Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer

Luigi Perelli; Federica Carbone; Li Zhang; Justin K. Huang; Courtney Le; Hania Khan; Francesca Citron; Edoardo Del Poggetto; Tony Gutschner; Hideo Tomihara; Melinda Soeung; Rosalba Minelli; Sanjana Srinivasan; Michael Peoples; Truong Nguyen Anh Lam; Sebastian Lundgren; Ruohan Xia; Cihui Zhu; Alaa M. T. Mohamed; Jianhua Zhang; Kanishka Sircar; Alessandro Sgambato; Jianjun Gao; Eric Jonasch; Giulio F. Draetta; Andrew Futreal; Ziad Bakouny; Eliezer M. Van Allen; Toni Choueiri; Sabina Signoretti; Pavlos Msaouel; Kevin Litchfield; Samra Turajlic; Linghua Wang; Ying Bei Chen; Renzo G. Di Natale; A. Ari Hakimi; Virginia Giuliani; Timothy P. Heffernan; Andrea Viale; Christopher A. Bristow; Nizar M. Tannir; Alessandro Carugo; Giannicola Genovese

doi:10.1038/s43018-023-00584-1

Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer

Luigi Perelli, Federica Carbone, Li Zhang, Justin K. Huang, Courtney Le, Hania Khan, Francesca Citron, Edoardo Del Poggetto, Tony Gutschner, Hideo Tomihara, Melinda Soeung, Rosalba Minelli, Sanjana Srinivasan, Michael Peoples, Truong Nguyen Anh Lam, Sebastian Lundgren, Ruohan Xia, Cihui Zhu, Alaa M. T. Mohamed, Jianhua ZhangKanishka Sircar, Alessandro Sgambato, Jianjun Gao, Eric Jonasch, Giulio F. Draetta, Andrew Futreal, Ziad Bakouny, Eliezer M. Van Allen, Toni Choueiri, Sabina Signoretti, Pavlos Msaouel, Kevin Litchfield, Samra Turajlic, Linghua Wang, Ying Bei Chen, Renzo G. Di Natale, A. Ari Hakimi, Virginia Giuliani, Timothy P. Heffernan, Andrea Viale, Christopher A. Bristow, Nizar M. Tannir, Alessandro Carugo, Giannicola Genovese

Risultato della ricerca: Contributo in rivista › Articolo in rivista

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.

Lingua originale	English
pagine (da-a)	984-1000
Numero di pagine	17
Rivista	Nature Cancer
Volume	4
DOI	https://doi.org/10.1038/s43018-023-00584-1
Stato di pubblicazione	Pubblicato - 2023

Keywords

renal cancer

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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., ... Genovese, G. (2023). Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer. Nature Cancer, 4, 984-1000. https://doi.org/10.1038/s43018-023-00584-1

@article{338f2ed75c6944c0a83432625ff17620,

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.",

keywords = "renal cancer, renal cancer",

author = "Luigi Perelli and Federica Carbone and Li Zhang and Huang, {Justin K.} and Courtney Le and Hania Khan and Francesca Citron and {Del Poggetto}, Edoardo and Tony Gutschner and Hideo Tomihara and Melinda Soeung and Rosalba Minelli and Sanjana Srinivasan and Michael Peoples and Lam, {Truong Nguyen Anh} and Sebastian Lundgren and Ruohan Xia and Cihui Zhu and Mohamed, {Alaa M. T.} and Jianhua Zhang and Kanishka Sircar and Alessandro Sgambato and Jianjun Gao and Eric Jonasch and Draetta, {Giulio F.} and Andrew Futreal and Ziad Bakouny and {Van Allen}, {Eliezer M.} and Toni Choueiri and Sabina Signoretti and Pavlos Msaouel and Kevin Litchfield and Samra Turajlic and Linghua Wang and Chen, {Ying Bei} and {Di Natale}, {Renzo G.} and Hakimi, {A. Ari} and Virginia Giuliani and Heffernan, {Timothy P.} and Andrea Viale and Bristow, {Christopher A.} and Tannir, {Nizar M.} and Alessandro Carugo and Giannicola Genovese",

year = "2023",

doi = "10.1038/s43018-023-00584-1",

language = "English",

volume = "4",

pages = "984--1000",

journal = "Nature Cancer",

issn = "2662-1347",

publisher = "Nature Research",

}

Perelli, L, Carbone, F, Zhang, L, Huang, JK, Le, C, Khan, H, Citron, F, Del Poggetto, E, Gutschner, T, Tomihara, H, Soeung, M, Minelli, R, Srinivasan, S, Peoples, M, Lam, TNA, Lundgren, S, Xia, R, Zhu, C, Mohamed, AMT, Zhang, J, Sircar, K, Sgambato, A, Gao, J, Jonasch, E, Draetta, GF, Futreal, A, Bakouny, Z, Van Allen, EM, Choueiri, T, Signoretti, S, Msaouel, P, Litchfield, K, Turajlic, S, Wang, L, Chen, YB, Di Natale, RG, Hakimi, AA, Giuliani, V, Heffernan, TP, Viale, A, Bristow, CA, Tannir, NM, Carugo, A & Genovese, G 2023, 'Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer', Nature Cancer, vol. 4, pagg. 984-1000. https://doi.org/10.1038/s43018-023-00584-1

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, Jianjun

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

PY - 2023

Y1 - 2023

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.

KW - renal cancer

UR - http://hdl.handle.net/10807/300918

U2 - 10.1038/s43018-023-00584-1

DO - 10.1038/s43018-023-00584-1

M3 - Article

SN - 2662-1347

VL - 4

SP - 984

EP - 1000

JO - Nature Cancer

JF - Nature Cancer

ER -

Interferon signaling promotes tolerance to chromosomal instability during metastatic evolution in renal cancer

Abstract

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