Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation
© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc..
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.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
---|---|
Enthalten in: |
Nature cancer - 5(2024), 3 vom: 22. März, Seite 433-447 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Rogava, Meri [VerfasserIn] |
---|
Links: |
---|
Themen: |
EC 2.7.1.- |
---|
Anmerkungen: |
Date Completed 28.03.2024 Date Revised 23.04.2024 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1038/s43018-023-00704-x |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM367771705 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM367771705 | ||
003 | DE-627 | ||
005 | 20240423232119.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240130s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1038/s43018-023-00704-x |2 doi | |
028 | 5 | 2 | |a pubmed24n1384.xml |
035 | |a (DE-627)NLM367771705 | ||
035 | |a (NLM)38286827 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Rogava, Meri |e verfasserin |4 aut | |
245 | 1 | 0 | |a Loss of Pip4k2c confers liver-metastatic organotropism through insulin-dependent PI3K-AKT pathway activation |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 28.03.2024 | ||
500 | |a Date Revised 23.04.2024 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2024. The Author(s), under exclusive licence to Springer Nature America, Inc. | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 7 | |a Proto-Oncogene Proteins c-akt |2 NLM | |
650 | 7 | |a EC 2.7.11.1 |2 NLM | |
650 | 7 | |a Phosphatidylinositol 3-Kinases |2 NLM | |
650 | 7 | |a EC 2.7.1.- |2 NLM | |
650 | 7 | |a Insulin |2 NLM | |
650 | 7 | |a Pip4k2c protein, mouse |2 NLM | |
650 | 7 | |a EC 2.7.1.149 |2 NLM | |
650 | 7 | |a Phosphotransferases (Alcohol Group Acceptor) |2 NLM | |
650 | 7 | |a EC 2.7.1.- |2 NLM | |
700 | 1 | |a Aprati, Tyler J |e verfasserin |4 aut | |
700 | 1 | |a Chi, Wei-Yu |e verfasserin |4 aut | |
700 | 1 | |a Melms, Johannes C |e verfasserin |4 aut | |
700 | 1 | |a Hug, Clemens |e verfasserin |4 aut | |
700 | 1 | |a Davis, Stephanie H |e verfasserin |4 aut | |
700 | 1 | |a Earlie, Ethan M |e verfasserin |4 aut | |
700 | 1 | |a Chung, Charlie |e verfasserin |4 aut | |
700 | 1 | |a Deshmukh, Sachin K |e verfasserin |4 aut | |
700 | 1 | |a Wu, Sharon |e verfasserin |4 aut | |
700 | 1 | |a Sledge, George |e verfasserin |4 aut | |
700 | 1 | |a Tang, Stephen |e verfasserin |4 aut | |
700 | 1 | |a Ho, Patricia |e verfasserin |4 aut | |
700 | 1 | |a Amin, Amit Dipak |e verfasserin |4 aut | |
700 | 1 | |a Caprio, Lindsay |e verfasserin |4 aut | |
700 | 1 | |a Gurjao, Carino |e verfasserin |4 aut | |
700 | 1 | |a Tagore, Somnath |e verfasserin |4 aut | |
700 | 1 | |a Ngo, Bryan |e verfasserin |4 aut | |
700 | 1 | |a Lee, Michael J |e verfasserin |4 aut | |
700 | 1 | |a Zanetti, Giorgia |e verfasserin |4 aut | |
700 | 1 | |a Wang, Yiping |e verfasserin |4 aut | |
700 | 1 | |a Chen, Sean |e verfasserin |4 aut | |
700 | 1 | |a Ge, William |e verfasserin |4 aut | |
700 | 1 | |a Melo, Luiza Martins Nascentes |e verfasserin |4 aut | |
700 | 1 | |a Allies, Gabriele |e verfasserin |4 aut | |
700 | 1 | |a Rösler, Jonas |e verfasserin |4 aut | |
700 | 1 | |a Gibney, Goeffrey T |e verfasserin |4 aut | |
700 | 1 | |a Schmitz, Oliver J |e verfasserin |4 aut | |
700 | 1 | |a Sykes, Megan |e verfasserin |4 aut | |
700 | 1 | |a Creusot, Rémi J |e verfasserin |4 aut | |
700 | 1 | |a Tüting, Thomas |e verfasserin |4 aut | |
700 | 1 | |a Schadendorf, Dirk |e verfasserin |4 aut | |
700 | 1 | |a Röcken, Martin |e verfasserin |4 aut | |
700 | 1 | |a Eigentler, Thomas K |e verfasserin |4 aut | |
700 | 1 | |a Molotkov, Andrei |e verfasserin |4 aut | |
700 | 1 | |a Mintz, Akiva |e verfasserin |4 aut | |
700 | 1 | |a Bakhoum, Samuel F |e verfasserin |4 aut | |
700 | 1 | |a Beyaz, Semir |e verfasserin |4 aut | |
700 | 1 | |a Cantley, Lewis C |e verfasserin |4 aut | |
700 | 1 | |a Sorger, Peter K |e verfasserin |4 aut | |
700 | 1 | |a Meckelmann, Sven W |e verfasserin |4 aut | |
700 | 1 | |a Tasdogan, Alpaslan |e verfasserin |4 aut | |
700 | 1 | |a Liu, David |e verfasserin |4 aut | |
700 | 1 | |a Laughney, Ashley M |e verfasserin |4 aut | |
700 | 1 | |a Izar, Benjamin |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Nature cancer |d 2020 |g 5(2024), 3 vom: 22. März, Seite 433-447 |w (DE-627)NLM307030067 |x 2662-1347 |7 nnns |
773 | 1 | 8 | |g volume:5 |g year:2024 |g number:3 |g day:22 |g month:03 |g pages:433-447 |
856 | 4 | 0 | |u http://dx.doi.org/10.1038/s43018-023-00704-x |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 5 |j 2024 |e 3 |b 22 |c 03 |h 433-447 |