p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors

Alessandro Carugo; Rosalba Minelli; Luigi Sapio; Melinda Soeung; Federica Carbone; Frederick S. Robinson; James Tepper; Ziheng Chen; Sara Lovisa; Maria Svelto; Samirkumar Amin; Sanjana Srinivasan; Edoardo Del Poggetto; Sara Loponte; Francesca Puca; Prasenjit Dey; Gabriel G. Malouf; Xiaoping Su; Liren Li; Dolores Lopez-Terrada; Dinesh Rakheja; Alexander J. Lazar; George J. Netto; Priya Rao; Alessandro Sgambato; Anirban Maitra; Durga N. Tripathi; Cheryl L. Walker; Jose A. Karam; Timothy P. Heffernan; Andrea Viale; Charles W.M. Roberts; Pavlos Msaouel; Nizar M. Tannir; Giulio F. Draetta; Giannicola Genovese

doi:10.1016/j.ccell.2019.01.006

p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors

Alessandro Carugo, Rosalba Minelli, Luigi Sapio, Melinda Soeung, Federica Carbone, Frederick S. Robinson, James Tepper, Ziheng Chen, Sara Lovisa, Maria Svelto, Samirkumar Amin, Sanjana Srinivasan, Edoardo Del Poggetto, Sara Loponte, Francesca Puca, Prasenjit Dey, Gabriel G. Malouf, Xiaoping Su, Liren Li, Dolores Lopez-TerradaDinesh Rakheja, Alexander J. Lazar, George J. Netto, Priya Rao, Alessandro Sgambato, Anirban Maitra, Durga N. Tripathi, Cheryl L. Walker, Jose A. Karam, Timothy P. Heffernan, Andrea Viale, Charles W.M. Roberts, Pavlos Msaouel, Nizar M. Tannir, Giulio F. Draetta, Giannicola Genovese

Risultato della ricerca: Contributo in rivista › Articolo in rivista

20 Citazioni (Scopus)

Abstract

Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19 ARF -p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.

Lingua originale	English
pagine (da-a)	204-220.e9
Rivista	Cancer Cell
Volume	35
DOI	https://doi.org/10.1016/j.ccell.2019.01.006
Stato di pubblicazione	Pubblicato - 2019

Keywords

Animals
Antineoplastic Agents
Autophagy
BIRC5
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p16
ER stress
Endoplasmic Reticulum Stress
Female
Gene Expression Regulation, Neoplastic
Humans
MYC
Male
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Proteasome Inhibitors
Proteostasis
Proto-Oncogene Proteins c-myc
Rhabdoid Tumor
SMARCB1
SMARCB1 Protein
Signal Transduction
Tumor Cells, Cultured
Tumor Suppressor Protein p53
Unfolded Protein Response
autophagy
embryonic mosaic GEM models
p53
proteasome inhibitors
renal medullary carcinoma
rhabdoid tumors

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10.1016/j.ccell.2019.01.006

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Carugo, A., Minelli, R., Sapio, L., Soeung, M., Carbone, F., Robinson, F. S., Tepper, J., Chen, Z., Lovisa, S., Svelto, M., Amin, S., Srinivasan, S., Del Poggetto, E., Loponte, S., Puca, F., Dey, P., Malouf, G. G., Su, X., Li, L., ... Genovese, G. (2019). p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors. Cancer Cell, 35, 204-220.e9. https://doi.org/10.1016/j.ccell.2019.01.006

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abstract = "Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19 ARF -p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.",

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author = "Alessandro Carugo and Rosalba Minelli and Luigi Sapio and Melinda Soeung and Federica Carbone and Robinson, {Frederick S.} and James Tepper and Ziheng Chen and Sara Lovisa and Maria Svelto and Samirkumar Amin and Sanjana Srinivasan and {Del Poggetto}, Edoardo and Sara Loponte and Francesca Puca and Prasenjit Dey and Malouf, {Gabriel G.} and Xiaoping Su and Liren Li and Dolores Lopez-Terrada and Dinesh Rakheja and Lazar, {Alexander J.} and Netto, {George J.} and Priya Rao and Alessandro Sgambato and Anirban Maitra and Tripathi, {Durga N.} and Walker, {Cheryl L.} and Karam, {Jose A.} and Heffernan, {Timothy P.} and Andrea Viale and Roberts, {Charles W.M.} and Pavlos Msaouel and Tannir, {Nizar M.} and Draetta, {Giulio F.} and Giannicola Genovese",

