A live single-cell reporter assay links intratumor heterogeneity to metastatic proclivity in Ewing sarcoma

Keskin, Tuğba; Rucci, Beatrice; Cornaz-Buros, Sandrine; Martin, Patricia; Fusco, Carlo; Broye, Liliane C.; Cisarova, Katarina; Perez, Elizabeth M.; Letovanec, Igor; Rosa, Stefano La; Cherix, Stéphane; Diezi, Manuel; Renella, Raffaele; Provero, Paolo; Suvà, Mario L.; Stamenkovic, Ivan; Riggi, Nicolò

doi:10.1126/sciadv.abf9394

Cited by 7 publications

(4 citation statements)

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“…The inactivation of EPHB2 accelerates the occurrence of CRC. Besides, EPHB2 mutations are closely associated with tumor suppression in gastric cancer and involved in the prognosis and metastasis of other tumors such as Ewing sarcoma ( Davalos et al, 2007 ; Keskin et al, 2021 ). ATOH1 is a target of the JNK1 and MUC2 pathways and closely associated with the proliferation, invasion, and metastasis of CRC cells ( Shen et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Profile Reveals a Prognostic Signature of Non–MSI-H/pMMR Colorectal Cancer

Liu

et al. 2022

Front. Cell Dev. Biol.

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Studies have demonstrated that non–MSI-H/pMMR colorectal cancer (CRC) has a worse prognosis and relapse rate than microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) CRC. Hence, searching for a novel tool to advance the prognostic management of non–MSI-H/pMMR CRC is vital. In this study, using three independent public cohorts and a clinical in-house cohort, we developed and validated a microsatellite stable–associated signature (MSSAS). The initial signature establishment was performed in GSE39582 (n = 454). This was followed by independent validation of this signature in The Cancer Genome Atlas–CRC (n = 312), GSE39084 (n = 54), and in-house cohort (n = 146). As a result, MSSAS was proven to be an independent risk factor for overall survival and relapse-free survival in non–MSI-H/pMMR CRC. Receiver operating characteristic analysis showed that MSSAS had a stable and accurate performance in all cohorts for 1, 3, and 5 years, respectively. Further analysis suggested that MSSAS performed better than age, gender, and the T, N, M, and AJCC stages, adjuvant chemotherapy, tumor mutation burden, neoantigen, and TP53, KRAS, BRAF, and PIK3CA mutations. The clinical validation was executed to further ensure the robustness and clinical feasibility of this signature. In conclusion, MSSAS might be a robust and promising biomarker for advancing clinical management of non–MSI-H/pMMR CRC.

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Section: Discussionmentioning

confidence: 99%

Gene Expression Profile Reveals a Prognostic Signature of Non–MSI-H/pMMR Colorectal Cancer

Liu

et al. 2022

Front. Cell Dev. Biol.

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“…Overexpression of EphB2 increases the aggressiveness of EwS2 in threedimensional cultures. The miR-145 enabled us to identify EphB2 as a facilitator of EwS metastasis, which can serve both as a predictor of tumor behavior and as a potential therapeutic target for eliminating that most adventitious cell [47].…”

Section: Eph/ephrin and Ewing's Sarcomamentioning

confidence: 99%

The Eph/Ephrin system in primary bone tumor and bone cancer pain

Wang

Pan

2023

Aging

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The family of Eph receptor tyrosine kinases and their Ephrin ligands system constitutes a bidirectional signaling pathway. Eph/Ephrin system coordinate a wide spectrum of pathologic processes during development, metastasis, prognosis, drug resistance and angiogenesis in carcinogenesis. Chemotherapy, surgery and radiotherapy are the most commonly used clinical treatments for primary bone tumors. Therefore, surgical resection is often unable to completely eliminate the tumor, and this is the main cause of metastasis and postoperative recurrence. A growing body of literature has been published lately revitalizing our scientific interest towards the role of Eph/Ephrins in pathogenesis and the treatment of bone tumor and bone cancer pain. This study mainly reviewed the roles of Eph/Ephrin system that has both tumor-suppressing andpromoting roles in primary bone tumors and bone cancer pain. Understanding the intracellular mechanisms of Eph/Ephrin system in tumorigenesis and metastasis of bone tumors might provide a foundation for the development of Eph/Ephrin targeted anti-cancer therapy.

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“…The EWSR1::FLI1/ERG fusion oncoproteins function as activators and repressors of gene expression (7). Several recent studies have suggested that genes typically repressed by EWSR1::FLI1/ERG fusion proteins may become activated due to variable fusion protein levels or external stimuli and that such changes in gene expression may contribute to the development of metastatic EWS (8)(9)(10)(11). Repressed EWSR1::FLI1/ERG gene targets include many encoding proteins involved in cell-cell and cell-extracellular interactions, specifically proteins involved in actin cytoskeletal organization, extracellular matrix (ECM)-receptor interactions, and focal adhesion formation -processes associated with cell migration and invasion (9).…”

Section: Introductionmentioning

confidence: 99%

ETS1, a target gene of the EWSR1::FLI1 fusion oncoprotein, regulates the expression of the focal adhesion protein TENSIN3

Ebegboni,

Jones,

Brownmiller

et al. 2023

Preprint

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The mechanistic basis for the metastasis of Ewing sarcomas remains poorly understood, as these tumors harbor few mutations beyond the chromosomal translocation that initiates the disease. Instead, the epigenome of Ewing sarcoma (EWS) cells reflects the regulatory state of genes associated with the DNA binding activity of the fusion oncoproteins EWSR1::FLI1 or EWSR1::ERG. In this study, we examined the EWSR1::FLI1/ERG’s repression of transcription factor genes, concentrating on those that exhibit a broader range of expression in tumors than in EWS cell lines. Focusing on one of these target genes,ETS1, we detected EWSR1::FLI1 binding and an H3K27me3 repressive mark at this locus. Depletion of EWSR1::FLI1 results in ETS1’s binding of promoter regions, substantially altering the transcriptome of EWS cells, including the upregulation of the gene encoding TENSIN3 (TNS3), a focal adhesion protein. EWS cell lines expressing ETS1 (CRISPRa) exhibited increased TNS3 expression and enhanced movement compared to control cells. The cytoskeleton of control cells and ETS1-activated EWS cell lines also differed. Specifically, control cells exhibited a distributed vinculin signal and a network-like organization of F-actin. In contrast, ETS1-activated EWS cells showed an accumulation of vinculin and F-actin towards the plasma membrane. Interestingly, the phenotype of ETS1-activated EWS cell lines depleted of TNS3 resembled the phenotype of the control cells. Critically, these findings have clinical relevance asTNS3expression in EWS tumors positively correlates with that ofETS1.SignificanceETS1’s transcriptional regulation of the gene encoding the focal adhesion protein TENSIN3 in Ewing sarcoma cells promotes cell movement, a critical step in the evolution of metastasis.Graphical abstract

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A live single-cell reporter assay links intratumor heterogeneity to metastatic proclivity in Ewing sarcoma

Cited by 7 publications

References 50 publications

Gene Expression Profile Reveals a Prognostic Signature of Non–MSI-H/pMMR Colorectal Cancer

Gene Expression Profile Reveals a Prognostic Signature of Non–MSI-H/pMMR Colorectal Cancer

The Eph/Ephrin system in primary bone tumor and bone cancer pain

ETS1, a target gene of the EWSR1::FLI1 fusion oncoprotein, regulates the expression of the focal adhesion protein TENSIN3

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