how do cancer cells and normal cells work together to develop metastatic disease?

Small cell lung cancer (SCLC) is a recalcitrant and highly metastatic cancer. Using SCLC metastasis as a model, Dr. Tang hopes to dissect the genetic drivers in cancer-stroma (connected tissue) interactions leading to metastatic development. Specifically, he will pursue two fundamental questions, each focusing on a distinct aspect of cancer-stroma interaction. First, he hopes to elucidate how cancer cells interact with endothelial cells (the cells that create a single cell-lining in blood vessels) to impact SCLC metastatic seeding. To track cancer-endothelium interactions in live animals, he has established a new mouse model with a genetic mutation where SCLC-contacted-endothelial cells (ECs) can be labeled with GFP (Green Florescent Protein.) He will perform multi-omics profiling on SCLC-contacted (GFP+) and non-contacted (GFP-) endothelial cells. He also plans to develop a functional endothelial cell screening platform by combining SCLC-EC interaction-dependent labeling with EC-specific genomic editing. His proposed research will identify endothelial cell-derived genetic drivers in SCLC metastatic seeding and establish new strategies for investigating cancer-stroma interactions across many cancer types in live models.

Dr. Tang also hopes to use his models to elucidate how alterations in cancer drivers impact the interactions between cancer cells and T-cells in cancer immune response. To quantify these interactions in a live model, he is developing a new method that uses tumor barcode sequencing of T cell contacted cancer cells. He plans to quantify the impact of 50 frequently mutated genes in SCLC on T cell – cancer cell interactions using combinatorial CRISPR gene inactivation in transplanted SCLC cells. Dr. Tang hopes to identify novel immune regulators in T cell – cancer cell interactions in SCLC and establish a robust novel platform to study diverse cancer-immune interactions across many primary and metastatic cancer types. His proposed research on how metastases are drawn to particular organs and how cancer cells modulate the immune-suppressive tumor microenvironment has the potential to translate into novel and precise therapies to treat metastatic cancer.