RESUMEN
Alveolar soft part sarcoma(ASPS)is a rare malignant tumor whose origin is unidentified, arising from deep soft tissue and affecting adolescents and young adults. ASPS is characterized by its abundant vascular network forming alveolar structures, and demonstrates frequent hematogenous metastasis. An ASPSCR1-TFE3 fusion gene derived from t(X;17)chromosome translocation is detected as a disease gene in all cases, and the ASPSCR1-TFE3 protein causes abnormal transcriptional regulation. We generated a mouse model for ASPS by introducing ASPSCR1-TFE3 into mouse embryonic mesenchymal cells. In the model, tumor angiogenesis and alveolar structures of human ASPS were reproduced, revealing pericyte-rich blood vessels and metastatic processes with pericytic encapsulation of tumor cell nests. ASPSCR1-TFE3 is frequently associated with active enhancers and super-enhancers, and angiogenesis-related enhancers were significantly diminished by the loss of ASPSCR1- TFE3. Angiogenesis-associated enhancers and important target genes, Rab27a, Sytl2, Pdgfb and Vwf were identified by epigenetic CRISPR screening. Rab27a and Sytl2 facilitates trafficking of cytoplasmic vesicles containing angiogenic factors such as Pdgfb and Vwf, resulting in pericyte-rich vascular structures in ASPS. These studies highlight the importance of the Rab27/Sytl axis as a novel drug target in cancer.
Asunto(s)
Neovascularización Patológica , Sarcoma de Parte Blanda Alveolar , Sarcoma de Parte Blanda Alveolar/genética , Sarcoma de Parte Blanda Alveolar/patología , Humanos , Animales , Neovascularización Patológica/genética , Proteínas de Fusión Oncogénica/genética , Ratones , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-HéliceRESUMEN
Alveolar soft-part sarcoma (ASPS) is a slow-growing soft tissue sarcoma with high mortality rates that affects adolescents and young adults. ASPS resists conventional chemotherapy; thus, decades of research have elucidated pathogenic mechanisms driving the disease, particularly its angiogenic capacities. Integrated blood vessels that are rich in pericytes (PCs) and metastatic potential are distinctive of ASPS. To mimic ASPS angiogenic microenvironment, a microfluidic coculture vasculature chip has been developed as a three-dimensional (3D) spheroid composed of mouse ASPS, a layer of PCs, and endothelial cells (ECs). This ASPS-on-a-chip provided functional and morphological similarity as the in vivo mouse model to elucidate the cellular crosstalk within the tumor vasculature before metastasis. We successfully reproduce ASPS spheroid and leaky vessels representing the unique tumor vasculature to assess effective drug delivery into the core of a solid tumor. Furthermore, this ASPS angiogenesis model enabled us to investigate the role of proteins in the intracellular trafficking of bioactive signals from ASPS to PCs and ECs during angiogenesis, including Rab27a and Sytl2. The results can help to develop drugs targeting the crosstalk between ASPS and the adjacent cells in the tumoral microenvironment.
Asunto(s)
Sarcoma de Parte Blanda Alveolar , Animales , Ratones , Sarcoma de Parte Blanda Alveolar/tratamiento farmacológico , Sarcoma de Parte Blanda Alveolar/metabolismo , Sarcoma de Parte Blanda Alveolar/patología , Células Endoteliales/metabolismo , Técnicas de Cocultivo , Microfluídica , Microambiente TumoralRESUMEN
BACKGROUND/AIM: Individuals with Down syndrome (DS), attributed to triplication of human chromosome 21 (Hsa21), exhibit a reduced incidence of solid tumors. However, the prevalence of glioblastoma among individuals with DS remains a contentious issue in epidemiological studies. Therefore, this study examined the gliomagenicity in Ts1Cje mice, a murine model of DS. MATERIALS AND METHODS: We employed the Sleeping Beauty transposon system for the integration of human oncogenes into cells of the subventricular zone of neonatal mice. RESULTS: Notably, Sleeping Beauty-mediated de novo murine gliomagenesis was significantly suppressed in Ts1Cje mice compared to wild-type mice. In glioblastomas of Ts1je mice, we observed an augmented presence of M1-polarized tumor-associated macrophages and microglia, known for their anti-tumor efficacy in the early stage of tumor development. CONCLUSION: Our findings in a mouse model of DS offer novel perspectives on the diminished gliomagenicity observed in individuals with DS.