RT Journal Article
SR Electronic
T1 Senescence-Induced Immune Remodeling Facilitates Metastatic Adrenal Cancer in a Sex-Dimorphic Manner
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.04.29.488426
DO 10.1101/2022.04.29.488426
A1 Kate M. Warde
A1 Lihua Liu
A1 Lorenzo J. Smith
A1 Brian K. Lohman
A1 Chris J. Stubben
A1 H. Atakan Ekiz
A1 Julia L. Ammer
A1 Kimber Converso-Baran
A1 Thomas J. Giordano
A1 Gary D. Hammer
A1 Kaitlin J. Basham
YR 2022
UL http://biorxiv.org/content/early/2022/04/29/2022.04.29.488426.abstract
AB 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. Graphical abstract created with BioRender.comCompeting Interest StatementThe authors have declared no competing interest.