Background Desmoid tumors (DTs) are rare and understudied fibroblastic lesions that are frequently recurrent and locally invasive. DT patients often experience chronic pain, organ dysfunction, decrease in quality of life, and even death. Methods Sorafenib has emerged as a promising therapeutic strategy, which has led to the first randomized phase 3 clinical trial devoted to DTs. Concurrently, we conducted a comprehensive analysis of sorafenib efficacy in a large panel of desmoid cell strains to probe for response mechanism. Results We found distinctive groups of higher‐ and lower‐responder cells. Clustering the lower‐responder group, we observed that CTNNB1 mutation was determinant of outcome. Our results revealed that a lower dose of sorafenib was able to inhibit cell viability, migration, and invasion of wild‐type and T41A‐mutated DTs. Apoptosis induction was observed in those cells after treatment with sorafenib. On the other hand, the lower dose of sorafenib was not able to inhibit cell viability, migration, or invasion or to induce apoptosis in the S45F‐mutated DTs. The investigation of autophagy showed the dependency of S45F‐mutated DTs on this pathway as a part of cell survival mechanism. Significantly, when autophagy was inhibited genetically or pharmacologically in the S45F mutant cell strains, sensitivity to sorafenib was restored. Conclusions Our findings suggest that the response to sorafenib differs when comparing S45F‐mutated DTs and T41A‐mutated or wild‐type DTs. Furthermore, the combination of hydroxychloroquine and sorafenib enhances the antiproliferative and proapoptotic effects in S45F‐mutated DT cells, suggesting that profiling β‐catenin status could guide clinical management of desmoid patients who are considering sorafenib treatment.

Wnt/β-catenin signaling is one of the key cascades regulating embryogenesis and tissue homeostasis; it has also been intimately associated with carcinogenesis. This pathway is deregulated in several tumors, including colorectal cancer, breast cancer, and desmoid tumors. It has been shown that CTNNB1 exon 3 mutations are associated with an aggressive phenotype in several of these tumor types and may be associated with therapeutic tolerance. Desmoid tumors typically have a stable genome with β-catenin mutations as a main feature, making these tumors an ideal model to study the changes associated with different types of β-catenin mutations. Here, we show that the apoptosis mechanism is deregulated in β-catenin S45F mutants, resulting in decreased induction of apoptosis in these cells. Our findings also demonstrate that RUNX3 plays a pivotal role in the inhibition of apoptosis found in the β-catenin S45F mutants. Restoration of RUNX3 overcomes this inhibition in the S45F mutants, highlighting it as a potential therapeutic target for malignancies harboring this specific CTNNB1 mutation. While the regulatory effect of RUNX3 in β-catenin is already known, our results suggest the possibility of a feedback loop involving these two genes, with the CTNNB1 S45F mutation downregulating expression of RUNX3 , thus providing additional possible novel therapeutic targets for tumors having deregulated Wnt/β-catenin signaling induced by this mutation.

BackgroundSarcomas are malignant heterogeneous tumors of mesenchymal derivation. Dedifferentiated liposarcoma (DDLPS) is aggressive with recurrence in 80% and metastasis in 20% of patients. We previously found that miR-133a was significantly underexpressed in liposarcoma tissues. As this miRNA has recently been shown to be a tumor suppressor in many cancers, the objective of this study was to characterize the biological and molecular consequences of miR-133a underexpression in DDLPS.MethodsReal-time PCR was used to evaluate expression levels of miR-133a in human DDLPS tissue, normal fat tissue, and human DDLPS cell lines. DDLPS cells were stably transduced with miR-133a vector to assess the effects in vitro on proliferation, cell cycle, cell death, migration, and metabolism. A Seahorse Bioanalyzer system was also used to assess metabolism in vivo by measuring glycolysis and oxidative phosphorylation (OXPHOS) in subcutaneous xenograft tumors from immunocompromised mice.ResultsmiR-133a expression was significantly decreased in human DDLPS tissue and cell lines. Enforced expression of miR-133a decreased cell proliferation, impacted cell cycle progression kinetics, decreased glycolysis, and increased OXPHOS. There was no significant effect on cell death or migration. Using an in vivo xenograft mouse study, we showed that tumors with increased miR-133a expression had no difference in tumor growth compared to control, but did exhibit an increase in OXPHOS metabolic respiration.ConclusionsBased on our collective findings, we propose that in DDPLS, loss of miR-133a induces a metabolic shift due to a reduction in oxidative metabolism favoring a Warburg effect in DDLPS tumors, but this regulation on metabolism was not sufficient to affect DDPLS.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0583-2) contains supplementary material, which is available to authorized users.