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

Cancer Cell. 2019 Feb 11;35(2):204-220.e9. doi: 10.1016/j.ccell.2019.01.006.

Authors

Alessandro Carugo¹, Rosalba Minelli², Luigi Sapio², Melinda Soeung², Federica Carbone², Frederick S Robinson¹, James Tepper², Ziheng Chen², Sara Lovisa³, Maria Svelto⁴, Samirkumar Amin⁵, Sanjana Srinivasan⁶, Edoardo Del Poggetto², Sara Loponte², Francesca Puca², Prasenjit Dey³, Gabriel G Malouf⁷, Xiaoping Su⁸, Liren Li⁹, Dolores Lopez-Terrada¹⁰, Dinesh Rakheja¹¹, Alexander J Lazar¹², George J Netto¹³, Priya Rao¹⁴, Alessandro Sgambato¹⁵, Anirban Maitra¹⁶, Durga N Tripathi¹⁷, Cheryl L Walker¹⁷, Jose A Karam¹⁸, Timothy P Heffernan¹, Andrea Viale², Charles W M Roberts¹⁹, Pavlos Msaouel²⁰, Nizar M Tannir²¹, Giulio F Draetta²², Giannicola Genovese²³

Affiliations

¹ Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
² Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
³ Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁴ Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, Pozzuoli 80078, Italy.
⁵ The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06032, USA.
⁶ Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁷ Centre Hospitalier Régional et Universitaire Strasbourg, Hôpital Civil, 1 Place de L'Hôpital, Strasbourg 67091, France; Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS, INSERM, Université de Strasbourg, Illkirch 67400, France.
⁸ Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
⁹ Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China.
¹⁰ Department of Pathology, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030, USA.
¹¹ Department of Pathology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
¹² Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
¹³ Department of Pathology, Johns Hopkins University, 600 N. Wolfe Street/Carnegie 417, Baltimore, MD 21287, USA.
¹⁴ Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
¹⁵ Dipartimento di Patologia Generale, Policlinico Agostino Gemelli, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1, Roma 00168, Italy.
¹⁶ Department of Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
¹⁷ Center for Precision Environmental Health, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
¹⁸ Department of Urology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
¹⁹ Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38120, USA.
²⁰ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
²¹ Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: ntannir@mdanderson.org.
²² Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: gdraetta@mdanderson.org.
²³ Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA; David H. Koch Center for Applied Research of Genitourinary Cancers, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Electronic address: ggenovese@mdanderson.org.

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.

Keywords: BIRC5; ER stress; MYC; SMARCB1; autophagy; embryonic mosaic GEM models; p53; proteasome inhibitors; renal medullary carcinoma; rhabdoid tumors.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Autophagy* / drug effects
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p16 / genetics
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Endoplasmic Reticulum Stress* / drug effects
Female
Gene Expression Regulation, Neoplastic
Humans
Male
Mice, 129 Strain
Mice, Inbred C57BL
Mice, Knockout
Proteasome Inhibitors / pharmacology
Proteostasis* / drug effects
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
Rhabdoid Tumor / drug therapy
Rhabdoid Tumor / genetics
Rhabdoid Tumor / metabolism*
Rhabdoid Tumor / pathology
SMARCB1 Protein / deficiency*
SMARCB1 Protein / genetics
Signal Transduction
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / deficiency
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism*
Unfolded Protein Response

Substances

Antineoplastic Agents
Cdkn2a protein, mouse
Cyclin-Dependent Kinase Inhibitor p16
Myc protein, mouse
Proteasome Inhibitors
Proto-Oncogene Proteins c-myc
SMARCB1 Protein
SMARCB1 protein, human
Smarcb1 protein, mouse
TP53 protein, human
Trp53 protein, mouse
Tumor Suppressor Protein p53

Abstract

Publication types

MeSH terms

Substances

Grants and funding