STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma

Adane, Biniam; Alexe, Gabriela; Seong, Bo Kyung A.; Lu, Diana; Hwang, Elizabeth E.; Hnisz, Denes; Lareau, Caleb A.; Ross, Linda S.; Lin, Shuo; Cruz, Filemon S. Dela; Richardson, Melissa; Weintraub, Abraham S.; Wang, Sarah; Iniguez, Amanda Balboni; Dharia, Neekesh V.; Conway, Amy Saur; Robichaud, Amanda L.; Tanenbaum, Benjamin; Krill-Burger, John M.; Vázquez, Francisca; Schenone, Monica; Berman, Jason N.; Kung, Andrew L.; Carr, Steven A.; Aryee, Martin J.; Young, Richard A.; Crompton, Brian D.; Stegmaier, Kimberly

doi:10.1016/j.ccell.2021.05.007

Cited by 74 publications

(64 citation statements)

References 85 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pediatric cancers, however, often have quiet genomes with few recurrent mutations that can be exploited for therapeutic intervention. For example, loss-of-function mutations in the gene STAG2 , which has been shown to play a critical role in cis -chromatin interactions and metastasis, were identified as one of the only recurrent mutations (∼15%) in Ewing sarcoma tumors ( Adane et al., 2021 ; Brohl et al., 2014 ; Crompton et al., 2014 ; Surdez et al., 2021 ; Tirode et al., 2014 ). Our work suggests an alternative therapeutic strategy for Ewing sarcoma by targeting TRIM8, an E3 ligase for EWS/FLI.…”

Section: Discussionmentioning

confidence: 99%

TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

et al. 2021

Self Cite

View full text Add to dashboard Cite

Summary Fusion-transcription factors (fusion-TFs) represent a class of driver oncoproteins that are difficult to therapeutically target. Recently, protein degradation has emerged as a strategy to target these challenging oncoproteins. The mechanisms that regulate fusion-TF stability, however, are generally unknown. Using CRISPR-Cas9 screening, we discovered tripartite motif-containing 8 (TRIM8) as an E3 ubiquitin ligase that ubiquitinates and degrades EWS/FLI, a driver fusion-TF in Ewing sarcoma. Moreover, we identified TRIM8 as a selective dependency in Ewing sarcoma compared with >700 other cancer cell lines. Mechanistically, TRIM8 knockout led to an increase in EWS/FLI protein levels that was not tolerated. EWS/FLI acts as a neomorphic substrate for TRIM8, defining the selective nature of the dependency. Our results demonstrate that fusion-TF protein stability is tightly regulated and highlight fusion oncoprotein-specific regulators as selective therapeutic targets. This study provides a tractable strategy to therapeutically exploit oncogene overdose in Ewing sarcoma and potentially other fusion-TF-driven cancers.

show abstract

Section: Discussionmentioning

confidence: 99%

TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…The protein expression of STAG2 was reported as a prognostic biomarker in low-grade, nonmuscle-invasive bladder cancer [38]. On the contrary, loss of STAG2 promotes migratory and metastatic potential of Ewing sarcoma cells [58]. However, the exact mechanism by which STAG2 drives or suppresses cancer pathogenesis remains unknown.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Values and Underlying Regulatory Network of Cohesin Subunits in Esophageal Carcinoma

