Directed cell migration towards a softer environment is called negative durotaxis. The mechanism and pathological relevance of negative durotaxis in tumor progression still requires in-depth investigation. Here, we report that YAP promotes the negative durotaxis of melanoma. We uncovered that the RhoA-myosin II pathway may underlie the YAP enhanced negative durotaxis of melanoma cells. Acral melanoma is the most common subtype of melanoma in non-Caucasians and tends to develop in a stress-bearing area. We report that acral melanoma patients exhibit YAP amplification and increased YAP activity. We detected a decreasing stiffness gradient from the tumor to the surrounding area in the acral melanoma microenvironment. We further identified that this stiffness gradient could facilitate the negative durotaxis of melanoma cells. Our study advanced the understanding of mechanical force and YAP in acral melanoma and we proposed negative durotaxis as a new mechanism for melanoma dissemination.

Purpose: Alveolar soft part sarcoma (ASPS) is an ultrarare soft-tissue sarcoma with a high rate of metastasis and no established treatment. This study aimed to explore the efficacy and safety of anlotinib (a tyrosine kinase inhibitor) and TQB2450 (a PD-L1 inhibitor) in patients with ASPS. Patients and Methods: This single-arm, phase II study evaluated the efficacy of TQB2450, an anti–PD-L1 agent, combined with anlotinib, a tyrosine kinase inhibitor, in adults with advanced ASPS. TQB2450 was given intravenously (1,200 mg) on day 1, and anlotinib (12 mg/day) was taken orally from day 1 to 14 every 3 weeks. The primary endpoint was overall response rate, with secondary endpoints including duration of response, progression-free survival, and overall survival. Lymphocyte infiltration and tertiary lymphoid structure (TLS) were also analyzed as potential prognostic biomarkers. Results: The study enrolled 29 patients, of whom 28 were evaluable (one withdrew because of acute pancreatitis). An objective response was achieved in 82.1% of patients, including 4 complete and 19 partial responses. The median time to response was 2.8 months, and the duration of response was not reached, with an estimated median progression-free survival of 35.2 months. Grade 3 to 4 treatment-related adverse events occurred in 44.8% of patients, with no study-related deaths. Responders had a higher proportion of TLS area, TLS density, and CD20-positive immune cells. Conclusions: The combination of anlotinib and TQB2450 is effective and tolerable in patients with ASPS. TLS may serve as a prognostic biomarker, meriting further investigation.

Background: The goal of this study was to retrospectively analyze the efficacy and safety of pembrolizumab in the real-world treatment of soft tissue sarcoma (STS). Methods: We analyzed 38 patients who suffered from STS and received pembrolizumab treatment from July 2017 to December 2018 in our hospital. We investigated the influence of clinical characteristics, treatment timing, and treatment protocol on objective response rate (ORR). We also investigated the factors affecting overall survival (OS) and progression-free survival (PFS), as well as the occurrence of severe adverse events (SAEs). Results: The overall ORR was 19.4% (7/36). The ORRs of patients who received pembrolizumab treatment as first-line, second-line, and third-line therapy were 42.9% (3/7), 25.0% (4/16), and 0% (0/13), respectively, which showed marginal significance (P=0.052). Four patients (11.1%) maintained a complete response (CR) or partial response (PR) for at least 6 months with pembrolizumab monotherapy, or after withdrawal of chemotherapy or targeted therapy regimens. The median PFS was 2.9 months [95% confidence interval (CI): 2.4–3.4 months] and the median OS was 12.0 months (95% CI: 10.2–13.8 months). Cox regression analysis showed that treatment time was an independent factor affecting PFS (P=0.041), while Eastern Cooperative Oncology Group (ECOG) performance status (PS) score was the only independent factor affecting OS (P=0.028). Conclusions: In the real world, the effectiveness of pembrolizumab in the treatment of STS was low. Some subtypes showed a limited response to pembrolizumab, including alveolar soft part sarcoma (ASPS), undifferentiated pleomorphic sarcoma (UPS), exoskeletal chondrosarcoma (ESCS), and angiosarcoma (AS), while the response in leiomyosarcoma (LMS) was low. Combination therapy may increase the risk of SAEs, especially when combined with pazopanib.

