Decellularized Extracellular Matrix Scaffolds to Engineer the Dormant Landscape of Microscopic Colorectal Cancer Liver Metastasis.

Abstract

Recurrent liver-metastatic colorectal cancer contributes to high mortality. Recurrence occurs when dormant, microscopic residual disease survives initial treatment to escape dormancy. In their dormant, microscopic state within the liver, these metastatic lesions are undetectable by clinical diagnostic imaging until they form overt, chemoresistant metastases. Therefore, understanding the molecular mechanisms underlying dormancy in colorectal cancer liver metastases is a significant knowledge gap, motivating the engineering of nuanced in vitro models of disease. The current work presents an engineered model of liver-metastatic colorectal cancer dormancy. Decellularized extracellular matrix (dECM) scaffolds are used to provide microscopic colorectal cancer cell clusters with a biomimetic, 3D liver-specific architecture to colonize. Combined with nutrient deprivation and low dose chemotherapy, liver dECM significantly promotes dormancy, which manifests as slowed proliferation, nutrient/chemo-dependent G1/S and ECM-driven G2/M cell cycle arrest, diminished tumorigenicity, and robust chemotherapy resistance. The engineered dormancy signature is reversible, mimicking dormancy escape. The dECM-based model of engineered dormant colorectal cancer liver metastasis is crucial for advancing knowledge of dormancy induction and reversal, to improve therapeutics and patient survival.