Gan¹,

Wang²,

Li³

et al. 2022

J. Cancer

View full text Add to dashboard Cite

Background: Cohesin is a highly conserved and ubiquitously expressed protein complex. While increasing evidence suggests that cohesin dysregulation is vital in the carcinogenesis of numerous malignancies, little is known about the prognostic values and potential mechanisms of cohesin subunits and direct regulators in esophageal carcinoma (ESCA). Methods: RNA-sequencing data from The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) were used. The subunits and regulators of cohesin affecting the prognosis of ESCA were screened by Kaplan-Meier survival analysis; univariate and multivariate Cox regression analyses were performed; and the receiver-operating characteristic (ROC) curve was determined. The ESCA hazard model and nomogram map were constructed by integrating the clinical data. We used functional analysis and protein-protein interaction (PPI) networks to explore underlying pathways. Finally, immunohistochemistry was performed to examine the expression levels of cohesin subunits in tissue microarray (TMA). Results: Transcriptome data from multiple ESCA patient datasets showed cohesin subunits SMC1A, SMC1B, SMC3, STAG1, STAG2, RAD21, and cohesin regulators including ESCO2, NIPBL, MAU2, WAPL, PDS5A and PDS5B were all upregulated in ESCA tissues compared to normal tissues. Survival analysis demonstrated that high STAG2 expression was significantly associated with poorer overall survival (OS) and progression-free survival (PFS) in esophageal adenocarcinoma (EAC). In contrast, high RAD21 expression was significantly correlated with better OS in esophageal squamous cell carcinoma (ESCC). Moreover, STAG2 and RAD21 were identified as independent prognostic factors and predictive biomarkers in EAC and ESCC, respectively. Functional enrichment analysis further revealed that STAG2 and RAD21 were mainly involved in the mitotic nuclear division, DNA repair, angiogenesis, epithelial-mesenchymal transition (EMT), and oncogenic signaling pathways. PPI analysis illustrated that STAG2 and RAD21 could cross-talk through cancer-associated modules and performed the core roles of the whole PPI network. Using TMA, STAG2 protein expression positively correlated with lymph node metastasis and advanced clinical stage of EAC patients, whereas there was a negative correlation between RAD21 protein expression and the malignant clinicopathological parameters in ESCC. Conclusion: These findings suggest that STAG2 and RAD21 can be used as predictive biomarkers for risk assessment and prognostic stratification in ESCA, which provide potential novel insights into molecular targets of ESCA.

show abstract

“…On the other hand, fluctuations in EWS-FLI1 activity levels promote Ewing sarcoma EMT and increase its metastatic potential [ 173 , 174 , 175 ]. These may either be due to modulations in the expression of the chimeric protein [ 175 ], or the result of perturbations in 3D chromatin organization at EWS-FLI1 binding regions caused by the loss of the cohesion component STAG2 [ 176 , 177 ]. Experimental modulation of EWS-FLI1 upregulates the activity of several key players in EMT, including master regulators SNAI1/SNAI2 and ZEB1, mechanosensitive transcriptional cofactors YAP/TAZ [ 178 ] and the NOTCH effector protein and transcriptional repressor Hairy/enhancer-of-split related with YRPW motif protein 1 (HEY1) [ 179 ].…”

Section: Mechanisms Of Metastasismentioning

confidence: 99%

Mechanisms, Diagnosis and Treatment of Bone Metastases

Ban

Fock

Aryee

et al. 2021

Cells

View full text Add to dashboard Cite

Bone and bone marrow are among the most frequent metastatic sites of cancer. The occurrence of bone metastasis is frequently associated with a dismal disease outcome. The prevention and therapy of bone metastases is a priority in the treatment of cancer patients. However, current therapeutic options for patients with bone metastatic disease are limited in efficacy and associated with increased morbidity. Therefore, most current therapies are mainly palliative in nature. A better understanding of the underlying molecular pathways of the bone metastatic process is warranted to develop novel, well-tolerated and more successful treatments for a significant improvement of patients’ quality of life and disease outcome. In this review, we provide comparative mechanistic insights into the bone metastatic process of various solid tumors, including pediatric cancers. We also highlight current and innovative approaches to biologically targeted therapy and immunotherapy. In particular, we discuss the role of the bone marrow microenvironment in the attraction, homing, dormancy and outgrowth of metastatic tumor cells and the ensuing therapeutic implications. Multiple signaling pathways have been described to contribute to metastatic spread to the bone of specific cancer entities, with most knowledge derived from the study of breast and prostate cancer. However, it is likely that similar mechanisms are involved in different types of cancer, including multiple myeloma, primary bone sarcomas and neuroblastoma. The metastatic rate-limiting interaction of tumor cells with the various cellular and noncellular components of the bone-marrow niche provides attractive therapeutic targets, which are already partially exploited by novel promising immunotherapies.

show abstract

STAG2 loss rewires oncogenic and developmental programs to promote metastasis in Ewing sarcoma

Cited by 74 publications

References 85 publications

TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

TRIM8 modulates the EWS/FLI oncoprotein to promote survival in Ewing sarcoma

Prognostic Values and Underlying Regulatory Network of Cohesin Subunits in Esophageal Carcinoma

Mechanisms, Diagnosis and Treatment of Bone Metastases

Contact Info

Product

Resources

About