognizing that physical stresses act in close concert with the biochemical signaling between circulating TCs (CTCs), other cells in the circulation, and stromal cells in the metastatic organ.
Central to these studies are parallel and supporting efforts in computational modeling, advanced transcriptomic analysis, and high-resolution imaging of chromatin dynamics to capture and further probe the mechanisms of disease progression and changes in the transcriptome and chromatin structure resulting from various stressors.
Research
Despite tremendous advances in our understanding over the years, cancer continues to rank as a major cause of mortality in the US, second only to cardiac disease, with metastatic complications being responsible for over 90% of these deaths. There are numerous reasons for this, but one substantial barrier to progress has been developing in vitro and in vivo models that can be reliably accessed and that faithfully replicate the multistep process of metastasis (in humans).
A major effort is therefore needed to develop new models, new understanding, and new therapeutics. Whereas individual models are suited to study isolated steps of metastatic organ colonization, including tumor cell (TC) transport in the circulation, arrest in a peripheral organ, extravasation and perivascular survival followed by dormancy and/or outgrowth, the integration of each step and the associated molecular and mechanical changes in the TC require a multipronged approach. The Center addresses this need through the use of complementary state-of-the-art technologies, including organotypic perfused vascular organ models in vitro, preclinical mouse models and intravital microscopy, and mechanistic integration by molecular analyses and computational modeling, that facilitate the modeling of several of the critical steps in metastatic cancer. The focus is on physical factors that continuously act on TCs and their environment and the phenotypic changes that occur as a result. The Center draws upon computational modeling and molecular intervention to capture and further probe the mechanisms of disease progression and changes in the transcriptome and chromatin structure resulting from various stressors.
An emphasis of the Center is to identify how each physical stressor affects the probability of survival and formation of a metastatic tumor, and identify strategies to promote cell death and minimize the emergence of dormancy and/or outgrowth. The major focus is on interactions and crosstalk between metastatic cells and the vasculature and physical environment through comprehensive modeling of physical stresses in the metastatic niche and their consequences on TC phenotype. The Center also investigates the effects of the mechanical history of tumor cells related to arrest and extravasation on the acquisition of, maintenance of, or emergence of metastatic dormancy and the adaptive mechanisms of metastatic cells to targeted intervention.