SWI/SNF Alterations in Squamous Bladder Cancers

Achenbach, Fabian; Rose, Michael; Ortiz-Brüchle, Nadina; Seillier, Lancelot; Knüchel, Ruth; Weyerer, Veronika; Hartmann, Arndt; Morsch, Ronja; Maurer, Angela; Ecke, Thorsten; Garczyk, Stefan; Gaisa, Nadine T.

doi:10.3390/genes11111368

Cited by 3 publications

(2 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Squamous differentiation is observed in 25% of human endometrial cancer and was recently associated with disease recurrence, and it has been observed in mouse models [99][100][101]. ARID1A and SWI/SNF mutations have been shown to promote carcinogenesis of various squamous tumor types [102,103]. We observed that ARID1A mutant UCEC tumors have higher TP63 expression than TP53 mutant tumors.…”

Section: Plos Geneticsmentioning

confidence: 57%

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

et al. 2021

View full text Add to dashboard Cite

TP53 and ARID1A are frequently mutated across cancer but rarely in the same primary tumor. Endometrial cancer has the highest TP53-ARID1A mutual exclusivity rate. However, the functional relationship between TP53 and ARID1A mutations in the endometrium has not been elucidated. We used genetically engineered mice and in vivo genomic approaches to discern both unique and overlapping roles of TP53 and ARID1A in the endometrium. TP53 loss with oncogenic PIK3CAH1047R in the endometrial epithelium results in features of endometrial hyperplasia, adenocarcinoma, and intraepithelial carcinoma. Mutant endometrial epithelial cells were transcriptome profiled and compared to control cells and ARID1A/PIK3CA mutant endometrium. In the context of either TP53 or ARID1A loss, PIK3CA mutant endometrium exhibited inflammatory pathway activation, but other gene expression programs differed based on TP53 or ARID1A status, such as epithelial-to-mesenchymal transition. Gene expression patterns observed in the genetic mouse models are reflective of human tumors with each respective genetic alteration. Consistent with TP53-ARID1A mutual exclusivity, the p53 pathway is activated following ARID1A loss in the endometrial epithelium, where ARID1A normally directly represses p53 pathway genes in vivo, including the stress-inducible transcription factor, ATF3. However, co-existing TP53-ARID1A mutations led to invasive adenocarcinoma associated with mutant ARID1A-driven ATF3 induction, reduced apoptosis, TP63+ squamous differentiation and invasion. These data suggest TP53 and ARID1A mutations drive shared and distinct tumorigenic programs in the endometrium and promote invasive endometrial cancer when existing simultaneously. Hence, TP53 and ARID1A mutations may co-occur in a subset of aggressive or metastatic endometrial cancers, with ARID1A loss promoting squamous differentiation and the acquisition of invasive properties.

show abstract

Section: Plos Geneticsmentioning

confidence: 57%

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…In contrast, the opposite results were observed when FBXO28 was knocked down. Mutations and loss of expression of the SWI/SNF complex and its subunits are found in various tumors, such as endometrial cancer [ 36 ], esophageal adenocarcinoma [ 37 ], lung cancer [ 38 ], thyroid cancer [ 39 ], and bladder cancer [ 40 ]. Tsuda et al [ 41 ] showed that SWI/SNF subunits and their downstream pathways are potential therapeutic targets in PC.…”

Section: Discussionmentioning

confidence: 99%

FBXO28 promotes proliferation, invasion, and metastasis of pancreatic cancer cells through regulation of SMARCC2 ubiquitination

Liu,

Zhu

et al. 2023

Aging

View full text Add to dashboard Cite

The E3 ligase F-box only protein 28 (FBXO28) belongs to the F-box family of proteins that play a critical role in tumor development. However, the potential function of FBXO28 in pancreatic cancer (PC) and its molecular mechanism remain unclear. In this study, we examined FBXO28 expression in PC and its biological role and explored the mechanism of FBXO28-mediated proliferation, invasion, and metastasis of PC cells. Compared with paracancerous tissues and human normal pancreatic ductal epithelial cells, FBXO28 was highly expressed in PC tissues and cell lines. High expression of FBXO28 was negatively correlated with the survival prognosis of patients with PC. Functional assays indicated that FBXO28 promoted PC cell proliferation, invasion, and metastasis in vitro and in vivo. Furthermore, immunoprecipitation-mass spectrometry was used to identify SMARCC2 as the target of FBXO28; upregulation of SMARCC2 can reverse the effect of overexpression of FBXO28 on promoting the proliferation, invasion, and metastasis of PC cells. Mechanistically, FBXO28 inhibited SMARCC2 expression in posttranslation by increasing SMARCC2 ubiquitination and protein degradation. In conclusion, FBXO28 has a potential role in PC, possibly promoting PC progression through SMARCC2 ubiquitination. Thus, FBXO28 might be a potential treatment target in PC.

show abstract

Characterisation of tumour-immune phenotypes and PD-L1 positivity in squamous bladder cancer

et al. 2023

Self Cite

View full text Add to dashboard Cite

Aims Immune checkpoint inhibitor (ICI) therapy has become a viable treatment strategy in bladder cancer. However, treatment responses vary, and improved biomarkers are needed. Crucially, the characteristics of immune cells remain understudied especially in squamous differentiated bladder cancer (sq-BLCA). Here, we quantitatively analysed the tumour-immune phenotypes of sq-BLCA and correlated them with PD-L1 expression and FGFR3 mutation status. Methods Tissue microarrays (TMA) of n = 68 non-schistosomiasis associated pure squamous cell carcinoma (SCC) and n = 46 mixed urothelial carcinoma with squamous differentiation (MIX) were subjected to immunohistochemistry for CD3, CD4, CD8, CD56, CD68, CD79A, CD163, Ki67, perforin and chloroacetate esterase staining. Quantitative image evaluation was performed via digital image analysis. Results Immune infiltration was generally higher in stroma than in tumour regions. B-cells (CD79A) were almost exclusively found in stromal areas (sTILs), T-lymphocytes and macrophages were also present in tumour cell areas (iTILs), while natural killer cells (CD56) were nearly missing in any area. Tumour-immune phenotype distribution differed depending on the immune cell subset, however, hot tumour-immune phenotypes (high density of immune cells in tumour areas) were frequently found for CD8 + T-cells (33%), especially perforin + lymphocytes (52.2%), and CD68 + macrophages (37.6%). Perforin + CD8 lymphocytes predicted improved overall survival in sq-BLCA while high PD-L1 expression (CPS ≥ 10) was significantly associated with higher CD3 + , CD8 + and CD163 + immune cell density and high Ki67 (density) of tumour cells. Furthermore, PD-L1 expression was positively associated with CD3 + /CD4 + , CD3 + /CD8 + and CD68 + /CD163 + hot tumour-immune phenotypes. FGFR3 mutation status was inversely associated with CD8 + , perforin + and CD79A + lymphocyte density. Conclusions Computer-based image analysis is an efficient tool to analyse immune topographies in squamous bladder cancer. Hot tumour-immune phenotypes with strong PD-L1 expression might pose a promising subgroup for clinically successful ICI therapy in squamous bladder cancer and warrant further investigation.

show abstract

SWI/SNF Alterations in Squamous Bladder Cancers

Cited by 3 publications

References 53 publications

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

FBXO28 promotes proliferation, invasion, and metastasis of pancreatic cancer cells through regulation of SMARCC2 ubiquitination

Characterisation of tumour-immune phenotypes and PD-L1 positivity in squamous bladder cancer

Contact Info

Product

Resources

About