The role of PBRM1 in clear cell renal cell carcinoma

Abstract: Clear cell renal cell carcinoma (ccRCC) is the 14th most common cancer type worldwide, accounting for 2 % of cancer-related deaths. Despite the recent advances in therapy with the combination of checkpoint inhibitors with tyrosine kinase inhibitors, the prognosis for patients with advanced ccRCC remains poor in many cases. Besides almost universal loss of VHL, PBRM1 is mutated in approximately 40 % of ccRCC tumours. However, the contribution of loss of PBRM1 to tumour formation and metastatic spread is poorly understood. Moreover, there is no tailored therapy for PBRM1-mutant ccRCC.
Thus, to identify compounds preferentially targeting PBRM1-mutant cancer cells, a compound screening using Sellekchem Bioactive Compound library of approximately 2,700 compounds was performed on human ccRCC cell lines. This did not identify compounds preferentially targeting PBRM1-mutant cells over their isogenic PBRM1-competent counterparts.
Using an established autochthonous mouse model of ccRCC, it was shown that additional deletion of Pbrm1 accelerates tumour formation in male, but not in female mice, suggesting a potentially sex-specific role in tumour formation. Single-cell RNA-sequencing of tumour-infiltrating immune cells indicated altered frequencies of immune cell types attributable to deletion of Pbrm1. Moreover, there were indications of altered immune cell behaviour and reduced tumour cell killing capacities, which will be further followed up on.
In a xenograft model of metastatic ccRCC, knock out of PBRM1 moderately increased metastatic spread. Metastatic subclones were isolated from mouse lungs and characterised in vitro. RNA-sequencing of parental cell lines and metastatic subclones suggested a context-dependent role of PBRM1, rather than a distinct set of target genes, in line with the cell line-specific effects and discrepancies between in vivo and in vitro data published. Moreover, it identified a transcriptional signature of genes controlled by PBRM1 and upregulated in metastatic, PBRM1-mutant subclones. Taken together, these findings rather argue for metastasis by other means than for general increase of metastasis upon loss of PBRM1.
In the metastatic subclones of 786-O, there were striking discrepancies between the relative mRNA and protein levels of the gene signature identified. General alterations in the transcription or translation machinery and differences in mRNA stability attributable to loss of PBRM1 could be ruled out. To identify the mechanism underlying the discrepancies between mRNA and protein levels and to define whether this mechanism contributes to increased metastatic spread and/or might represent an approach to target metastatic PBRM1-mutant ccRCC, further investigations will be required

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Universität Freiburg, Dissertation, 2022

Classification and Topics

• Keyword: Hypernephrom ; Nierenkrankheit ; Molekulargenetik ; Tumor ; Chromatin ; Metastase ; Nierentumor

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2022
• Creator: Jäger, Stefan
• Contributor: Frew, Ian ; Arnold, Sebastian Johannes ; Timmers, Hermanus T. ; Universitätsklinikum Freiburg. Klinik für Innere Medizin I ; Albert-Ludwigs-Universität Freiburg. Medizinische Fakultät ; Albert-Ludwigs-Universität Freiburg. Fakultät für Biologie

Further information

• DOI: 10.6094/UNIFR/231957
• URN: urn:nbn:de:bsz:25-freidok-2319570
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:49 PM CET