U54CA261701

Center for Systems-Level Study of Metastasis - Project Summary:

Metastatic disease is a complex, dynamic, and emergent process that requires collective and coordinated interactions between many cell types, metabolites, and the host. There is substantial clinico-pathologic and experimental evidence for critical roles of neural innervation, lymphatic interactions, metabolites, and endothelial cells in regulating metastatic progression by altering cancer and immune cell functions. As such, these cellular interactions likely shape metastatic progression, responses to therapy, and metastatic dissemination. However, we have a limited understanding of how these components coordinately regulate metastatic progression.

This application describes a series of highly innovative multidisciplinary molecular, cell-biological, metabolic, massively-parallel single-cell sequencing, and organismal methods applied towards defining the dynamic and emergent mechanisms by which neural cells, lymphatics, immune cells, and metabolites interact to coordinately regulate metastatic progression - contributing to a systems-level understanding of metastasis.

We aim to:

(I) Define the role of neural innervation on metastatic progression by characterizing neuro-tumor and neuro-immune interactions and identifying neural signals and their pro-metastatic mechanisms of action.

(II) Determine how endothelial cells regulate innervation of metastatic tumors.

(III) Define the role of regionalized lymphatic interactions in driving metastatic progression and anti-metastatic immunity.

(IV) Assess the role of neuro-immune and neuro-epithelial interactions on early metastatic dissemination and colonization.

(V) Identify metabolite and protein signals that drive metastatic colonization.

(VI) Discover tumoral transcription factors and RNA-binding proteins that act downstream of neural and metabolic signals to drive emergent pro-metastatic gene expression programs.

(VII) Determine the impact of standard chemotherapy on these diverse cellular interactions and metabolic determinants of metastatic progression.

Our proposed MetNet Center will enhance our understanding of how interactions and crosstalk between cancer cells with nervous system cells, lymphatics, vasculature, and immune cells enable the emergence of metastatic disease. We will also assess how therapy impacts specific cell-cell and metabolic interactions of metastatic cells and provide insights into the impact of specific cellular interactions in the primary microenvironment on metastatic dissemination, including early dissemination.

These findings will generate an integrated, systems-level understanding of metastasis, enabling the development of a new generation of anti-cancer therapies that prevent critical emergent coordinated pro-metastatic interactions.

Rockefeller University

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]

New York, New York 100656307 United States

Single Zip Code

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

Amendment Since initial award the total obligations have increased 406% from $1,696,261 to $8,585,829.