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Senescence-Induced Immune Remodeling Facilitates Metastatic Adrenal Cancer in a Sex-Dimorphic Manner

Kate M. Warde, Lihua Liu, Lorenzo J. Smith, Brian K. Lohman, Chris J. Stubben, H. Atakan Ekiz, Julia L. Ammer, Kimber Converso-Baran, Thomas J. Giordano, Gary D. Hammer, Kaitlin J. Basham
doi: https://doi.org/10.1101/2022.04.29.488426
Kate M. Warde
1Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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Lihua Liu
1Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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Lorenzo J. Smith
1Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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Brian K. Lohman
2Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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Chris J. Stubben
2Bioinformatics Shared Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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H. Atakan Ekiz
3Department of Molecular Biology and Genetics, Izmir Institute of Technology, Urla Izmir, Turkey
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Julia L. Ammer
4Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
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Kimber Converso-Baran
5Frankel Cardiovascular Center Physiology and Phenotyping Core, University of Michigan, Ann Arbor, MI, USA
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Thomas J. Giordano
4Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
6Department of Pathology, University of Michigan, Ann Arbor, MI, USA
7Endocrine Oncology Program, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
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Gary D. Hammer
4Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, Ann Arbor, MI, USA
7Endocrine Oncology Program, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA
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  • For correspondence: kaitlin.basham@hci.utah.edu ghammer@med.umich.edu
Kaitlin J. Basham
1Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA
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  • For correspondence: kaitlin.basham@hci.utah.edu ghammer@med.umich.edu
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Abstract

Aging is a carcinogen that markedly increases cancer risk, yet we have limited mechanistic understanding of cancer initiation in aged cells. Here, we demonstrate induction of the hallmark aging process cellular senescence, triggered by loss of Wnt inhibitor ZNRF3, remodels the tissue microenvironment and ultimately permits metastatic adrenal cancer. Detailed characterization reveals a striking sexual dimorphism. Males exhibit earlier senescence activation and a greater innate immune response. This results in high myeloid cell accumulation and lower incidence of malignancy. Conversely, females present a dampened immune response and are more prone to metastatic cancer. Senescence-recruited myeloid cells become increasingly depleted with advanced tumor progression, which is recapitulated in patients where a low myeloid signature is associated with worse outcome. Collectively, our study reveals a novel role for myeloid cells in restraining adrenal cancer progression with significant prognostic value, and provides a model for interrogating pleiotropic effects of cellular senescence in cancer.

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Competing Interest Statement

The authors have declared no competing interest.

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Posted April 29, 2022.
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Senescence-Induced Immune Remodeling Facilitates Metastatic Adrenal Cancer in a Sex-Dimorphic Manner
Kate M. Warde, Lihua Liu, Lorenzo J. Smith, Brian K. Lohman, Chris J. Stubben, H. Atakan Ekiz, Julia L. Ammer, Kimber Converso-Baran, Thomas J. Giordano, Gary D. Hammer, Kaitlin J. Basham
bioRxiv 2022.04.29.488426; doi: https://doi.org/10.1101/2022.04.29.488426
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Senescence-Induced Immune Remodeling Facilitates Metastatic Adrenal Cancer in a Sex-Dimorphic Manner
Kate M. Warde, Lihua Liu, Lorenzo J. Smith, Brian K. Lohman, Chris J. Stubben, H. Atakan Ekiz, Julia L. Ammer, Kimber Converso-Baran, Thomas J. Giordano, Gary D. Hammer, Kaitlin J. Basham
bioRxiv 2022.04.29.488426; doi: https://doi.org/10.1101/2022.04.29.488426

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