Karuna Ganesh, MD, PhD, is a physician-scientist focused on investigating and treating metastatic gastrointestinal cancers at Memorial Sloan Kettering Cancer Center, New York, USA. Dr. Ganesh leads a research laboratory in the Molecular Pharmacology Program, is an Attending Physician in the Gastrointestinal Oncology Service, and Director of Metastasis Research in the Center for Colorectal Cancer at Memorial Sloan Kettering. She established an institutional program to generate organoids from primary and metastatic colorectal cancer, defined metastasis-stem cells (MetSCs) as a regenerative entity distinct from tumor-initiating cancer stem cells in patients, and identified L1CAM as a marker and mediator of MetSCs. The Ganesh laboratory employs (1) hypothesis-generation using transcriptomics, epigenomics and spatial/histological analysis of patient samples of primary and metastatic gastrointestinal (GI) cancer with (2) mechanistic dissection in cutting-edge patient-derived organoid models, including co-cultures with immune/stromal cells (3) genetically engineered and orthotopic transplantation models of metastatic GI cancer. By combining murine and clinically relevant patient-derived models, we seek to define the molecular mechanisms that underpin the phenotypic plasticity of metastatic cancer, and the co-evolution of the tumor microenvironmental response to dynamically emerging tumor regenerative states. Our goal is to identify crucial signaling nodes required for metastatic plasticity that can be therapeutically target to improve outcomes for patients with advanced cancer.