Background: Ewing sarcoma is a malignancy of primitive cells, possibly of mesenchymal origin. It is probable that genetic perturbations other than EWS-FLI1 cooperate with it to produce the tumor. Sequencing studies identified STAG2 mutations in approximately 15% of cases in humans. In the present study, we hypothesize that loss of Stag2 cooperates with EWS-FLI1 in generating sarcomas derived from murine mesenchymal stem cells (MSCs). Methods: Mice bearing an inducible EWS-FLI1 transgene were crossed to p53^−/− mice in pure C57/Bl6 background. MSCs were derived from the bone marrow of the mice. EWS-FLI1 induction and Stag2 knockdown were achieved in vitro by adenovirus-Cre and shRNA-bearing pGIPZ lentiviral infection, respectively. The cells were then treated with ionizing radiation to 10 Gy. Anchorage independent growth in vitro was assessed by soft agar assays. Cellular migration and invasion were evaluated by transwell assays. Cells were injected with Matrigel intramuscularly into C57/Bl6 mice to test for tumor formation. Results: Primary murine MSCs with the genotype EWS-FLI1 p53^−/− were resistant to transformation and did not form tumors in syngeneic mice without irradiation. Stag2 inhibition increased the efficiency and speed of sarcoma formation significantly in irradiated EWS-FLI1 p53^−/− MSCs. The efficiency of tumor formation was 91% for cells in mice injected with Stag2-repressed cells and 22% for mice receiving cells without Stag2 inhibition (p < .001). Stag2 knockdown reduced survival of mice in Kaplan-Meier analysis (p < .001). It also increased MSC migration and invasion in vitro but did not affect proliferation rate or aneuploidy. Conclusion: Loss of Stag2 has a synergistic effect with EWS-FLI1 in the production of sarcomas from murine MSCs, but the mechanism may not relate to increased proliferation or chromosomal instability. Primary murine MSCs are resistant to transformation, and the combination of p53 null mutation, EWS-FLI1, and Stag2 inhibition does not confer immediate conversion of MSCs to sarcomas. Irradiation is necessary in this model, suggesting that perturbations of other genes beside Stag2 and p53 are likely to be essential in the development of EWS-FLI1-driven sarcomas from MSCs.

Background: Alveolar soft part sarcoma (ASPS) is a translocation-associated soft-tissue tumor resistant to conventional cytotoxic agents. This report aims to compare the efficacy of anlotinib versus pazopanib as targeted monotherapy in metastatic ASPS and to determine the impact of drug dosage reduction on disease control. Methods: Sixteen and 31 patients with metastatic ASPS were respectively treated with anlotinib and pazopanib monotherapy at a single institution. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were retrieved and compared between both therapeutic arms. Adverse events (AEs) within each group were recorded. Kaplan-Meier survivorship curves computed the impact of drug dosage reduction on PFS. Results: The anlotinib group showed an ORR of 31.2%, compared to 35.5% in the pazopanib arm (P=0.772). Median PFS was 23.6 months [95% confidence interval (CI), 16.2–31.0 months] in patients treated with anlotinib, but dropped to 13.7 months (95% CI, 10.8–16.7 months) in those managed with pazopanib (P=0.023). One (6.3%) patient on anlotinib and 11 (35.5%) on pazopanib developed AEs requiring drug dosage reduction (P=0.029), which significantly reduced patients’ PFS in the latter setting (10.5 vs. 15.8 months, P=0.012). In patients without dosage reduction, anlotinib showed a bordering advantage than pazopanib on median PFS (24.5 vs. 15.8 months, P=0.112). Conclusions: Compared to pazopanib, anlotinib yielded longer PFS and lower incidence of AEs in ASPS patients. Drug dosage reduction was more frequently encountered with the former agent and affected the disease control.

Background: Intratumoral oncolytic herpes simplex virus 2-GM CSF (OH2) injection has shown safety and antitumor efficacy in patients with solid tumors. Here, we examined the safety and efficacy of OH2 as a single agent or in combination with HX008, an NMPA-approved PD-1 inhibitor, in locally advanced or metastatic sarcoma patients. Methods: This multicenter, phase 1/2 trial enrolled patients with injectable sarcoma lesions, who had failed at least 1 or more lines of standard treatment. Patients were treated with OH2 at three dose levels (10⁶, 10⁷ and 10⁸ CCID₅₀/mL) as single agent or in combination with a fixed dose of HX008. The primary endpoints were safety and tolerability in phase 1 and objective response rate determined by RECIST (V.1.1) criteria and immune-RECIST in phase 2. Results: Between October 20, 2020 and December 30, 2023, 26 patients were enrolled. Seven patients were treated with single-agent OH2 and 19 with HX008 and OH2 combination. No dose-limiting toxicities were observed during the dose escalation. We documented four partial or complete responses in injected lesions, and one partial response in non-injected lesions, which were all from the combination group. Hence, the overall response rate was 0% and 16.7% in the single agent and combination groups, respectively. The duration of response was 3.9–6.5 months. The most frequent treatment-related adverse events (TRAEs) were fever (n=9). Grade 3 or 4 TRAEs were reported in four patients (15.4%). A clear increase in CD8+cell density in the tumor microenvironment was observed in the patients’ post-treatment specimens compared with baseline. Conclusions: Intratumoral injection of oncolytic virus OH2 is well tolerable in patients with sarcoma. Further investigation of OH2 with HX008 in select sarcoma subtypes is warranted.