Coevolution of tumor and microenvironment during colorectal cancer liver metastasis

• Applicant: Dr. Andres Rettig
• Subject Area: Gastroenterology ; Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537793645

Tumors and their microenvironment coevolve during cancer progression and metastasis. Cell-intrinsic adaptations of cancer cells and the creation of an immunesuppressive tumor microenvironment (TME) influence responses to immunotherapy. In clinical trials, primary tumors treated in the neoadjuvant setting with immune checkpoint inhibitors demonstrate up to 100% pathological response, while only 20-60% of patients with metastatic disease from the same tumor types respond. The intercellular communication circuits that enable tumor-immune coevolution and therapy resistance during tumor progression remain poorly defined. Using single-cell RNA sequencing, multiplex immunofluorescence and organoid analyses of matched biospecimen trios from normal colon, primary and metastatic colorectal cancer from 31 patients, the Ganesh laboratory at Memorial Sloan Kettering Cancer Center (MSKCC) has delineated a sequential progression of cancer cells through distinct phenotypic states (Moorman et al., in revision at Nature). Initial selection for an LGR5+ cancer stem cell state in primary tumors (1) is followed by entry into a fetal progenitor-like state during the transition from primary to metastasis-initiating cells (2) leading to microenvironment-induced differentiation into diverse, non-intestinal cell lineages in metastasis and after therapy (3).The relationship between this phenotypic plasticity of cancer cells and the coevolving TME remains unresolved. Continuous phenotypic plasticity in metastasis is further accompanied by immune cell plasticity in the metastatic TME. Employing single-cell RNA sequencing, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq), spatial transcriptomics, and novel computational algorithms, the Ganesh laboratory is identifying putative cell-cell communication networks that differ between normal colon, CRC primary tumors and matched liver metastases from the same patients. Preliminary analysis identifies a tripartite signaling circuit among metastatic cancer cells, liver sinusoidal endothelial cells and a unique population of innate-like CD8+ effector T cells in CRC liver metastasis. Leveraging patient-derived tumor-stromal co-culture models from the same clinical biospecimens that were profiled and syngeneic metastatic CRC organoid mouse models, we intend to test the hypothesis that the signaling circuit of metastatic cancer cells with liver sinusoids and innate-like T cells is critical to initiate and sustain the immune suppressive metastatic TME. Understanding the molecular circuitry will inform development of therapeutic strategies to disrupt these interactions, with the goal of improving outcomes for patients with metastatic cancer.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Dr. Karuna Ganesh