The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma

Nargund, Amrita M.; Pham, Can G.; Dong, Yiyu; Wang, Patricia I.; Osmangeyoglu, Hatice U.; Xie, Yuchen; Aras, Ömer; Han, Song Iy; Oyama, Toshinao; Takeda, Shugaku; Ray, Chelsea; Dong, Zhenghong; Bergé, Mathieu; Hakimi, A. Ari; Monette, Sébastien; Lekaye, Carl L.; Koutcher, Jason A.; Leslie, Christina; Creighton, Chad J.; Weinhold, Nils; Lee, William; Tickoo, Satish K.; Wang, Zhong; Cheng, Emily H.; Hsieh, James J.

doi:10.1016/j.celrep.2017.02.074

Cited by 157 publications

(186 citation statements)

References 66 publications

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“…While this manuscript was under review, a manuscript was published reporting the generation of mice with targeted disruption of Vhl and Pbrm1 in the mouse kidney (60). There are several important differences between the studies.…”

Section: Discussionmentioning

confidence: 99%

“…There are several important differences between the studies. First, Nargund et al, targeted Vhl and Pbrm1 by using the traditional Ksp-Cre driver, and the phenotype was dominated by the development of large cysts sometimes taking up half of the kidney (60). In contrast, cysts are infrequently observed in mice with targeted loss of Vhl and Pbrm1 using a Pax8 driver, and the mice survive significantly longer.…”

Section: Discussionmentioning

confidence: 99%

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Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade

et al. 2017

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Clear cell renal cell carcinoma (ccRCC) is characterized by BAP1 and PBRM1 mutation, which are associated with tumors of different grade and prognosis. However, whether BAP1 and PBRM1 loss causes ccRCC and determines tumor grade is unclear. We conditionally targeted Bap1 and Pbrm1 (with Vhl) in the mouse using several Cre drivers. Sglt2 and Villin proximal convoluted tubule drivers failed to cause tumorigenesis, challenging the conventional notion of ccRCC origins. In contrast, targeting with Pax8, a developmental lineage-specific transcription factor, led to ccRCC of different grade. Bap1-deficient tumors were high grade and showed greater mTORC1 activation than Pbrm1-deficient tumors, which exhibited longer latency. Disrupting one allele of the mTORC1 negative regulator, Tsc1, in Pbrm1-deficient kidneys triggered higher grade ccRCC. This study establishes Bap1 and Pbrm1 as lineage-specific drivers of ccRCC and histological grade, implicates mTORC1 as a tumor grade rheostat, and suggests that ccRCC may arise from Bowman capsule cells.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade

et al. 2017

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“…Accordingly, several groups have recently demonstrated the development of ccRCC in mice models upon the combined loss of Vhl and different genes; Harlander et al [20] showed that combined deletion of Vhl, p53 and Rb1 specifically in renal epithelial cells in mice caused ccRCC arising from proximal tubule epithelial cells. Nargund et al [21] demonstrated that activation of mTORC1 constituted a third driver event after loss of Vhl and Pbmr1 in their ccRCC tumour model, and Bailey et al [22] showed that Myc activation when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion, produced murine kidney tumours that approximate human ccRCC. pVHL might also exert a broader role in maintaining renal integrity.…”

Section: Introductionmentioning

confidence: 99%

The <b><i>von Hippel-Lindau</i></b> Gene Is Required to Maintain Renal Proximal Tubule and Glomerulus Integrity in Zebrafish Larvae

Rooijen

Hoek

Logister

et al. 2018

Nephron

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Background: von Hippel-Lindau (VHL) disease is characterized by the development of benign and malignant tumours in many organ systems, including renal cysts and clear cell renal cell carcinoma. It is not completely understood what underlies the development of renal pathology, and the use of murine Vhl models has been challenging due to limitations in disease conservation. We previously described a zebrafish model bearing inactivating mutations in the orthologue of the human VHL gene. Methods: We used histopathological and functional assays to investigate the pronephric and glomerular developmental defects in vhl mutant zebrafish, supported by human cell culture assays. Results: Here, we report that vhl is required to maintain pronephric tubule and glomerulus integrity in zebrafish embryos. vhl mutant glomeruli are enlarged, cxcr4a+ capillary loops are dilated and the Bowman space is widened. While we did not observe pronephric cysts, the cells of the proximal convoluted and anterior proximal straight tubule are enlarged, periodic acid schiff (PAS) and Oil Red O positive, and display a clear cytoplasm after hematoxylin and eosine staining. Ultrastructural analysis showed the vhl^–/– tubule to accumulate large numbers of vesicles of variable size and electron density. Microinjection of the endocytic fluorescent marker AM1–43 in zebrafish embryos revealed an accumulation of endocytic vesicles in the vhl mutant pronephric tubule, which we can recapitulate in human cells lacking VHL. Conclusions: Our data indicates that vhl is required to maintain pronephric tubule and glomerulus integrity during zebrafish development, and suggests a role for VHL in endocytic vesicle trafficking.

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“…The PBAF complex suppresses the hypoxia transcriptional signature in VHL −/− ccRCC (18, 19) but its effects on tumor-immune interactions have not been thoroughly studied. To explore the potential impact of this complex on the immunophenotype of ccRCC, we analyzed previously reported whole transcriptome sequencing (RNA-seq) data from A704 ccRCC cell lines with perturbations in the PBAF complex (19).…”

mentioning

confidence: 99%

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma

Miao

Margolis

Gao

et al. 2018

Science

942

857

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Immune checkpoint inhibitors targeting the programmed cell death-1 receptor (PD-1) improve survival in a subset of patients with clear cell renal cell carcinoma (ccRCC). To identify genomic alterations in ccRCC that correlate with response to anti-PD-1 monotherapy, we performed whole exome sequencing of metastatic ccRCC from 35 patients. We found that clinical benefit was associated with loss-of-function mutations in the PBRM1 gene (p=0.012), which encodes a subunit of a SWI/SNF chromatin remodeling complex (the PBAF subtype). We confirmed this finding in an independent validation cohort of 63 ccRCC patients treated with PD-(L)1 blockade therapy alone or in combination with anti-CTLA-4 therapies (p=0.0071). Gene expression analysis of PBAF-deficient ccRCC cell lines and PBRM1-deficient tumors revealed altered transcriptional output in JAK/STAT, hypoxia, and immune signaling pathways. PBRM1 loss in ccRCC may alter global tumor cell expression profiles to influence responsiveness to immune checkpoint therapy.

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The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma

Cited by 157 publications

References 66 publications

Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade

Modeling Renal Cell Carcinoma in Mice: Bap1 and Pbrm1 Inactivation Drive Tumor Grade

The <b><i>von Hippel-Lindau</i></b> Gene Is Required to Maintain Renal Proximal Tubule and Glomerulus Integrity in Zebrafish Larvae

Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma

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