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

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

doi:10.1038/s43018-023-00704-x

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

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 ZanettiYiping 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

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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.

Original language	English
Pages (from-to)	433-447
Number of pages	15
Journal	Nature Cancer
Volume	5
Issue number	3
Early online date	29 Jan 2024
DOIs	https://doi.org/10.1038/s43018-023-00704-x
State	Published - Mar 2024
Externally published	Yes

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

Funding

We sincerely thank S. H. Davis, who sadly passed away during the completion of this study, for her dedication to excellence in cancer biology research and her passion for conducting humane animal research. We also thank J. Doench (genome perturbation platform at the Broad Institute) for technical guidance on the in vivo CRISPR screen, A. V. Parent from UCSF for technical advice, and E. Choi, A. Hung, S.-H. Wilhelm and L. Hsiauo-Yun from Columbia University for technical advice. B.I. is supported by National Institute of Health grants R37CA258829, R01CA280414, R01CA266446 and U54CA274506 and by the Pershing Square Sohn Cancer Research Alliance Award, the Burroughs Wellcome Fund Career Award for Medical Scientists, a Tara Miller Melanoma Research Alliance Young Investigator Award, the Louis V. Gerstner, Jr. Scholars Program and the V Foundation Scholars Award. B.N. was supported by K00CA234950. M. Röcken is supported by Wilhelm-Sander-Stiftung (2020.100.1); DFG RO 764 15/2; Cluster of Excellence iFIT (EXC 2180) “Image-Guided and Functionally Instructed Tumor Therapies”, University of Tübingen, Germany, funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanyʼs Excellence Strategy EXC 2180-390900677. E.M.E. partially supported by NIH T32 (grant GM132083). L.C. is supported by NIH/NCI grant F30CA281104. S.F.B. is supported by Mark Foundation for Cancer Research (20-028-EDV), Oliver S. and Jennie R. Donaldson Charitable Trust, Mathers Foundation, CSHL Cancer Center Shared Resources (Animal and Histology Core Facilities) and acknowledges support by NCI Cancer Center Support grant P30CA045508. L.C.C. is supported by NCI R35 CA197588. This work was supported by NIH/NCI Cancer Center Support Grant P30CA013696 and MSTP training grant T32GM007367 (for MD/PHD Students). Metabolomics Workbench is supported by NIH grant U2C-DK119886 and OT2-OD030544 grants. The following illustrations were prepared using BioRender.com : Fig. , Fig. and Fig. .

Funders	Funder number
MSTP	OT2-OD030544, T32GM007367, U2C-DK119886
Oliver S. and Jennie R. Donaldson Charitable Trust
V Foundation Scholars Award	DFG RO 764 15/2, EXC 2180, 2020.100.1, K00CA234950
National Institutes of Health	U54CA274506, GM132083, R01CA266446, R01CA280414, R37CA258829
National Cancer Institute	F30CA281104
Burroughs Wellcome Fund
Cold Spring Harbor Laboratory	P30CA045508, R35 CA197588, P30CA013696
Pershing Square Sohn Cancer Research Alliance
Mark Foundation For Cancer Research	20-028-EDV
Deutsche Forschungsgemeinschaft	EXC 2180-390900677
Eberhard Karls Universität Tübingen

UN SDGs

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Cite this

Rogava, M., Aprati, T. J., Chi, W. Y., Melms, J. C., Hug, C., Davis, S. H., Earlie, E. M., Chung, C., Deshmukh, S. K., Wu, S., Sledge, G., Tang, S., Ho, P., Amin, A. D., Caprio, L., Gurjao, C., Tagore, S., Ngo, B., Lee, M. J., ... Izar, B. (2024). Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation. Nature Cancer, 5(3), 433-447. https://doi.org/10.1038/s43018-023-00704-x

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title = "Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation",

