Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer
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Published:2023-06-26
Issue:7
Volume:4
Page:984-1000
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ISSN:2662-1347
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Container-title:Nature Cancer
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language:en
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Short-container-title:Nat Cancer
Author:
Perelli LuigiORCID, Carbone FedericaORCID, Zhang Li, Huang Justin K., Le CourtneyORCID, Khan Hania, Citron FrancescaORCID, Del Poggetto Edoardo, Gutschner Tony, Tomihara Hideo, Soeung MelindaORCID, Minelli Rosalba, Srinivasan Sanjana, Peoples Michael, Lam Truong Nguyen Anh, Lundgren SebastianORCID, Xia Ruohan, Zhu Cihui, Mohamed Alaa M. T., Zhang JianhuaORCID, Sircar Kanishka, Sgambato Alessandro, Gao JianJunORCID, Jonasch EricORCID, Draetta Giulio F.ORCID, Futreal AndrewORCID, Bakouny ZiadORCID, Van Allen Eliezer M.ORCID, Choueiri ToniORCID, Signoretti Sabina, Msaouel PavlosORCID, Litchfield Kevin, Turajlic SamraORCID, Wang LinghuaORCID, Chen Ying BeiORCID, Di Natale Renzo G.ORCID, Hakimi A. Ari, Giuliani VirginiaORCID, Heffernan Timothy P.ORCID, Viale Andrea, Bristow Christopher A., Tannir Nizar M., Carugo AlessandroORCID, Genovese GiannicolaORCID
Abstract
AbstractMolecular routes to metastatic dissemination are critical determinants of aggressive cancers. Through in vivo CRISPR–Cas9 genome editing, we generated somatic mosaic genetically engineered models that faithfully recapitulate metastatic renal tumors. Disruption of 9p21 locus is an evolutionary driver to systemic disease through the rapid acquisition of complex karyotypes in cancer cells. Cross-species analysis revealed that recurrent patterns of copy number variations, including 21q loss and dysregulation of the interferon pathway, are major drivers of metastatic potential. In vitro and in vivo genomic engineering, leveraging loss-of-function studies, along with a model of partial trisomy of chromosome 21q, demonstrated a dosage-dependent effect of the interferon receptor genes cluster as an adaptive mechanism to deleterious chromosomal instability in metastatic progression. This work provides critical knowledge on drivers of renal cell carcinoma progression and defines the primary role of interferon signaling in constraining the propagation of aneuploid clones in cancer evolution.
Funder
U.S. Department of Defense UT | University of Texas MD Anderson Cancer Center U.S. Department of Health & Human Services | NIH | National Cancer Institute
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Oncology
Reference68 articles.
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