bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/589648

Hippo pathway effectors YAP1/TAZ induce a EWS-FLI1-opposing gene signature and associate with disease progression in Ewing Sarcoma

Rodriguez-Nunez, P.·Romero-Perez, L.·Amaral, A. T.·Puerto-Camacho, P.·Jordan, C.·Grunewald, T.·Marcilla, D.·de Alava, E.·Diaz-Martin, J.
View original source ↗Export metadata ↓

Abstract

YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of Hippo tumor suppressor pathway. Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing Sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involving EWSR1 gene, and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome.\n\nWe did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation of RASSF1 locus -a regulator of Hippo pathway- was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the protumorigenic isoform RASSF1C promoting YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells, and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be partly explained by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS.

Source connections

Explore related subjects

cancer biologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Rodriguez-Nunez, P., Romero-Perez, L., Amaral, A. T., Puerto-Camacho, P., Jordan, C., Grunewald, T., Marcilla, D., de Alava, E., Diaz-Martin, J.. 2019-03-27. Hippo pathway effectors YAP1/TAZ induce a EWS-FLI1-opposing gene signature and associate with disease progression in Ewing Sarcoma. https://doi.org/10.1101/589648

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

BCL10 Gain-of-Function Impairs Germinal Center Participation by Naive B Cells and Cooperates with BCL6 to Drive Extrafollicular Diffuse Large B-Cell Lymphoma

BCL10 gain-of-function (GoF) mutations occur in diffuse large B-cell lymphoma (DLBCL) cases of the BN2/C1 molecular subgroup. These alterations activate CARD11-BCL10-MALT1 (CBM) signaling and drive resistance to multiple drug classes, but their role in disease pathogenesis is incompletely understood. In particular, interactions between BCL10 GoF and additional DLBCL oncogenes are undefined. Here, we show BCL10 GoF in naive B cells blocks their participation in germinal center (GC) reactions and permits transformation to DLBCL with a non-GC B-cell phenotype. Most clinical cases with BCL10 GoF also carry translocation of the BCL6 proto-oncogene, and we show that co-activation of these two lesions together promotes pronounced oncogenic synergy. Detailed single-cell analyses of underlying premalignant B-cell populations revealed expansion of extrafollicular memory B cells whose gene-expression program remains prominent in resulting lymphomas in both the mouse and corresponding human tumors. We therefore define a novel role for BCL10 activating mutations in enabling BCL6 lymphomagenesis.

cancer biology↗
bioRxiv2026

Targeting NF-κB prevents Schwann cell reprogramming and plexiform neurofibroma initiation in mouse model of Nf1

Plexiform neurofibromas arise in approximately half of all individuals with Neurofibromatosis Type I (NF1). Genetic lesions apart from NF1 pathogenic variants are not present in NF1 mutant Schwann cells, suggesting that tumorigenesis may instead require cellular rewiring. To identify putatively re-wired tumor cells, we used multiplex imaging and flow cytometry to delineate markers that distinguish tumor Schwann cell from non-tumor Schwann cells. We identified tumor Schwann cells as CD44+;CD49f+ cells that show increased transcription of epithelial to mesenchymal plasticity (EMP)- associated genes. CD44+;CD49f+ expression was induced by treating Nf1-/- Schwann cells with stressors or by direct NF-{kappa}B pathway activation via IKK2; treated Schwann cells increased secretion of NF-{kappa}B targets and immune cell chemoattractants CCL2 and CCL3. In established tumors, MEK inhibition plus NF-{kappa}B blockade diminished tumor cell proliferation, tumor Schwann cells, immune cell populations, tumor cytokines and tumor number. Notably, transient single agent NF-{kappa}B pathway blockade was sufficient to significantly delay tumor formation in mice. Thus, Nf1 loss in Schwann cells is followed by NF-{kappa}B activation and cellular reprogramming that drives tumor initiation and targeting NF-{kappa}B activation can reduce NF1-deficient tumor formation.

cancer biology↗
bioRxiv2026

Response to azacitidine and the TIM-3 inhibitor, sabatolimab, in MDS and CMML is associated with distinct immune and antigen-presentation states

Targeting the immune checkpoint TIM-3 is of interest in myeloid neoplasms, yet the hematopoietic and immune changes associated with anti-TIM-3 therapy remain poorly characterized. We used single-cell RNA sequencing to profile bone marrow (BM) and peripheral blood from patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) treated with the hypomethylating agent azacitidine combined with sabatolimab, a monoclonal antibody targeting TIM-3, and integrated Human Cell Atlas reference datasets for comparison. CITE-seq profiling showed that TIM-3 was predominantly expressed on dendritic cells and NK cells, with variable expression across other populations, including CD34 cells and CD8 T cells. At baseline, we identified a population of CD34 myeloid-biased progenitors specific to MDS/CMML samples ("HSPC-like") characterized by inflammatory gene expression programs and features of impaired differentiation. In MDS, elevated baseline HLA class II expression across hematopoietic stem and progenitor cells (HSPCs), HSPC-like cells, and multiple myeloid populations was associated with response. Consistent with this finding, trajectory analysis suggested that nonresponders bypassed HLA class II-high states during myeloid differentiation. In MDS, the presence of distinct CD8 T-cell populations and increased interferon-response programs in CD8 T and NK cells at baseline was also associated with response. In both MDS and CMML, treatment among responders was associated with contraction of BM CD8 and CD4 T-cell populations characterized by type I interferon-responsive and inflammatory programs, including IFIT1, IFIT2, and TNF, along with expansion of a distinct GZMH/IFITM1-expressing cytotoxic CD8 T-cell population. Together, these findings identify baseline antigen-presentation and immune-response programs associated with therapeutic response and reveal coordinated remodeling of myeloid and lymphoid compartments during azacitidine/sabatolimab treatment in MDS and CMML.

cancer biology↗