U54CA261719

Evolutionary Dynamics and Microenvironmental Determinants of Metastatic Breast Cancer - Abstract/Project Summary

Metastatic breast cancer and relapse following therapy are dependent on two factors: (1) the development of intrinsic resistance to targeted and endocrine therapies, and (2) resistance to recognition and destruction of cancer cells by the immune system. The Stanford Breast Metastasis Center (SBMC) is focused on three main objectives: (1) quantifying the timing of metastatic dissemination in breast cancer, (2) functionally delineating the contribution of cellular and microenvironmental crosstalk on metastatic proclivity, and (3) characterizing the mechanisms of responses by metastatic cells to therapies.

In order to achieve these goals, mechanistic computational models that capture dynamic and emergent tumor cell intrinsic and extrinsic properties are needed, as are clinically annotated longitudinal tissue cohorts and experimental models that capture disease heterogeneity. The SBMC addresses each of these outstanding challenges.

First, we have established an unparalleled collection of clinically annotated breast cancer cohorts sampled through treatment and metastasis, including both prospective and retrospective longitudinal cohorts, with multiple metastatic sites. We leverage a living biobank of breast cancer patient-derived organoids (PDOs) from primary tumors and metastases that recapitulate the heterogeneity of disease, high-risk of relapse subgroups, and tumor-immune interactions. This greatly facilitates the proposed functional studies.

We characterize these vast tissue resources and model systems using state-of-the-art molecular profiling technologies to probe tumor tissue in situ at single cell and subcellular resolution. Specifically, with multiplexed ion beam imaging by time of flight (MIBI-TOF) and matrix-assisted laser desorption ionization imaging (MALDI), we simultaneously visualize the composition, lineage, function, and spatial distribution of tumor and stromal cell populations and perform co-registered analysis of the glycome. We integrate these data within the genomic landscape of metastatic disease and analyze them within robust machine learning and computational frameworks to uncover disease dynamics and features associated with clinical outcomes.

Lastly, we conduct genome-scale CRISPR screens in 3D breast cancer models to systematically define oncogenic dependencies, therapeutic vulnerabilities, and macrophage-tumor cell interactions. This integrated systems biology and functional genomics approach will contribute to a quantitative and mechanistic understanding of metastatic breast cancer and the dynamic relationship between tumor cells and the host, with implications for therapeutic targeting.

The Leland Stanford Junior 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]

Stanford, California 94305 United States

Single Zip Code

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

Amendment Since initial award the End Date has been shortened from 08/31/26 to 09/02/24 and the total obligations have increased 323% from $1,580,091 to $6,685,084.