year = "2019",

doi = "10.1016/j.ccell.2019.01.006",

language = "English",

volume = "35",

pages = "204--220.e9",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

}

Carugo, A, Minelli, R, Sapio, L, Soeung, M, Carbone, F, Robinson, FS, Tepper, J, Chen, Z, Lovisa, S, Svelto, M, Amin, S, Srinivasan, S, Del Poggetto, E, Loponte, S, Puca, F, Dey, P, Malouf, GG, Su, X, Li, L, Lopez-Terrada, D, Rakheja, D, Lazar, AJ, Netto, GJ, Rao, P, Sgambato, A, Maitra, A, Tripathi, DN, Walker, CL, Karam, JA, Heffernan, TP, Viale, A, Roberts, CWM, Msaouel, P, Tannir, NM, Draetta, GF & Genovese, G 2019, 'p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors', Cancer Cell, vol. 35, pagg. 204-220.e9. https://doi.org/10.1016/j.ccell.2019.01.006

TY - JOUR

T1 - p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors

AU - Carugo, Alessandro

AU - Minelli, Rosalba

AU - Sapio, Luigi

AU - Soeung, Melinda

AU - Carbone, Federica

AU - Robinson, Frederick S.

AU - Tepper, James

AU - Chen, Ziheng

AU - Lovisa, Sara

AU - Svelto, Maria

AU - Amin, Samirkumar

AU - Srinivasan, Sanjana

AU - Del Poggetto, Edoardo

AU - Loponte, Sara

AU - Puca, Francesca

AU - Dey, Prasenjit

AU - Malouf, Gabriel G.

AU - Su, Xiaoping

AU - Li, Liren

AU - Lopez-Terrada, Dolores

AU - Rakheja, Dinesh

AU - Lazar, Alexander J.

AU - Netto, George J.

AU - Rao, Priya

AU - Sgambato, Alessandro

AU - Maitra, Anirban

AU - Tripathi, Durga N.

AU - Walker, Cheryl L.

AU - Karam, Jose A.

AU - Heffernan, Timothy P.

AU - Viale, Andrea

AU - Roberts, Charles W.M.

AU - Msaouel, Pavlos

AU - Tannir, Nizar M.

AU - Draetta, Giulio F.

AU - Genovese, Giannicola

PY - 2019

Y1 - 2019

N2 - Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19 ARF -p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.

AB - Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19 ARF -p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.

KW - Animals

KW - Antineoplastic Agents

KW - Autophagy

KW - BIRC5

KW - Cell Line, Tumor

KW - Cyclin-Dependent Kinase Inhibitor p16

KW - ER stress

KW - Endoplasmic Reticulum Stress

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - MYC

KW - Male

KW - Mice, 129 Strain

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Proteasome Inhibitors

KW - Proteostasis

KW - Proto-Oncogene Proteins c-myc

KW - Rhabdoid Tumor

KW - SMARCB1

KW - SMARCB1 Protein

KW - Signal Transduction

KW - Tumor Cells, Cultured

KW - Tumor Suppressor Protein p53

KW - Unfolded Protein Response

KW - autophagy

KW - embryonic mosaic GEM models

KW - p53

KW - proteasome inhibitors

KW - renal medullary carcinoma

KW - rhabdoid tumors

KW - Animals

KW - Antineoplastic Agents

KW - Autophagy

KW - BIRC5

KW - Cell Line, Tumor

KW - Cyclin-Dependent Kinase Inhibitor p16

KW - ER stress

KW - Endoplasmic Reticulum Stress

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - MYC

KW - Male

KW - Mice, 129 Strain

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Proteasome Inhibitors

KW - Proteostasis

KW - Proto-Oncogene Proteins c-myc

KW - Rhabdoid Tumor

KW - SMARCB1

KW - SMARCB1 Protein

KW - Signal Transduction

KW - Tumor Cells, Cultured

KW - Tumor Suppressor Protein p53

KW - Unfolded Protein Response

KW - autophagy

KW - embryonic mosaic GEM models

KW - p53

KW - proteasome inhibitors

KW - renal medullary carcinoma

KW - rhabdoid tumors

UR - http://hdl.handle.net/10807/170584

U2 - 10.1016/j.ccell.2019.01.006

DO - 10.1016/j.ccell.2019.01.006

M3 - Article

SN - 1535-6108

VL - 35

SP - 204-220.e9

JO - Cancer Cell

JF - Cancer Cell

ER -

p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors

Abstract

Keywords

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