Characterization and functional modulation of the cancer stem cell state in colorectal cancer

Abstract

Colorectal cancer (CRC) is the second leading cause of death among cancer patients in the United States and is characterized by a high degree of intratumor heterogeneity, which likely contributes to the difficulty in curative treatments and its common recurrence. Transplantation and lineage tracing studies have identified a subset of tumor cells, Lgr5+ cancer stem cells, as a driver of tumor progression in CRC, but recent studies suggest plasticity of the cancer stem cell state. Thus, the role of distinct tumor cell states in the progression of CRC remains unclear. Furthermore, no inhibitors against Wnt signaling, the most commonly mutated pathway driving CRC, have been approved for use in the clinic, underscoring the need for orthogonal approaches for the treatment of this disease. Studies have shown that activation of the Hippo transcriptional coactivator YAP inhibits Wnt in the intestine, but whether YAP behaves as a tumor suppressor in CRC by suppressing this pathway remains unknown. Here we demonstrate that activation of YAP through Hippo kinase inhibition reprograms intestinal stem cells into a wound-healing-like cell state that is low in Wnt and cannot self-renew. Leveraging this finding, we found that loss of the LATS1/2 Hippo kinases or activation of YAP is sufficient to reprogram colon cancer stem cells to this state and thereby suppress both tumor growth and initiation in organoids, patient-derived xenografts, and mouse models of primary and metastatic CRC, establishing the role of YAP as a tumor suppressor in the adult colon. Complimentary to these genetic studies, we have developed small molecule inhibitors against LATS1/2, which we found to suppress the growth of CRC organoids. Altogether, this body of work provides a deeper understanding of the mechanistic underpinnings driving progression of colorectal malignancies, paving the way for the translation of these findings to novel therapeutics.