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In cancer cells the small compounds erastin and RSL3 promote a novel type of cell death called ferroptosis, which requires iron‐dependent accumulation of lipid reactive oxygen species. Here we assessed the contribution of lipid peroxidation activity of lipoxygenases (LOX) to ferroptosis in oncogenic Ras‐expressing cancer cells. Several 12/15‐LOX inhibitors prevented cell death induced by erastin and RSL3. Furthermore, siRNA‐mediated silencing of ALOX15 significantly decreased both erastin‐induced and RSL3‐induced ferroptotic cell death, whereas exogenous overexpression of ALOX15 enhanced the effect of these compounds. Immunofluorescence analyses revealed that the ALOX15 protein consistently localizes to cell membrane during the course of ferroptosis. Importantly, treatments of cells with ALOX15‐activating compounds accelerated cell death at low, but not high doses of erastin and RSL3. These observations suggest that tumor ferroptosis is promoted by LOX‐catalyzed lipid hydroperoxide generation in cellular membranes. The lipid‐peroxidizing enzyme (ALOX15) constitutively localizes on the cell membrane in human fibrosarcoma HT1080 cells, and cells with enhanced ALOX15 activity are more sensitive to ferroptosis‐inducing compounds.

Mesenchymal neoplasms of the uterus (corpus and cervix) encompass a heterogeneous group of tumors with differing morphologies, immunophenotypes and molecular alterations. With the advent of modern molecular techniques, such as next generation sequencing, newly defined genetic abnormalities are being reported in this group of neoplasms. Herein we report the clinicopathological and molecular features of a series of 13 spindle cell sarcomas of the uterus and vagina (10 cervix, 2 uterine corpus, 1 vagina) with morphology resembling fibrosarcoma. After targeted RNA-sequencing, dual FISH fusion and array-CGH analysis, 7 of 13 tumors exhibited NTRK rearrangements (6 TPM3-NTRK1 and 1 EML4-NTRK3 ) and 3 a COL1A1-PDGFB fusion; in the other 3 neoplasms, all of which were positive with S100 (2 diffuse, 1 focal), we identified no rearrangement. All the NTRK fusion-positive sarcomas were located in the cervix and exhibited diffuse staining with Trk while all the other neoplasms were negative. CD34 was diffusely positive in all 3 of the COL1A1-PDGFB fusion sarcomas. The latter molecular abnormality is identical to that commonly found in dermatofibrosarcoma protuberans and has not been reported previously in uterine mesenchymal neoplasms. We suggest that uterine sarcomas with a morphology resembling fibrosarcoma (and in which leiomyosarcoma and the known molecularly confirmed high-grade endometrial stromal sarcomas have been excluded) can be divided into 3 groups:- an NTRK fusion group, a COL1A1-PDGFB fusion group and a group containing neither of these molecular abnormalities which, on the basis of positive staining with S100, could be tentatively classified as malignant peripheral nerve sheath tumor, although additional molecular studies may identify specific genetic alterations necessitating a nomenclature change. We suggest a diagnostic algorithm when reporting such neoplasms. Identification of these newly described fusion-associated sarcomas is important given the potential for targeted treatments.

Myxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by an infiltrative growth pattern and a high local recurrence rate. Here we report the genetic and epigenetic landscape of MFS based on the results of whole-exome sequencing ( N  = 41), RNA sequencing ( N  = 29), and methylation analysis ( N  = 41), using 41 MFSs as a discovery set, and subsequent targeted sequencing of 140 genes in the entire cohort of 99 MFSs and 17 MFSs' data from TCGA. Fourteen driver genes are identified, including potentially actionable therapeutic targets seen in 37% of cases. There are frequent alterations in p53 signaling (51%) and cell cycle checkpoint genes (43%). Other conceivably actionable driver genes including ATRX , JAK1 , NF1 , NTRK1 , and novel oncogenic BRAF fusion gene are identified. Methylation patterns cluster into three subtypes associated with unique combinations of driver mutations, clinical outcomes, and immune cell compositions. Our results provide a valuable genomic resource to enable the design of precision medicine for MFS. Myxofibrosarcoma occurs in adults and is associated with high local relapse. Here, based on exome/transcriptome sequencing and DNA methylation analysis, the authors identify driver genes and methylation clusters associated with unique combinations of mutations, outcomes, and immune cell compositions.

Undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS) are genetically complex soft tissue sarcomas with distinct morphological features. Treatment typically involves surgery, often combined with neoadjuvant chemo- or radiotherapy. To better understand the immunobiology of these sarcomas and its associations with treatment response and prognosis, we performed transcriptomic and immunophenotypic profiling. RNA sequencing was performed on 13 UPS and 10 MFS, and immunological profiles were compared with soft tissue sarcoma data from The Cancer Genome Atlas ( n  = 206 including 44 UPS and 17 MFS). Immune contextures were further evaluated in 14 UPS and 15 MFS using imaging mass cytometry. Characterization of T cell and macrophage infiltration in tumors was further assessed in 23 UPS and 22 MFS through multispectral immunofluorescence and immunohistochemical analysis. UPS and MFS demonstrated immunogenic features compared to other soft tissue sarcomas, with subsets of UPS and MFS demonstrating high T cell infiltration, while UPS demonstrated a higher infiltration by myeloid cells as compared to MFS. Prognostically, T cells and CD68 + CD163 + macrophages were associated with metastasis-free survival in UPS but not in MFS. Notably, in UPS, neoadjuvant radiotherapy appeared to induce cytotoxic T cell infiltration and depletion of myeloid cells, whereas these effects were not observed in MFS. These findings highlight important differences in the immunobiology of UPS and MFS with therapeutic and prognostic implications. These differences should be taken into account given the growing availability of immunotherapeutic options for treating patients with soft tissue sarcomas.

The venom of Macrovipera lebetinus obtusa (MLO) has remarkable properties that are hard to overlook. This venom’s described 38 protein components work synergistically, forming complexes that greatly enhance their combined effectiveness. Previous studies have shown that both crude venom and one of its components, obtustatin, can reduce sarcoma tumors by 50% and 30%, respectively. Obtustatin, a member of the short disintegrin family, inhibits the angiogenic activity of α1β1 integrin, the adhesive receptor of collagen IV. However, the mechanisms of the greater efficacy of the crude venom compared to its isolated components remain unclear. To investigate this, we propose an experimental work to explore the activity of certain low-molecular-weight components of MLO venom. Our in vitro tests on fibrosarcoma (HT-1080) cells using six venom fractions revealed cytotoxic fractions, which, through mass spectrometry, were identified as containing protein classes such as dimeric and short disintegrins, acidic phospholipase A2, and serine proteinases. Notably, these fractions exhibited minimal toxicity to human dermal microvascular endothelial (HDEC) cells, suggesting their potential as a promising candidate for oncotherapy in the future.

Infantile fibrosarcoma (IFS) is malignant fibroblastic tumor of infants characterized genetically by ETV6::NTRK3 fusion. Tumors that show morphology indistinguishable from IFS but harbor alternative genetic alterations are uncommon, which have been designated as IFS-like tumors. We report two cases of IFS-like tumors harboring an NTRK1 rearrangement and arsing from genitourinary system. The patients aged 3 and 14 years. One arose in the kidney and one in the paratesticular region. The tumors measured 13 and 3.5 cm in greatest dimension. Both tumors were composed of cellular, mildly atypical, spindle to ovoid cells arranged haphazardly or in intersecting fascicles within a collagenized to myxoid stroma. Mitoses numbered 3 and 5/10 high-power fields. Tumor cells in both neoplasms demonstrated variable co-expression of CD34 and S100 protein, and diffuse and strong cytoplasmic staining for pan-TRK and TrkA. Fluorescence in-situ hybridization demonstrated NTRK1 rearrangement in both tumors. Targeted RNA-sequencing identified CPSF6::NTRK1 fusion and TMP3::NTRK1 fusion. Limited follow-up showed no tumor recurrences or metastases. We expand the clinicopathologic spectrum of IFS-like tumors harboring alternative NTRK1 fusions.

