Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation

Rogava, Meri, Aprati, Tyler J, Chi, Wei-Yu, Melms, Johannes C, Hug, Clemens, Davis, Stephanie H, Earlie, Ethan M, Chung, Charlie, Deshmukh, Sachin K, Wu, Sharon, Sledge, George, Tang, Stephen, Ho, Patricia, Amin, Amit Dipak, Caprio, Lindsay, Gurjao, Carino, Tagore, Somnath, Ngo, Bryan, Lee, Michael J, Zanetti, Giorgia, Wang, Yiping, Chen, Sean, Ge, William, Melo, Luiza Martins Nascentes, Allies, Gabriele, Rösler, Jonas, Gibney, Goeffrey T, Schmitz, Oliver J, Sykes, Megan, Creusot, Rémi J, Tüting, Thomas, Schadendorf, Dirk, Röcken, Martin, Eigentler, Thomas K, Molotkov, Andrei, Mintz, Akiva, Bakhoum, Samuel F, Beyaz, Semir, Cantley, Lewis C, Sorger, Peter K, Meckelmann, Sven W, Tasdogan, Alpaslan, Liu, David, Laughney, Ashley M, Izar, Benjamin (January 2024) Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation. Nature Cancer. ISSN 2662-1347 (Public Dataset)

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Abstract

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. We found that systemic PI3K inhibition exacerbated LM burden in mice injected with Pip4k2c-deficient cancer cells through host-mediated increase in hepatic insulin levels; however, this circuit could be broken by concurrent administration of an SGLT2 inhibitor or feeding of a ketogenic diet. Thus, this work demonstrates a rare example of metastatic organotropism through co-optation of physiological metabolic cues and proposes therapeutic avenues to counteract these mechanisms.

Item Type:	Paper
Subjects:	diseases & disorders > cancer diseases & disorders Investigative techniques and equipment Investigative techniques and equipment > CRISPR-Cas9 organs, tissues, organelles, cell types and functions > organs types and functions > liver diseases & disorders > cancer > metastasis organs, tissues, organelles, cell types and functions > organs types and functions organs, tissues, organelles, cell types and functions
CSHL Authors:	Chung, Charlie Beyaz, Semir
Communities:	CSHL labs > Beyaz lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	29 January 2024
Date Deposited:	02 Feb 2024 13:42
Last Modified:	02 Feb 2024 13:42
Related URLs:	Publisher
Dataset ID:	GEO: GSE188391 GEO: GSE143812 t https://xenabrowser.net/datapages/?cohort=MET500%20(expression%20centric https://doi.org/10.21228/M8043D
URI:	https://repository.cshl.edu/id/eprint/41428

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