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.",

author = "Meri Rogava and Aprati, {Tyler J.} and Chi, {Wei Yu} and Melms, {Johannes C.} and Clemens Hug and Davis, {Stephanie H.} and Earlie, {Ethan M.} and Charlie Chung and Deshmukh, {Sachin K.} and Sharon Wu and George Sledge and Stephen Tang and Patricia Ho and Amin, {Amit Dipak} and Lindsay Caprio and Carino Gurjao and Somnath Tagore and Bryan Ngo and Lee, {Michael J.} and Giorgia Zanetti and Yiping Wang and Sean Chen and William Ge and Melo, {Luiza Martins Nascentes} and Gabriele Allies and Jonas R{\"o}sler and Gibney, {Goeffrey T.} and Schmitz, {Oliver J.} and Megan Sykes and Creusot, {R{\'e}mi J.} and Thomas T{\"u}ting and Dirk Schadendorf and Martin R{\"o}cken and Eigentler, {Thomas K.} and Andrei Molotkov and Akiva Mintz and Bakhoum, {Samuel F.} and Semir Beyaz and Cantley, {Lewis C.} and Sorger, {Peter K.} and Meckelmann, {Sven W.} and Alpaslan Tasdogan and David Liu and Laughney, {Ashley M.} and Benjamin Izar",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

month = mar,

doi = "10.1038/s43018-023-00704-x",

language = "אנגלית",

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Rogava, M, Aprati, TJ, Chi, WY, Melms, JC, Hug, C, Davis, SH, Earlie, EM, Chung, C, Deshmukh, SK, Wu, S, Sledge, G, Tang, S, Ho, P, Amin, AD, Caprio, L, Gurjao, C, Tagore, S, Ngo, B, Lee, MJ, Zanetti, G, Wang, Y, Chen, S, Ge, W, Melo, LMN, Allies, G, Rösler, J, Gibney, GT, Schmitz, OJ, Sykes, M, Creusot, RJ, Tüting, T, Schadendorf, D, Röcken, M, Eigentler, TK, Molotkov, A, Mintz, A, Bakhoum, SF, Beyaz, S, Cantley, LC, Sorger, PK, Meckelmann, SW, Tasdogan, A, Liu, D, Laughney, AM & Izar, B 2024, 'Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation', Nature Cancer, vol. 5, no. 3, pp. 433-447. https://doi.org/10.1038/s43018-023-00704-x

TY - JOUR

T1 - Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation

AU - Rogava, Meri

AU - Aprati, Tyler J.

AU - Chi, Wei Yu

AU - Melms, Johannes C.

AU - Hug, Clemens

AU - Davis, Stephanie H.

AU - Earlie, Ethan M.

AU - Chung, Charlie

AU - Deshmukh, Sachin K.

AU - Wu, Sharon

AU - Sledge, George

AU - Tang, Stephen

AU - Ho, Patricia

AU - Amin, Amit Dipak

AU - Caprio, Lindsay

AU - Gurjao, Carino

AU - Tagore, Somnath

AU - Ngo, Bryan

AU - Lee, Michael J.

AU - Zanetti, Giorgia

AU - Wang, Yiping

AU - Chen, Sean

AU - Ge, William

AU - Melo, Luiza Martins Nascentes

AU - Allies, Gabriele

AU - Rösler, Jonas

AU - Gibney, Goeffrey T.

AU - Schmitz, Oliver J.

AU - Sykes, Megan

AU - Creusot, Rémi J.

AU - Tüting, Thomas

AU - Schadendorf, Dirk

AU - Röcken, Martin

AU - Eigentler, Thomas K.

AU - Molotkov, Andrei

AU - Mintz, Akiva

AU - Bakhoum, Samuel F.

AU - Beyaz, Semir

AU - Cantley, Lewis C.

AU - Sorger, Peter K.

AU - Meckelmann, Sven W.

AU - Tasdogan, Alpaslan

AU - Liu, David

AU - Laughney, Ashley M.

AU - Izar, Benjamin

PY - 2024/3

Y1 - 2024/3

N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

Funding

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