The potential role of the extracellular matrix in the activity of trabectedin in UPS and L-sarcoma: evidences from a patient‐derived primary culture case series in tridimensional and zebrafish models

Abstract

Background Soft tissue sarcomas (STS) are a rare group of solid neoplasm including among others liposarcoma, leiomyosarcoma (L-sarcoma) and undifferentiated pleomorphic sarcoma (UPS) entities. The current first-line treatment is represented by anthracycline based- regimens, second-line may include trabectedin. Currently the activity of trabectedin and its mechanism of action is not completely elucidated. Methods Taking the advantages of our 3D patient-derived primary culture translational model we performed genomic-, chemobiogram, proteomic- and in vivo analysis in a UPS culture (S1). Furthermore pharmacological profiling of a UPS and L-sarcoma patient-derived case series and in silico analysis were carried out. Results Trabectedin exhibited an increased activity in 3D respect to 2D cultures suggesting an extracellular matrix (ECM) and timp1 involvement in its mechanism of action. Moreover 3D S1 xenotranspanted zebrafish model showed an increased sensitivity to trabectedin. Finally the results were further validated in a UPS and L-sarcoma case series. Conclusions Taken together these results confirmed the activity of trabectedin in these STS histotypes. Moreover the data underline the ECM involvement in the cytotoxic effect mediated by trabectedin and could open the door for researches aimed to focus on the patient setting that could benefit from this agent.

Deciphering the Genomic Landscape and Pharmacological Profile of Uncommon Entities of Adult Rhabdomyosarcomas

“…In RMS3, among all investigated EMT-related genes, an upregulation of MMP9 was detected. In this regard, metallopeptidases have already been associated with tumor aggressiveness in many studies including STS and could represent therapeutic targets for these lesions [ 35 ]. Interestingly, while a chemoresistance profile was expected for a pleomorphic RMS, a downregulation of chemoresistance-related genes was observed.…”

“…RMS patient-derived primary cells (RMS1 patients) were isolated and established according to the protocol previously reported [ 35 , 57 ]. Briefly, surgical-resected tumor tissue was washed in PBS, sectioned, and finely crumbled with surgical scalpels.…”

“…For the 2D culture model, a cell density of 80,000 per cm 2 was used. For the 3D culture system, the seeding was obtained following the simple soaking of the cell suspension in the dry scaffolds as previously reported [ 35 ], with a cell density of 500,000 cells/mm 3 . RMS primary cultures were maintained in DMEM supplemented with 10% fetal bovine serum (Invitrogen), 1% penicillin/streptomycin, and 1% glutamine at 37 °C in a 5% CO 2 atmosphere.…”

The Extracellular Matrix in Soft Tissue Sarcomas: Pathobiology and Cellular Signalling

“…Trabectedin is an approved second-line treatment for advanced STS and in addition to its cytotoxic mode of action, it exerts its therapeutic effect via modulation of the tumour microenvironment ( Zewail-Foote and Hurley, 1999 ; Carter and Keam, 2010 ). A recent study investigated the response of commonly used first- and second-line chemotherapy drugs, including trabectedin, in patient-derived cell cultures grown on plastic and embedded in collagen-based scaffolds ( de Vita et al, 2021 ). Patient-derived cultures were obtained by a single cell dissociation of fresh surgical specimens from one leiomyosarcoma, three dedifferentiated liposarcoma, three well-differentiated liposarcoma, three undifferentiated pleomorphic sarcoma patients.…”

The mir-423-5p/MMP-2 Axis Regulates the Nerve Growth Factor-Induced Promotion of Chondrosarcoma Metastasis

“…The metastatic process involves the secretion of proteolytic enzymes such as matrix metalloproteinases (MMPs) and cathepsins, capable of degrading the extracellular matrix (ECM) and basement membrane [5,6]. It is likely that the ECM component alpha-1 type I collagen (col1a1) contributes to the tumor growth as col1a1 is upregulated in various tumors [7] and significantly higher levels of MMP-2 expression have not only been recorded in human chondrosarcoma specimens than in normal cartilage [8] but also increasingly higher levels of MMP-2 expression in human chondrosarcoma cells stimulate their migratory and metastatic potential [7,8]. Interestingly, microtubule depolymerizing drugs display antitumor activities in soft tissue sarcomas [9] while the transcription factor ETV5 reportedly regulates MMP-2 expression in human chondrosarcomas [10].…”