Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis

Omer Goldman; Lital N Adler; Emma Hajaj; Tommaso Croese; Naama Darzi; Sivan Galai; Hila Tishler; Yarden Ariav; Dor Lavie; Liat Fellus-Alyagor; Roni Oren; Yuri Kuznetsov; Eyal David; Rami Jaschek; Chani Stossel; Oded Singer; Sergey Malitsky; Renana Barak; Rony Seger; Neta Erez; Ido Amit; Amos Tanay; Ann Saada; Talia Golan; Tamar Rubinek; Joo Sang Lee; Shay Ben-Shachar; Ido Wolf; Ayelet Erez

doi:10.1158/2159-8290.CD-22-1062

Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis

Omer Goldman, Lital N Adler, Emma Hajaj, Tommaso Croese, Naama Darzi, Sivan Galai, Hila Tishler, Yarden Ariav, Dor Lavie, Liat Fellus-Alyagor, Roni Oren, Yuri Kuznetsov, Eyal David, Rami Jaschek, Chani Stossel, Oded Singer, Sergey Malitsky, Renana Barak, Rony Seger, Neta ErezIdo Amit, Amos Tanay, Ann Saada, Talia Golan, Tamar Rubinek, Joo Sang Lee, Shay Ben-Shachar, Ido Wolf, Ayelet Erez^*

^*Corresponding author for this work

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

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Abstract

Multiple studies have identified metabolic changes within the tumor and its microenvironment during carcinogenesis. Yet, the mechanisms by which tumors affect the host metabolism are unclear. We find that systemic inflammation induced by cancer leads to liver infiltration of myeloid cells at early extrahepatic carcinogenesis. The infiltrating immune cells via IL6-pSTAT3 immune-hepatocyte cross-talk cause the depletion of a master metabolic regulator, HNF4α, consequently leading to systemic metabolic changes that promote breast and pancreatic cancer proliferation and a worse outcome. Preserving HNF4α levels maintains liver metabolism and restricts carcinogenesis. Standard liver biochemical tests can identify early metabolic changes and predict patients' outcomes and weight loss. Thus, the tumor induces early metabolic changes in its macroenvironment with diagnostic and potentially therapeutic implications for the host. SIGNIFICANCE: Cancer growth requires a permanent nutrient supply starting from early disease stages. We find that the tumor extends its effect to the host's liver to obtain nutrients and rewires the systemic and tissue-specific metabolism early during carcinogenesis. Preserving liver metabolism restricts tumor growth and improves cancer outcomes. This article is highlighted in the In This Issue feature, p. 1501.

Original language	English
Pages (from-to)	1616-1635
Number of pages	20
Journal	Cancer Discovery
Volume	13
Issue number	7
DOIs	https://doi.org/10.1158/2159-8290.CD-22-1062
Publication status	Published - 1 Jul 2023

Funding

We acknowledge and thank the Weizmann Institute for providing financial and infrastructural support. The CCR2 KO mice were kindly provided to us by Ziv Shulman (Department of System Immunology, Weizmann Institute of Science, Rehovot, Israel). We thank Eli Pikarsky, Michal Schwartz, and Yaron Carmi for their intellectual input and Tomer Meir Salame, Keren Sasson, Jarmila Sekeresova Karlova, Yael Kuperman, Reinat Nevo, and Shani Ben-Moshe for their technical guidance. We thank Eytan Ruppin and Steffen Jung for their valuable comments and suggestions. A. Erez is supported by research grants from the European Research Council (ERC818943), the Israel Science Foundation (860/18), and the Israel Cancer Research Fund (837124). A. Erez received additional support from The Moross Integrated Cancer Center, the Blumberg Family Research Fellow Chair in Honor of Talia Lynn Steckman, Manya and Adolph Zarovinsky, and the Koret Foundation. We have a paid license to use BioRender.com through the Weizmann Institute. O. Goldman reports a patent for reexpression of HNF4A to alleviate cancer-associated cachexia issued. E. Hajaj reports a patent for reexpression of HNF4A to alleviate cancer-associated cachexia pending. T. Golan reports grants and personal fees from AstraZeneca, grants from Merck, and personal fees from AbbVie, Teva, and Roche outside the submitted work. I. Wolf reports grants and personal fees from Roche, and personal fees from Novartis, Sanofi, AstraZeneca, Bristol Myers Squibb, and Beyond Cancer outside the submitted work. A. Erez reports a patent for reexpression of HNF4A to alleviate cancer-associated cachexia issued. No disclosures were reported by the other authors.