Eribulin is a microtubule inhibitor used in the treatment of various malignancies, including soft-tissue sarcoma. However, the development of eribulin resistance is a recalcitrant clinical problem. The present study demonstrates that super eribulin-resistant HT1080 human fibrosarcoma cells become highly malignant but can be eradicated synergistically by the combination of eribulin and methionine restriction in nude mice. The cell viability of parental HT1080 cells and super eribulin-resistant HT1080 was determined following eribulin treatment using the WST-8 reagent. invasion assays, comprising wound-healing of cell monolayers, were performed to determine the degree of malignancy. Tumor growth to determine malignancy and tumor-growth sensitivity to eribulin, or a methionine-restricted diet, or their combination were analyzed in athymic nude mice. The IC of eribulin for parental HT1080 cells was 0.15 nM, whereas for super eribulin-resistant HT1080 cells, the IC of eribulin was 18 nM, a 120-fold increase. Super eribulin-resistant HT1080 cells had a more rapid wound-healing closure rate than their parental HT1080 cells, indicating increased malignancy. Similarly, , untreated super eribulin-resistant HT1080 tumors grew faster than parental HT1080 tumors, confirming their high malignancy. The combination of a methionine-restricted diet and eribulin synergistically arrested super eribulin-resistant HT1080 tumors. Methionine restriction sensitized these highly resistant and malignant cells to eribulin. Methionine restriction combined with eribulin represents a promising strategy to effectively treat eribulin-resistant high-malignancy fibrosarcoma, that can be immediately applied to the clinic.

A1-R (A1-R) expresses green fluorescent protein (GFP) and has the ability to selectively target and inhibit all major cancer types in murine models without persistently infecting healthy tissue. A1-R is being developed for tumor targeting by oral administration. The aim of the present study was to demonstrate real-time imaging of orally-administered A1-R in a fibrosarcoma nude-mouse model and to visualize its trafficking through the gastrointestinal system to the tumor and normal organs. A1-R-GFP (3.3×10 colony-forming units/ml) was administered orally to HT1080 human fibrosarcoma nude-mouse models which were fasted the day before administration. Fluorescence images of A1-R-GFP inside the gastrointestinal tract at 0, 2 and 4 hours after oral gavage were captured. The number of colonies of A1-R-GFP in tumors and liver were determined at 4 hours, and on days 1, 3 and 4 by growth from homogenized tumor and liver tissue on agar plates. The trafficking of A1-R-GFP through the murine gastrointestinal tract post-gavage was monitored in real-time GFP fluorescence imaging. Bacteria, initially observed in the stomach, migrated to the small intestine and the colon and subsequently to the subcutaneously-implanted fibrosarcoma. A1-R-GFP proliferated in the tumors over time. In contrast, A1-R-GFP in the liver diminished over time. The present study showed the pathway of orally administered A1-R-GFP in the gastrointestinal system and to the tumor and liver. A1-R selectively proliferated continuously in tumors and was cleared from the liver. These results are critical for future clinical trials of orally-administered A1-R-GFP.

Primary sclerosing epithelioid fibrosarcoma (SEF) of bone is a rare and scarcely reported neoplasm. We document clinicopathological and molecular features of 9 additional cases. Five males and 4 females had a mean age of 39 years (14–71 years). Most tumors affected flat/irregular bones; only 3 cases involved a long bone. By radiology, it has characteristic radiographic features of a predominantly lytic expansile lesion with a sclerotic rim. Referring diagnoses were SEF (n = 2), low-grade osteosarcoma (n = 2), chondrosarcoma (n = 1), and chondromyxoid fibroma (n = 1). Histologically, five cases revealed classical morphology of SEF of soft tissue. Remaining cases were classified as hybrid SEF/low-grade fibromyxoid sarcoma, characterized by spindle or stellate cells, prominent stroma, and giant hyalinized areas. Various morphological deviations such as prominent vasculature (n = 3), osteoid-like material (n = 4), or parallel bone trabeculae (n = 2) were observed. Immunohistochemically, all cases showed diffuse and strong MUC4 expression. SATB2 was observed in 5/8 cases. Using FISH, EWSR1, and FUS rearrangements were detected in 4 cases and 1 case, respectively. EWSR1-CREB3L1 fusion was identified in 1 additional case by next-generation sequencing. Recurrence and metastasis were observed in 1 case and 2 cases, respectively. All but one patient were alive with disease for a mean interval of 31 months. SEF of bone is a relatively indolent sarcoma of adults, most commonly located in the flat/irregular bones. Due to overlapping histological features, it is often misdiagnosed as osteosarcoma or a chondroid tumor. Most SEF of bone exhibit EWSR1 rearrangements, but rare cases may harbor a FUS gene fusion.