TY - JOUR
T1 - Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer
AU - Perelli, Luigi
AU - Carbone, Federica
AU - Zhang, Li
AU - Huang, Justin K.
AU - Le, Courtney
AU - Khan, Hania
AU - Citron, Francesca
AU - Del Poggetto, Edoardo
AU - Gutschner, Tony
AU - Tomihara, Hideo
AU - Soeung, Melinda
AU - Minelli, Rosalba
AU - Srinivasan, Sanjana
AU - Peoples, Michael
AU - Lam, Truong Nguyen Anh
AU - Lundgren, Sebastian
AU - Xia, Ruohan
AU - Zhu, Cihui
AU - Mohamed, Alaa M.T.
AU - Zhang, Jianhua
AU - Sircar, Kanishka
AU - Sgambato, Alessandro
AU - Gao, Jian Jun
AU - Jonasch, Eric
AU - Draetta, Giulio F.
AU - Futreal, Andrew
AU - Bakouny, Ziad
AU - Van Allen, Eliezer M.
AU - Choueiri, Toni
AU - Signoretti, Sabina
AU - Msaouel, Pavlos
AU - Litchfield, Kevin
AU - Turajlic, Samra
AU - Wang, Linghua
AU - Chen, Ying Bei
AU - Di Natale, Renzo G.
AU - Hakimi, A. Ari
AU - Giuliani, Virginia
AU - Heffernan, Timothy P.
AU - Viale, Andrea
AU - Bristow, Christopher A.
AU - Tannir, Nizar M.
AU - Carugo, Alessandro
AU - Genovese, Giannicola
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/7
Y1 - 2023/7
N2 - Molecular 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.
AB - Molecular 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.
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U2 - 10.1038/s43018-023-00584-1
DO - 10.1038/s43018-023-00584-1
M3 - Article
C2 - 37365326
AN - SCOPUS:85162962417
SN - 2662-1347
VL - 4
SP - 984
EP - 1000
JO - Nature Cancer
JF - Nature Cancer
IS - 7
ER -