All Science Journal Classification (ASJC) codes

Oncology

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10.1158/2159-8290.CD-22-1062Licence: CC BY-NC-ND

ae_CancerDiscov_EarlyInfiltrationofInnate_PV_2023Final published version, 14.2 MBLicence: CC BY-NC-ND

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Goldman, O., Adler, L. N., Hajaj, E., Croese, T., Darzi, N., Galai, S., Tishler, H., Ariav, Y., Lavie, D., Fellus-Alyagor, L., Oren, R., Kuznetsov, Y., David, E., Jaschek, R., Stossel, C., Singer, O., Malitsky, S., Barak, R., Seger, R., ... Erez, A. (2023). Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis. Cancer Discovery, 13(7), 1616-1635. https://doi.org/10.1158/2159-8290.CD-22-1062

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title = "Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis",

abstract = "Multiple studies have identified metabolic changes within the tumor and its microenvironment during carcinogenesis. Yet, the mechanisms by which tumors affect the host metabolism are unclear. We find that systemic inflammation induced by cancer leads to liver infiltration of myeloid cells at early extrahepatic carcinogenesis. The infiltrating immune cells via IL6-pSTAT3 immune-hepatocyte cross-talk cause the depletion of a master metabolic regulator, HNF4α, consequently leading to systemic metabolic changes that promote breast and pancreatic cancer proliferation and a worse outcome. Preserving HNF4α levels maintains liver metabolism and restricts carcinogenesis. Standard liver biochemical tests can identify early metabolic changes and predict patients' outcomes and weight loss. Thus, the tumor induces early metabolic changes in its macroenvironment with diagnostic and potentially therapeutic implications for the host. SIGNIFICANCE: Cancer growth requires a permanent nutrient supply starting from early disease stages. We find that the tumor extends its effect to the host's liver to obtain nutrients and rewires the systemic and tissue-specific metabolism early during carcinogenesis. Preserving liver metabolism restricts tumor growth and improves cancer outcomes. This article is highlighted in the In This Issue feature, p. 1501.",

author = "Omer Goldman and Adler, \{Lital N\} and Emma Hajaj and Tommaso Croese and Naama Darzi and Sivan Galai and Hila Tishler and Yarden Ariav and Dor Lavie and Liat Fellus-Alyagor and Roni Oren and Yuri Kuznetsov and Eyal David and Rami Jaschek and Chani Stossel and Oded Singer and Sergey Malitsky and Renana Barak and Rony Seger and Neta Erez and Ido Amit and Amos Tanay and Ann Saada and Talia Golan and Tamar Rubinek and \{Sang Lee\}, Joo and Shay Ben-Shachar and Ido Wolf and Ayelet Erez",

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doi = "10.1158/2159-8290.CD-22-1062",

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Goldman, O, Adler, LN , Hajaj, E, Croese, T, Darzi, N, Galai, S, Tishler, H , Ariav, Y, Lavie, D, Fellus-Alyagor, L , Oren, R , Kuznetsov, Y , David, E , Jaschek, R, Stossel, C, Singer, O , Malitsky, S, Barak, R, Seger, R, Erez, N, Amit, I , Tanay, A, Saada, A, Golan, T, Rubinek, T, Sang Lee, J, Ben-Shachar, S, Wolf, I & Erez, A 2023, 'Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis', Cancer Discovery, vol. 13, no. 7, pp. 1616-1635. https://doi.org/10.1158/2159-8290.CD-22-1062

