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Nature Communications May 2023Paediatric rhabdomyosarcoma (RMS) is a soft tissue malignancy of mesenchymal origin that is thought to arise as a consequence of derailed myogenic differentiation....
Paediatric rhabdomyosarcoma (RMS) is a soft tissue malignancy of mesenchymal origin that is thought to arise as a consequence of derailed myogenic differentiation. Despite intensive treatment regimens, the prognosis for high-risk patients remains dismal. The cellular differentiation states underlying RMS and how these relate to patient outcomes remain largely elusive. Here, we use single-cell mRNA sequencing to generate a transcriptomic atlas of RMS. Analysis of the RMS tumour niche reveals evidence of an immunosuppressive microenvironment. We also identify a putative interaction between NECTIN3 and TIGIT, specific to the more aggressive fusion-positive (FP) RMS subtype, as a potential cause of tumour-induced T-cell dysfunction. In malignant RMS cells, we define transcriptional programs reflective of normal myogenic differentiation and show that these cellular differentiation states are predictive of patient outcomes in both FP RMS and the less aggressive fusion-negative subtype. Our study reveals the potential of therapies targeting the immune microenvironment of RMS and suggests that assessing tumour differentiation states may enable a more refined risk stratification.
Topics: Child; Humans; Transcriptome; Cell Proliferation; Rhabdomyosarcoma; Rhabdomyosarcoma, Embryonal; Gene Expression Profiling; Cell Line, Tumor; Tumor Microenvironment
PubMed: 37244912
DOI: 10.1038/s41467-023-38886-8 -
Frontiers in Endocrinology 2023Uterine leiomyoma is the most common benign tumor in females of reproductive age. However, its causes have never been fully understood. The objective of our study was to... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVE
Uterine leiomyoma is the most common benign tumor in females of reproductive age. However, its causes have never been fully understood. The objective of our study was to analyze the causal association between various factors and uterine leiomyoma using Mendelian randomization (MR).
METHODS
Genetic variables associated with risk factors were obtained from genome-wide association studies. Summary-level statistical data for uterine leiomyoma were obtained from FinnGen and the UK Biobank (UKB) consortium. We used inverse variance weighted, MR-Egger, and weighted median methods in univariate analysis. Multivariable MR analysis was used to identify independent risk factors. A fixed-effect model meta-analysis was used to combine the results of the FinnGen and UKB data.
RESULTS
In the FinnGen data, higher genetically predicted age at natural menopause, systolic blood pressure (SBP), diastolic blood pressure (DBP), and fasting insulin were associated with an increased risk of uterine leiomyoma, while higher age at menarche was associated with a reduced risk of uterine leiomyoma. Multivariable MR analysis of SBP and DBP showed that higher DBP might be an independent risk factor of uterine leiomyoma. In the UKB data, the results for age at natural menopause, SBP, DBP, and age at menarche were replicated. The result of the meta-analysis suggested that uterine leiomyoma could also be affected by polycystic ovary syndrome (PCOS), endometriosis, and 2-hour glucose level.
CONCLUSION
Our MR study confirmed that earlier menstrual age, hypertension, obesity, and elevated 2-hour glucose post-challenge were risk factors for uterine leiomyoma, and the causal relationship between smoking and uterine leiomyoma was ruled out. In addition, later age of menopause and endometriosis were found to increase the risk of uterine leiomyoma, while PCOS was found to decrease the risk.
Topics: Female; Humans; Endometriosis; Genome-Wide Association Study; Mendelian Randomization Analysis; Leiomyoma; Polycystic Ovary Syndrome; Glucose
PubMed: 37576957
DOI: 10.3389/fendo.2023.1133260 -
Archivos de Cardiologia de Mexico Sep 2023
Topics: Humans; Leiomyoma; Heart; Heart Neoplasms
PubMed: 37669690
DOI: 10.24875/ACM.22000205 -
International Journal of Molecular... Nov 2020Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of children and adolescents. The fusion-positive (FP)-RMS variant expressing chimeric oncoproteins such as... (Review)
Review
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of children and adolescents. The fusion-positive (FP)-RMS variant expressing chimeric oncoproteins such as PAX3-FOXO1 and PAX7-FOXO1 is at high risk. The fusion negative subgroup, FN-RMS, has a good prognosis when non-metastatic. Despite a multimodal therapeutic approach, FP-RMS and metastatic FN-RMS often show a dismal prognosis with 5-year survival of less than 30%. Therefore, novel targets need to be discovered to develop therapies that halt tumor progression, reducing long-term side effects in young patients. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that regulates focal contacts at the cellular edges. It plays a role in cell motility, survival, and proliferation in response to integrin and growth factor receptors' activation. FAK is often dysregulated in cancer, being upregulated and/or overactivated in several adult and pediatric tumor types. In RMS, both in vitro and preclinical studies point to a role of FAK in tumor cell motility/invasion and proliferation, which is inhibited by FAK inhibitors. In this review, we summarize the data on FAK expression and modulation in RMS. Moreover, we give an overview of the approaches to inhibit FAK in both preclinical and clinical cancer settings.
