Project 1: Mouse models analysis of lymph node and distant metastasis
Edgar Engleman, MD, Lead
Our prior data in a mouse model showed that by colonizing LNs, tumor cells induce tumor-specific immune tolerance through interactions with LN immune cells. Leukocytes then establish systemic immune tolerance throughout the host, seeding metastatic spread.
We identified a conserved transcriptional signature for LN metastases in humans, suggesting that the mechanisms driving LN metastasis and immune tolerance in our mouse model are relevant to human cancers. We hypothesize that local interactions between tumor cells, leukocytes, and stroma within LNs tolerize distant tissues before, during, and after LN colonization.
We expect these interactions will involve cell-cell interactions; architectural changes within LNs, tumors, and distant tissues; as well as host-wide trafficking of various cell populations. Using syngeneic mouse models, we will identify the mechanisms by which tumor-immune-stromal interactions in lymph node microenvironments using three approaches.
- Use a high-dimensional imaging platform (CODEX) to uncover longitudinal changes in local microenvironments across the host.
- Use spatial transcriptomics to determine how gene expression patterns of cells interacting with malignant cells differ from those at a distance. To confirm the functional significance of these targets identified and those identified in Project 2, we will combine CRISPR-mediated gene editing of LN metastatic tumors with cell-depletion studies and knockout mice/inducible mouse models.
- Use a novel cell-labeling platform to evaluate trafficking of leukocytes and stromal cells from tumor-involved LNs to distant sites and back to the primary tumor.