Meri Rogava, Tyler J Aprati, Wei-Yu Chi, Johannes C Melms, Clemens Hug, Stephanie H Davis, Ethan M Earlie, Charlie Chung, Sachin K Deshmukh, Sharon Wu, George Sledge, Stephen Tang, Patricia Ho, Amit Dipak Amin, Lindsay Caprio, Carino Gurjao, Somnath Tagore, Bryan Ngo, Michael J Lee, Giorgia Zanetti, Yiping Wang, Sean Chen, William Ge, Luiza Martins Nascentes Melo, Gabriele Allies, Jonas Rösler, Goeffrey T Gibney, Oliver J Schmitz, Megan Sykes, Rémi J Creusot, Thomas Tüting, Dirk Schadendorf, Martin Röcken, Thomas K Eigentler, Andrei Molotkov, Akiva Mintz, Samuel F Bakhoum, Semir Beyaz, Lewis C Cantley, Peter K Sorger, Sven W Meckelmann, Alpaslan Tasdogan, David Liu, Ashley M Laughney, Benjamin Izar
Liver metastasis (LM) confers poor survival and therapy resistance across cancer types, but the mechanisms of liver-metastatic organotropism remain unknown. Here, through in vivo CRISPR-Cas9 screens, we found that Pip4k2c loss conferred LM but had no impact on lung metastasis or primary tumor growth. Pip4k2c-deficient cells were hypersensitized to insulin-mediated PI3K/AKT signaling and exploited the insulin-rich liver milieu for organ-specific metastasis. We observed concordant changes in PIP4K2C expression and distinct metabolic changes in 3,511 patient melanomas, including primary tumors, LMs and lung metastases...
March 2024: Nature Cancer