A CRISPR/Cas9-engineered ARID1A-deficient human gastric cancer organoid model reveals essential and non-essential modes of oncogenic transformation.
washington; seattle; isb
Mutations in ARID1A rank amongst the most common molecular aberrations in human cancer. However, oncogenic consequences of ARID1A mutation in human cells remain poorly defined due to lack of forward genetic models. Here, CRISPR/Cas9-mediated ARID1A knockout in primary TP53-/- human gastric organoids induced morphologic dysplasia, tumorigenicity and mucinous differentiation. Genetic Wnt/B-catenin activation rescued mucinous differentiation, but not hyperproliferation, suggesting alternative pathways of ARID1A KO-mediated transformation. ARID1A mutation induced transcriptional regulatory modules characteristic of MSI and EBV subtype human gastric cancer, including FOXM1-associated mitotic genes and BIRC5/survivin. Convergently, high-throughput compound screening indicated selective vulnerability of ARID1A-deficient organoids to inhibition of BIRC5/survivin, functionally implicating this pathway as an essential mediator of ARID1A KO-dependent early-stage gastric tumorigenesis. Overall, we define distinct pathways downstream of oncogenic ARID1A mutation, with non-essential Wnt-inhibited mucinous differentiation in parallel with essential transcriptional FOXM1/BIRC5-stimulated proliferation, illustrating the general utility of organoid-based forward genetic cancer analysis in human cells.
Institute for Systems Biology
Lo, Yuan-Hung; Kolahi, Kevin S; Du, Yuhong; Chang, Chiung-Ying; Krokhotin, Andrey; Nair, Ajay; Sobba, Walter D; Karlsson, Kasper; Jones, Sunny J; Longacre, Teri A; Mah, Amanda T; Tercan, Bahar; Sockell, Alexandra; Xu, Hang; Seoane, Jose A; Chen, Jin; Shmulevich, Ilya; Weissman, Jonathan S; Curtis, Christina; Califano, Andrea; Fu, Haian; Crabtree, Gerald R; and Kuo, Calvin J, "A CRISPR/Cas9-engineered ARID1A-deficient human gastric cancer organoid model reveals essential and non-essential modes of oncogenic transformation." (2021). Articles, Abstracts, and Reports. 4264.