TY - JOUR

T1 - Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis

AU - Goldman, Omer

AU - Adler, Lital N

AU - Hajaj, Emma

AU - Croese, Tommaso

AU - Darzi, Naama

AU - Galai, Sivan

AU - Tishler, Hila

AU - Ariav, Yarden

AU - Lavie, Dor

AU - Fellus-Alyagor, Liat

AU - Oren, Roni

AU - Kuznetsov, Yuri

AU - David, Eyal

AU - Jaschek, Rami

AU - Stossel, Chani

AU - Singer, Oded

AU - Malitsky, Sergey

AU - Barak, Renana

AU - Seger, Rony

AU - Erez, Neta

AU - Amit, Ido

AU - Tanay, Amos

AU - Saada, Ann

AU - Golan, Talia

AU - Rubinek, Tamar

AU - Sang Lee, Joo

AU - Ben-Shachar, Shay

AU - Wolf, Ido

AU - Erez, Ayelet

PY - 2023/7/1

Y1 - 2023/7/1

N2 - Multiple studies have identified metabolic changes within the tumor and its microenvironment during carcinogenesis. Yet, the mechanisms by which tumors affect the host metabolism are unclear. We find that systemic inflammation induced by cancer leads to liver infiltration of myeloid cells at early extrahepatic carcinogenesis. The infiltrating immune cells via IL6-pSTAT3 immune-hepatocyte cross-talk cause the depletion of a master metabolic regulator, HNF4α, consequently leading to systemic metabolic changes that promote breast and pancreatic cancer proliferation and a worse outcome. Preserving HNF4α levels maintains liver metabolism and restricts carcinogenesis. Standard liver biochemical tests can identify early metabolic changes and predict patients' outcomes and weight loss. Thus, the tumor induces early metabolic changes in its macroenvironment with diagnostic and potentially therapeutic implications for the host. SIGNIFICANCE: Cancer growth requires a permanent nutrient supply starting from early disease stages. We find that the tumor extends its effect to the host's liver to obtain nutrients and rewires the systemic and tissue-specific metabolism early during carcinogenesis. Preserving liver metabolism restricts tumor growth and improves cancer outcomes. This article is highlighted in the In This Issue feature, p. 1501.

AB - Multiple studies have identified metabolic changes within the tumor and its microenvironment during carcinogenesis. Yet, the mechanisms by which tumors affect the host metabolism are unclear. We find that systemic inflammation induced by cancer leads to liver infiltration of myeloid cells at early extrahepatic carcinogenesis. The infiltrating immune cells via IL6-pSTAT3 immune-hepatocyte cross-talk cause the depletion of a master metabolic regulator, HNF4α, consequently leading to systemic metabolic changes that promote breast and pancreatic cancer proliferation and a worse outcome. Preserving HNF4α levels maintains liver metabolism and restricts carcinogenesis. Standard liver biochemical tests can identify early metabolic changes and predict patients' outcomes and weight loss. Thus, the tumor induces early metabolic changes in its macroenvironment with diagnostic and potentially therapeutic implications for the host. SIGNIFICANCE: Cancer growth requires a permanent nutrient supply starting from early disease stages. We find that the tumor extends its effect to the host's liver to obtain nutrients and rewires the systemic and tissue-specific metabolism early during carcinogenesis. Preserving liver metabolism restricts tumor growth and improves cancer outcomes. This article is highlighted in the In This Issue feature, p. 1501.

UR - https://www.scopus.com/pages/publications/85164255258

U2 - 10.1158/2159-8290.CD-22-1062

DO - 10.1158/2159-8290.CD-22-1062

M3 - Article

C2 - 36972357

SN - 2159-8274

VL - 13

SP - 1616

EP - 1635

JO - Cancer Discovery

JF - Cancer Discovery

IS - 7

ER -

Early Infiltration of Innate Immune Cells to the Liver Depletes HNF4α and Promotes Extrahepatic Carcinogenesis

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