Myxofibrosarcoma is a common mesenchymal malignancy with complex genomics and heterogeneous clinical outcomes. Through gene-expression profiling of 64 primary high-grade myxofibrosarcomas, we defined an expression signature associated with clinical outcome. The gene most significantly associated with disease-specific death and distant metastasis was ITGA10 (integrin-α10). Functional studies revealed that myxofibrosarcoma cells strongly depended on integrin-α10, whereas normal mesenchymal cells did not. Integrin-α10 transmitted its tumor-specific signal via TRIO and RICTOR, two oncoproteins that are frequently co-overexpressed through gene amplification on chromosome 5p. TRIO and RICTOR activated RAC/PAK and AKT/mTOR to promote sarcoma cell survival. Inhibition of these proteins with EHop-016 (RAC inhibitor) and INK128 (mTOR inhibitor) had anti-tumor effects in tumor-derived cell lines and mouse xenografts, and combining the drugs enhanced the effects. Our results demonstrate the importance of integrin-α10/TRIO/RICTOR signaling for driving myxofibrosarcoma progression and provide the basis for promising targeted treatment strategies for patients with high-risk disease.
Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are highly genetically complex soft tissue sarcomas. Up to 50% of patients develop distant metastases, but current systemic therapies have limited efficacy. MFS and UPS have recently been shown to commonly harbor copy number alterations or mutations in the tumor suppressor genes RB1 and TP53. As these alterations have been shown to engender dependence on the oncogenic protein Skp2 for survival of transformed cells in mouse models, we sought to examine its function and potential as a therapeutic target in MFS/UPS. Comparative genomic hybridization (CGH) and next-generation sequencing (NGS) confirmed that a significant fraction of MFS and UPS patient samples (n=94) harbor chromosomal deletions and/or loss-of-function mutations in RB1 and TP53 (88% carry alterations in at least one gene; 60% carry alterations in both). Tissue microarray (TMA) analysis identified a correlation between absent Rb and p53 expression and positive expression of Skp2. Downregulation of Skp2 or treatment with the Skp2-specific inhibitor C1 revealed that Skp2 drives proliferation of patient-derived MFS/UPS cell lines deficient in both Rb and p53 by degrading p21 and p27. Inhibition of Skp2 using the neddylation-activating enzyme (NAE) inhibitor pevonedistat decreased growth of Rb/p53negative patient-derived cell lines and mouse xenografts. These results demonstrate that loss of both Rb and p53 renders MFS and UPS dependent on Skp2, which can be therapeutically exploited and could provide the basis for promising novel systemic therapies for MFS and UPS.Significance: Loss of both Rb and p53 renders myxofibrosarcoma and undifferentiated pleomorphic sarcoma dependent on Skp2, which could provide the basis for promising novel systemic therapies.Research.
The Pacific abalone Haliotis discus hannai is one of the most economically important mollusks in China. Even though it has been farmed in southern China for almost 20 years, summer mortality remains the most challengeable problem for Pacific abalone aquaculture recently. Here, we determined the different heat tolerance ability for five selective lines of H. discus hannai by measuring the cardiac performance and Arrhenius breakpoint temperature (ABT). The Red line (RL) and Yangxia line (YL) were determined as the most heat-sensitive and most heat-tolerant line, respectively. Heart rates for RL were significantly lower than those of the YL at the same temperature (p < 0.05). The differentially expressed genes (DEGs), which were enriched in several pathways including cardiac muscle contraction, glutathione metabolism and oxidative phosphorylation, were identified between RL and YL at control temperature (20°C) and heat stress temperature (28.5°C, the ABT of the RL) by RNA-seq method. In the RL, 3370 DEGs were identified between the control and the heat-stress temperature, while only 1351 DEGs were identified in YL between these two temperature tests. Most of these DEGs were enriched in the pathways such as protein processing in endoplasmic reticulum, nucleotide binding and oligomerization domain (NOD) like receptor signaling, and ubiquitin mediated proteolysis. Notably, the most heat-tolerant line YL used an effective heat-protection strategy based on moderate transcriptional changes and regulation on the expression of key genes.
Liposarcoma is the most common soft tissue sarcoma. Molecularly targeted therapeutics have had limited efficacy in liposarcomas, in part because of inadequate knowledge of the complex molecular alterations in these tumors. Our recent study revealed the tumor suppressive function of miR-193b in liposarcoma. Considering the biological and clinical heterogeneity of liposarcoma, here, we confirmed the under-expression of miR-193b in additional patient liposarcoma samples and cell lines. Based on STRING analysis of protein-protein interactions among the reported putative miR-193b targets, we validated three: PDGFRβ, SMAD4, and YAP1, belonging to strongly interacting pathways (focal adhesion, TGFβ, and Hippo, respectively). We show that all three are directly targeted by miR-193b in liposarcoma. Inhibition of PDGFRβ reduces liposarcoma cell viability and increases adipogenesis. Knockdown of SMAD4 promotes adipogenic differentiation. miR-193b targeting of the Hippo signaling effector YAP1 indirectly inhibits Wnt/β-catenin signaling. Both a PDGFR inhibitor (CP-673451) and a Wnt/ β-catenin inhibitor (ICG-001) had potent inhibitory effects on liposarcoma cells, suggesting their potential application in liposarcoma treatment. In summary, we demonstrate that miR-193b controls cell growth and differentiation in liposarcoma by targeting multiple key components (PDGFRβ, SMAD4, and YAP1) in several oncogenic signaling pathways.
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