TGF-β signaling promotes desmoid tumor formation via CSRP2 upregulation

Desmoid tumors (DTs), also called desmoid-type fibromatoses, are locally aggressive tumors of mesenchymal origin. In the present study, we developed a novel mouse model of DTs by inducing a local mutation in the Ctnnb1 gene, encoding β-catenin in PDGFRA-positive stromal cells, by subcutaneous injection of 4-hydroxy-tamoxifen. Tumors in this model resembled histologically clinical samples from DT patients and showed strong phosphorylation of nuclear SMAD2. Knockout of SMAD4 in the model significantly suppressed tumor growth. Proteomic analysis revealed that SMAD4 knockout reduced the level of Cysteine-and-Glycine-Rich Protein 2 (CSRP2) in DTs, and treatment of DT-derived cells with a TGF-β receptor inhibitor reduced CSRP2 RNA levels. Knockdown of CSRP2 in DT cells significantly suppressed their proliferation. These results indicate that the TGF-β/CSRP2 axis is a potential therapeutic target for DTs downstream of TGF-β signaling.

Introduction: Upper extremity (UE) desmoid tumors are locally aggressive neoplasms with high recurrence rates. Our study sought to analyze the demographics and treatment strategies of UE desmoid tumors and identify risk factors for recurrence.

Materials and methods: A retrospective review of 52 patients with histologically confirmed UE desmoid tumors treated at our institution between 1990 and 2015 was conducted. Survival was assessed using the Kaplan-Meier method and the Cox proportional hazards model was used for risk factor analysis.

Results: For the entire cohort, median age was 40 (29-47) years, 75% were female, and 48% had local recurrence. The median tumor size was 45 (15-111) cm3 on imaging. Twenty-two patients had a previous resection. The most common treatments were surgery alone (50%) and surgery with adjuvant radiotherapy (21%). Tumor size ≥5 cm and tumor volume ≥40 cm3 on imaging were associated with increased recurrence (p = 0.006 and p = 0.005, respectively). Age and sex were not associated with local recurrence. Patients with a tumor size ≥5 cm were 2.6 times more likely to present with recurrence. At the 10-year mark, a lower local recurrence-free survival was seen in patients with tumors ≥5 cm (72.2% vs. 36.3%, p = 0.042) or ≥40 cm3 (67.2% vs. 32.7%, p = 0.034).

Conclusion: In our study, only tumor dimensions appeared to modify recurrence risk.

Background: Precision surgery is becoming increasingly important in the field of Orthopaedic Oncology. Image-guided percutaneous cryosurgery (CRA) has emerged as a valid treatment modality for extra-abdominal desmoid tumors (EDTs). To date, most CRA procedures use CT-based guidance which fails to properly characterize tumor segments. Computer-guided MRI navigation can address this issue however, the lack of a fixed landmark for registration remains a challenge. Successful CRA correlates directly with precision approaches facilitated by intraoperative imaging guidance. This is the first study that attempts to assess the feasibility and efficacy of a novel approach of using skin fiducial markers to overcome the challenge of a MRI-based navigation CRA for symptomatic or progressive EDTs.

Methods: In this retrospective study conducted between 2018 and 2020, 11 patients at a single center with symptomatic or progressive EDTs were treated with CRA using intraoperative MRI navigation. Fifteen cryosurgery procedures were performed, each adhering to a personalized pre-operative plan. Total tumor size, viable and non-viable portions pre- and post-operation, and SF-36 questionnaire evaluating subjective health were recorded.

Results: All CRAs demonstrated 100% adherence to the predetermined plan. Overall, tumor size decreased Median= -56.9% [-25.6, -72.4]) with a reduction in viable tissue, (Median= -80.4% [-53.3, -95.2]). Four patients required additional CRAs. Only one patient’s tumor did not reduce in size. One patient suffered from local muscle necrosis. Pre-operation, the average physical and mental scores 41.6 [29.4, 43] and 26.3 [17.6, 40.9] respectively. Post-operation, the average physical and mental scores were 53.4[38, 59.7] and 38 [31.2, 52.7] respectively.

