Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 26, 2023
- Source ID
- 10.1038/s43018-023-00584-1
Entities
People
- A Ari Hakimi
- Alaa M. T. Mohamed
- Alessandro Carugo
- Alessandro Sgambato
- Andrea Viale
- Christopher A. Bristow
- Cihui Zhu
- Courtney N. Le
- Edoardo Del Poggetto
- Eliezer Van Allen
- Eric Jonasch
- Federica Carbone
- Francesca Citron
- Giannicola Genovese
- Giulio F Draetta
- Hania Khan
- Hideo Tomihara
- Jianhua Zhang
- Jianjun Gao
- Justin K. Huang
- Kanishka Sircar
- Kevin Litchfield
- Li Zhang
- Linghua Wang
- Luigi Perelli
- Melinda Soeung
- Michael Peoples
- Nizar M. Tannir
- P. Andrew Futreal
- Pavlos Msaouel
- Renzo G. DiNatale
- Rosalba Minelli
- Ruohan Xia
- Sabina Signoretti
- Samra Turajlic
- Sanjana Srinivasan
- Sebastian Lundgren
- Tim Heffernan
- Toni K Choueiri
- Tony Gutschner
- Truong Nguyen Anh Lam
- Virginia Giuliani
- Ying-Bei Chen
- Ziad Bakouny
Organizations
- National Cancer Institute
- The University of Texas MD Anderson Cancer Center
- United States Department of Defense