A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis

Fan Yao; Yalan Deng; Yang Zhao; Ying Mei; Yilei Zhang; Xiaoguang Liu; Consuelo Martinez; Xiaohua Su; Roberto R. Rosato; Hongqi Teng; Qinglei Hang; Shannon Yap; Dahu Chen; Yumeng Wang; Mei Ju May Chen; Mutian Zhang; Han Liang; Dong Xie; Xin Chen; Hao Zhu; Jenny C. Chang; M. James You; Yutong Sun; Boyi Gan; Li Ma

doi:10.1038/s41467-021-27452-9

A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis

Fan Yao, Yalan Deng, Yang Zhao, Ying Mei, Yilei Zhang, Xiaoguang Liu, Consuelo Martinez, Xiaohua Su, Roberto R. Rosato, Hongqi Teng, Qinglei Hang, Shannon Yap, Dahu Chen, Yumeng Wang, Mei Ju May Chen, Mutian Zhang, Han Liang, Dong Xie, Xin Chen, Hao ZhuJenny C. Chang, M. James You, Yutong Sun, Boyi Gan, Li Ma

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

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Abstract

The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.

Original language	English (US)
Article number	7333
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-27452-9
State	Published - Dec 2021

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/s41467-021-27452-9

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Yao, F., Deng, Y., Zhao, Y., Mei, Y., Zhang, Y., Liu, X., Martinez, C., Su, X., Rosato, R. R., Teng, H., Hang, Q., Yap, S., Chen, D., Wang, Y., Chen, M. J. M., Zhang, M., Liang, H., Xie, D., Chen, X., ... Ma, L. (2021). A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nature Communications, 12(1), [7333]. https://doi.org/10.1038/s41467-021-27452-9

A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. / Yao, Fan; Deng, Yalan; Zhao, Yang; Mei, Ying; Zhang, Yilei; Liu, Xiaoguang; Martinez, Consuelo; Su, Xiaohua; Rosato, Roberto R.; Teng, Hongqi; Hang, Qinglei; Yap, Shannon; Chen, Dahu; Wang, Yumeng; Chen, Mei Ju May; Zhang, Mutian; Liang, Han; Xie, Dong; Chen, Xin; Zhu, Hao; Chang, Jenny C.; You, M. James; Sun, Yutong; Gan, Boyi; Ma, Li.

In: Nature Communications, Vol. 12, No. 1, 7333, 12.2021.

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

Yao, F, Deng, Y, Zhao, Y, Mei, Y, Zhang, Y, Liu, X, Martinez, C, Su, X, Rosato, RR, Teng, H, Hang, Q, Yap, S, Chen, D, Wang, Y, Chen, MJM, Zhang, M, Liang, H, Xie, D, Chen, X, Zhu, H, Chang, JC, You, MJ, Sun, Y, Gan, B & Ma, L 2021, 'A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis', Nature Communications, vol. 12, no. 1, 7333. https://doi.org/10.1038/s41467-021-27452-9

Yao, Fan ; Deng, Yalan ; Zhao, Yang ; Mei, Ying ; Zhang, Yilei ; Liu, Xiaoguang ; Martinez, Consuelo ; Su, Xiaohua ; Rosato, Roberto R. ; Teng, Hongqi ; Hang, Qinglei ; Yap, Shannon ; Chen, Dahu ; Wang, Yumeng ; Chen, Mei Ju May ; Zhang, Mutian ; Liang, Han ; Xie, Dong ; Chen, Xin ; Zhu, Hao ; Chang, Jenny C. ; You, M. James ; Sun, Yutong ; Gan, Boyi ; Ma, Li. / A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. In: Nature Communications. 2021 ; Vol. 12, No. 1.

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title = "A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis",

abstract = "The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.",

author = "Fan Yao and Yalan Deng and Yang Zhao and Ying Mei and Yilei Zhang and Xiaoguang Liu and Consuelo Martinez and Xiaohua Su and Rosato, {Roberto R.} and Hongqi Teng and Qinglei Hang and Shannon Yap and Dahu Chen and Yumeng Wang and Chen, {Mei Ju May} and Mutian Zhang and Han Liang and Dong Xie and Xin Chen and Hao Zhu and Chang, {Jenny C.} and You, {M. James} and Yutong Sun and Boyi Gan and Li Ma",

note = "Funding Information: We thank Mien-Chie Hung for providing cell lines. We thank Kiersten Maldonado, Jie Zhang, and MD Anderson{\textquoteright}s Functional Genomics Core, Small Animal Imaging Facility, Advanced Technology Genomics Core, Cytogenetics and Cell Authentication Core, and High-Resolution Electron Microscopy Facility for technical assistance. We are grateful to all members of the Ma Lab for discussion, Lingyun Long for advice on flow cytometry analysis, and Junjie Chen for critical reading. L.M. is supported by a US National Institutes of Health (NIH) grant R01CA166051 and a Cancer Prevention and Research Institute of Texas (CPRIT) grant RP150319. The cores are supported by MD Anderson{\textquoteright}s Cancer Center Support Grant (CCSG, P30CA016672) from NIH. Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41467-021-27452-9",

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T1 - A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis

AU - Yao, Fan

AU - Deng, Yalan

AU - Zhao, Yang

AU - Mei, Ying

AU - Zhang, Yilei

AU - Liu, Xiaoguang

AU - Martinez, Consuelo

AU - Su, Xiaohua

AU - Rosato, Roberto R.

AU - Teng, Hongqi

AU - Hang, Qinglei

AU - Yap, Shannon

AU - Chen, Dahu

AU - Wang, Yumeng

AU - Chen, Mei Ju May

AU - Zhang, Mutian

AU - Liang, Han

AU - Xie, Dong

AU - Chen, Xin

AU - Zhu, Hao

AU - Chang, Jenny C.

AU - You, M. James

AU - Sun, Yutong

AU - Gan, Boyi

AU - Ma, Li

N1 - Funding Information: We thank Mien-Chie Hung for providing cell lines. We thank Kiersten Maldonado, Jie Zhang, and MD Anderson’s Functional Genomics Core, Small Animal Imaging Facility, Advanced Technology Genomics Core, Cytogenetics and Cell Authentication Core, and High-Resolution Electron Microscopy Facility for technical assistance. We are grateful to all members of the Ma Lab for discussion, Lingyun Long for advice on flow cytometry analysis, and Junjie Chen for critical reading. L.M. is supported by a US National Institutes of Health (NIH) grant R01CA166051 and a Cancer Prevention and Research Institute of Texas (CPRIT) grant RP150319. The cores are supported by MD Anderson’s Cancer Center Support Grant (CCSG, P30CA016672) from NIH. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.

AB - The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.

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SN - 2041-1723

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ER -

A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis

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