Conclusion: These findings provide an early indication of the feasibility and efficacy of performing percutaneous cryosurgery using skin fiducial marker registration for MRI-computed navigation to treat EDTs safely. Larger cohorts and multicenter evaluations are needed to determine the efficacy of this technique.

Diagnostic classification of soft tissue tumors is based on histology, immunohistochemistry, genetic findings, and radiologic and clinical correlations. Recently, a sarcoma DNA methylation classifier was developed, covering 62 soft tissue and bone tumor entities. The classifier is based on large-scale analysis of methylation sites across the genome. It includes DNA copy number analysis and determines O6 methylguanine DNA methyl-transferase methylation status. In this study, we evaluated 619 well-studied soft tissue and bone tumors with the sarcoma classifier. Problem cases and typical examples of different entities were included. The classifier had high sensitivity and specificity for fusion sarcomas: Ewing, synovial, CIC-rearranged, and BCOR-rearranged. It also performed well for leiomyosarcoma, malignant peripheral nerve sheath tumors (MPNST), and malignant vascular tumors. There was low sensitivity for diagnoses of desmoid fibromatosis, neurofibroma, and schwannoma. Low specificity of matches was observed for angiomatoid fibrous histiocytoma, inflammatory myofibroblastic tumor, Langerhans histiocytosis, schwannoma, undifferentiated sarcoma, and well-differentiated/dedifferentiated liposarcoma. Diagnosis of lipomatous tumors was greatly assisted by the detection of MDM2 amplification and RB1 loss in the copy plot. The classifier helped to establish diagnoses for KIT-negative gastrointestinal stromal tumors, MPNSTs with unusual immunophenotypes, and undifferentiated melanomas. O6 methylguanine DNA methyl-transferase methylation was infrequent and most common in melanomas (35%), MPNSTs (11%), and undifferentiated sarcomas (11%). The Sarcoma Methylation Classifier will likely evolve with the addition of new entities and refinement of the present methylation classes. The classifier may also help to define new entities and give new insight into the interrelationships of sarcomas.

Purpose: This study sought to identify β-catenin targets that regulate desmoid oncogenesis and determine whether external signaling pathways, particularly those inhibited by sorafenib (e.g., PDGFRβ), affect these targets to alter natural history or treatment response in patients.

Experimental design: In vitro experiments utilized primary desmoid cell lines to examine regulation of β-catenin targets. Relevance of results was assessed in vivo using Alliance trial A091105 correlative biopsies.

Results: CTNNB1 knockdown inhibited hypoxia-regulated gene expression in vitro and reduced levels of HIF1α protein. ChIP-seq identified ABL1 as a β-catenin transcriptional target that modulated HIF1α and desmoid cell proliferation. Abrogation of either CTNNB1 or HIF1 inhibited desmoid cell-induced VEGFR2 phosphorylation and tube formation in endothelial cell co-cultures. Sorafenib inhibited this activity directly but also reduced HIF1α protein expression and c-Abl activity while inhibiting PDGFRβ signaling in desmoid cells. Conversely, c-Abl activity and desmoid cell proliferation were positively regulated by PDGF-BB. Reduction in PDGFRβ and c-Abl phosphorylation was commonly observed in biopsy samples from patients after treatment with sorafenib; markers of PDGFRβ/c-Abl pathway activation in baseline samples were associated with tumor progression in patients on the placebo arm and response to sorafenib in patients receiving treatment.

Conclusions: The β-catenin transcriptional target ABL1 is necessary for proliferation and maintenance of HIF1α in desmoid cells. Regulation of c-Abl activity by PDGF signaling and targeted therapies modulates desmoid cell proliferation, thereby suggesting a reason for variable biologic behavior between tumors, a mechanism for sorafenib activity in desmoids, and markers predictive of outcome in patients.

none available