Dissecting and targeting plasticity during colorectal cancer metastasis

As cancers progress, they become increasingly aggressive; metastatic tumors are less responsive to first-line therapies than primary tumors, they acquire resistance to successive therapies, and eventually cause death. Mutations are largely conserved between primary and metastatic tumors from the same patients, suggesting that non-genetic phenotypic plasticity plays a major role in cancer progression and therapy resistance. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. In a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we find that while primary tumors largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues than their intestinal lineage-restricted primary tumor counterparts. We identify PROX1 as a repressor of non-intestinal lineage in the fetal progenitor state, whose downregulation licenses non-canonical reprogramming. These conserved mechanisms of cell state transitions during tumor progression suggest opportunities for therapeutic targeting by anticipating and intercepting tumor regenerative states.