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

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

doi:10.1016/j.ccell.2019.01.006

Cited by 72 publications

(82 citation statements)

References 63 publications

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“…These results further support the link between Myc and protein synthesis in ATRT cells. Moreover, the correlation of Myc activity and SMARCB1-deficient cancers has been identified in priors studies [26][27][28]. Alimova et al found that SMARCB1-deficient ATRTs expressed higher Myc activity compare to normal brain tissues, regardless of the subtypes of ATRTs [28].…”

Section: Discussionmentioning

confidence: 98%

Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors

Tran

Sung

et al. 2020

Cancers

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Atypical teratoid rhabdoid tumors (ATRTs) are among the most malignant brain tumors in early childhood and remain incurable. Myc-ATRT is driven by the Myc oncogene, which directly controls the intracellular protein synthesis rate. Proteasome inhibitor bortezomib (BTZ) was approved by the Food and Drug Administration as a primary treatment for multiple myeloma. This study aimed to determine whether the upregulation of protein synthesis and proteasome degradation in Myc-ATRTs increases tumor cell sensitivity to BTZ. We performed differential gene expression and gene set enrichment analysis on matched primary and recurrent patient-derived xenograft (PDX) samples from an infant with ATRT. Concomitant upregulation of the Myc pathway, protein synthesis and proteasome degradation were identified in recurrent ATRTs. Additionally, we found the proteasome-encoding genes were highly expressed in ATRTs compared with in normal brain tissues, correlated with the malignancy of tumor cells and were essential for tumor cell survival. BTZ inhibited proliferation and induced apoptosis through the accumulation of p53 in three human Myc-ATRT cell lines (PDX-derived tumor cell line Re1-P6, BT-12 and CHLA-266). Furthermore, BTZ inhibited tumor growth and prolonged survival in Myc-ATRT orthotopic xenograft mice. Our findings suggest that BTZ may be a promising targeted therapy for Myc-ATRTs.

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Section: Discussionmentioning

confidence: 98%

Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors

Tran

Sung

et al. 2020

Cancers

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“…In this study we have interrogated the interactions between SMARCB1 loss, cellular differentiation state, and transcriptional changes associated with tumorigenesis, while generating a cellular model which will have utility for future mechanistic studies as well as for identification of potential therapeutic vulnerabilities in SMARCB1-deficient cells. While other systems of SMARCB1 loss or reintroduction have been used to study the mechanisms underlying ATRT in a controlled manner (Wilson et al 2010;Han et al 2016;Nakayama et al 2017;Wang et al 2017;Carugo et al 2019;Langer et al 2019), this complementary system has the benefit of using human cells, having the flexibility to take into account the effects of differentiation processes, and using SMARCB1 loss alone without additional oncogenic drivers, consistent with the human tumor phenotype (Lee et al 2012). In addition, similar to a recent publication (Langer et al 2019), our study provides an interrogation of the interactions between SMARCB1 loss and neural development, however, here we illustrate novel insight into the dramatic phenotypic differences which can occur with loss of SMARCB1 at different stages of differentiation, such as lethality in pluripotent cells and impairment of neuronal commitment and maturation.…”

Section: Discussionmentioning

confidence: 99%

SMARCB1 loss interacts with neuronal differentiation state to block maturation and impact cell stability

Parisian

Koga

Miki³

et al. 2020

Preprint

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Atypical teratoid rhabdoid tumors (ATRT) are challenging pediatric brain cancers which are predominantly associated with inactivation of the gene SMARCB1, a conserved subunit of the chromatin remodeling BAF complex, which has known contributions to developmental processes.To identify potential interactions between SMARCB1 loss and the process of neural development, we introduced an inducible SMARCB1 loss of function system into human induced pluripotent stem cells (iPSCs) which were subjected to either directed neuronal differentiation or differentiation into cerebral organoids. Using this system, we have identified substantial differences in the downstream effects of SMARCB1 loss depending on differentiation state and identified an interaction between SMARCB1 loss and neural differentiation pressure which causes a resistance to terminal differentiation and a defect in maintenance of a normal cell state. Our results provide insight into how SMARCB1 loss might interact with neural development in the process of ATRT tumorigenesis.3

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“…Of note, RMC is resistant to the standard VEGF-directed therapies used for ccRCC and other RCC subtypes. A study of mosaic mouse models with inactivated SMARCB1 demonstrated that SMARCB1-negative tumors such as RMC are vulnerable to proteasome and autophagy blockade [34]. The sensitivity of RMC to proteasome inhibitors was further validated in a study of RMC cell lines [35].…”

Section: Kidney Cancer Geneticsmentioning

confidence: 99%

Cancer Genetics and Therapeutic Opportunities in Urologic Practice

Adashek

Leonard

Roszik

et al. 2020

Cancers

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This article aims to summarize the current literature on genetic alterations related to tumors of the genitourinary tract. Novel associations have recently been reported between specific DNA alterations and genitourinary malignancies. The most common cause of chromosome 3p loss in clear cell renal cell carcinoma is a chromothripsis event, which concurrently generates a chromosome 5q gain. Specific patterns of clear cell renal cell carcinoma metastatic evolution have been uncovered. The first therapy targeting a specific molecular alteration has now been approved for urothelial carcinoma. Germline mutations in DNA damage repair genes and the transcription factor HOXB13 are associated with prostate cancer and may be targeted therapeutically. The genetic associations noted across different genitourinary cancers can inform potential screening approaches and guide novel targeted treatment strategies.

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

Cited by 72 publications

References 63 publications

Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors

Upregulation of Protein Synthesis and Proteasome Degradation Confers Sensitivity to Proteasome Inhibitor Bortezomib in Myc-Atypical Teratoid/Rhabdoid Tumors

SMARCB1 loss interacts with neuronal differentiation state to block maturation and impact cell stability

Cancer Genetics and Therapeutic Opportunities in Urologic Practice

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