U54CA261694

Mechanical Determinants of Organ-Selective Metastatic Colonization, Dormancy, and Outgrowth - Overall: Project Summary

Metastatic disease is responsible for the vast majority of cancer mortality. Understanding of the fundamental mechanisms leading to metastatic cancer has been hampered by the need for models that replicate the step-wise metastatic process in vivo, yet are amenable to tight control and facilitate high-resolution, time-lapse imaging and quantitative analysis of cell behavior.

Over the past decade, our team has developed in vivo and in vitro methods capable of simulating many steps of the metastatic cascade including tumor cell invasion, intravasation, trapping in the microcirculation or adhesion to the vessel walls, and extravasation into the surrounding extracellular matrix. In parallel, we have developed computational studies that provided detailed insights often not possible through experiments.

This collective prior work has shed new light on central aspects of single-cell and collective cell behavior during metastasis and identified mechanical adaptations and vulnerabilities of the tumor cell with promise for targeted interventions.

The goal of our proposed U54 Center is to employ these developed assays and methods in combination with new measurement techniques to interrogate the full spectrum of stressors experienced by tumor cells in the metastatic niche during arrest and extravasation and couple these with parallel studies of changes in chromatin structure and the transcriptome of tumor cells (Core B). These changes are critical to mechano-adaptation of the tumor cells towards an organ-preferential initiation of a metastatic colony or transition to dormancy.

A hallmark of our proposed Center is the use of state-of-the-art in vitro (Project 1) and in vivo (Project 2) experiments and computation (Core A) to uncover and probe the factors that ultimately determine tumor cell fate. We anticipate that such integrated studies will provide new insights into metastatic cancer, not possible by the use of any method alone, and enhance our ability to identify and screen for new therapies to inhibit the tendency for metastatic spread of disease.

Massachusetts Institute Of Technology

TO PROVIDE AN ORGANIZATIONAL FOCUS AND STIMULUS FOR THE HIGHEST QUALITY CANCER RESEARCH THAT EFFECTIVELY PROMOTES INTERDISCIPLINARY CANCER RESEARCH AIMED TOWARD THE ULTIMATE GOAL OF REDUCING CANCER INCIDENCE, MORTALITY AND MORBIDITY. THE CANCER CENTER SUPPORT GRANT (CCSG) PROVIDES THE RESOURCES AND INFRASTRUCTURE TO FACILITATE THE COORDINATION OF INTERDISCIPLINARY PROGRAMS ACROSS A BROAD SPECTRUM OF RESEARCH FROM BASIC LABORATORY RESEARCH TO CLINICAL INVESTIGATION TO POPULATION SCIENCE. THE CCSG SUPPORTS SALARIES FOR SCIENTIFIC LEADERSHIP OF THE CENTER, SHARED RESOURCES FOR FUNDED CENTER INVESTIGATORS, CERTAIN ADMINISTRATIVE COSTS, PLANNING AND EVALUATION, AND DEVELOPMENTAL FUNDS FOR NEW RECRUITMENTS AND FEASIBILITY STUDIES.

93.397 - Cancer Centers Support Grants

National Cancer Institute (NCI) [HHS - NIH]

Massachusetts United States

State-Wide

Metastasis Research Network (U54 Clinical Trial Not Allowed) (RFA-CA-20-029)

Amendment Since initial award the total obligations have increased 328% from $1,542,971 to $6,598,320.