Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer Journal Article
| Authors: | Perelli, L.; Carbone, F.; Zhang, L.; Huang, J. K.; Le, C.; Khan, H.; Citron, F.; Del Poggetto, E.; Gutschner, T.; Tomihara, H.; Soeung, M.; Minelli, R.; Srinivasan, S.; Peoples, M.; Lam, T. N. A.; Lundgren, S.; Xia, R.; Zhu, C.; Mohamed, A. M. T.; Zhang, J.; Sircar, K.; Sgambato, A.; Gao, J. J.; Jonasch, E.; Draetta, G. F.; Futreal, A.; Bakouny, Z.; Van Allen, E. M.; Choueiri, T.; Signoretti, S.; Msaouel, P.; Litchfield, K.; Turajlic, S.; Wang, L.; Chen, Y. B.; Di Natale, R. G.; Hakimi, A. A.; Giuliani, V.; Heffernan, T. P.; Viale, A.; Bristow, C. A.; Tannir, N. M.; Carugo, A.; Genovese, G. |
| Article Title: | 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. © 2023, The Author(s). |
| Keywords: | immunohistochemistry; controlled study; human cell; somatic mutation; genetics; nonhuman; flow cytometry; nuclear magnetic resonance imaging; mouse; animal tissue; metastasis; tumor volume; animal experiment; animal model; evolution; immunofluorescence; histology; renal cell carcinoma; kidney neoplasms; genetic transfection; genetic engineering; kidney tumor; carcinoma, renal cell; western blotting; chromosomal instability; kidney cancer; autopsy; bioinformatics; cell separation; aneuploidy; dna copy number variations; tumor microenvironment; copy number variation; buprenorphine; cervical spine dislocation; high throughput sequencing; chemoluminescence; kidney tubule cell; partial trisomy; humans; human; article; whole exome sequencing; crispr-cas9 system; adeno associated virus vector; interferon signaling; baricitinib |
| Journal Title: | Nature Cancer |
| Volume: | 4 |
| Issue: | 7 |
| ISSN: | 2662-1347 |
| Publisher: | Nature Research |
| Date Published: | 2023-07-01 |
| Start Page: | 984 |
| End Page: | 1000 |
| Language: | English |
| DOI: | 10.1038/s43018-023-00584-1 |
| PUBMED: | 37365326 |
| PROVIDER: | scopus |
| PMCID: | PMC10368532 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work