Topics: Animals; Carcinogenesis; Child; Clinical Trials as Topic; Focal Adhesion Kinase 1; Gene Expression Regulation, Neoplastic; Humans; Models, Biological; Molecular Targeted Therapy; Muscle Development; Neoplasm Invasiveness; Neoplasm Metastasis; Oncogene Proteins, Fusion; Protein Kinase Inhibitors; Rhabdomyosarcoma; Signal Transduction; Soft Tissue Neoplasms
PubMed: 33182556
DOI: 10.3390/ijms21228422 -
African Journal of Paediatric Surgery :... 2022Rhabdomyosarcoma (RMS) is one of the common malignant soft-tissue sarcomas affecting children. It originates from the embryonic mesenchyme precursor of striated muscle...
Rhabdomyosarcoma (RMS) is one of the common malignant soft-tissue sarcomas affecting children. It originates from the embryonic mesenchyme precursor of striated muscle and is frequently seen in the head-and-neck region, genitourinary system and extremities. Occasionally, it arises from the retroperitoneum, biliary tract and abdomen and is rarely seen in the sacrococcygeal area. A 4-month-male child presented with a nodule over the sacrum. Based on histopathology and immunohistochemical marker studies, a final diagnosis of RMS was rendered. There was no evidence of any teratomatous elements.
Topics: Child; Humans; Male; Rhabdomyosarcoma; Sacrococcygeal Region; Soft Tissue Neoplasms; Teratoma
PubMed: 36018208
DOI: 10.4103/ajps.ajps_69_21 -
EMBO Molecular Medicine Oct 2022Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for...
Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here, we describe the generation of a collection of 19 pediatric RMS tumor organoid (tumoroid) models (success rate of 41%) comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within 4-8 weeks, indicating the feasibility of personalized drug screening. Molecular, genetic, and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to 6 months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions.
Topics: Child; Humans; Organoids; Rhabdomyosarcoma
PubMed: 35916583
DOI: 10.15252/emmm.202216001 -
International Journal of Biological... 2023Uterine leiomyoma is the most common gynecological tumor in reproductive women. Tumor-host interface is a complex ecosystem with intimate cell-cell communications and a...
Uterine leiomyoma is the most common gynecological tumor in reproductive women. Tumor-host interface is a complex ecosystem with intimate cell-cell communications and a critical scenario for tumor pathogenesis and progression. The pseudocapsule is the main tumor-host interface of uterine leiomyoma, but its cellular spatial disposition and gene expression are poorly explored. This study mapped the cellular architecture and corresponding gene profiles of the leiomyoma and its surrounding pseudocapsule by integrating spatial transcriptomics and single-nucleus RNA-sequencing at the first time. Here, we reported that estrogen receptor alpha and progesterone receptor mediated the occurrence and development of uterine leiomyoma and that estrogen receptor beta involved in the angiogenesis, which explained the effectiveness of hormonotherapy. Therapeutic targets including ERK1/ERK2 pathway and IGF1-IGF1R were found and might be applied for non-hormonal therapy of uterine leiomyoma. Furthermore, the injection of prostaglandin E2 was initially presented for bleeding control during myomectomy, injection site should be located at the junction between pseudocapsule and leiomyoma, and surrounding pseudocapsule should not be eliminated. Collectively, a single-cell and spatially resolved atlas of human uterine leiomyoma and its surrounding pseudocapsule was established. The results revealed potentially feasible strategies for hormonotherapy, non-hormonal targeted therapy and bleeding control during myomectomy.
Topics: Female; Humans; Uterine Neoplasms; Ecosystem; Transcriptome; Leiomyoma; Uterine Myomectomy
PubMed: 37215998
DOI: 10.7150/ijbs.83510 -
International Journal of Molecular... Oct 2022Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence that includes FP-RMS, harboring the fusion oncoprotein PAX3/7-FOXO1 and... (Review)
Review
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood and adolescence that includes FP-RMS, harboring the fusion oncoprotein PAX3/7-FOXO1 and FN-RMS, often mutant in the RAS pathway. Risk stratifications of RMS patients determine different prognostic groups and related therapeutic treatment. Current multimodal therapeutic strategies involve surgery, chemotherapy (CHT) and radiotherapy (RT), but despite the deeper knowledge of response mechanisms underpinning CHT treatment and the technological improvements that characterize RT, local failures and recurrence frequently occur. This review sums up the RMS classification and the management of RMS patients, with special attention to RT treatment and possible radiosensitizing strategies for RMS tumors. Indeed, RMS radioresistance is a clinical problem and further studies aimed at dissecting radioresistant molecular mechanisms are needed to identify specific targets to hit, thus improving RT-induced cytotoxicity.
Topics: Adolescent; Humans; Paired Box Transcription Factors; Rhabdomyosarcoma; Oncogene Proteins, Fusion
PubMed: 36362070
DOI: 10.3390/ijms232113281 -
Ear, Nose, & Throat Journal Sep 2021
Topics: Adolescent; Child; Female; Head and Neck Neoplasms; Humans; Male; Medical Illustration; Myofibroblasts; Neoplasms, Muscle Tissue; Young Adult
PubMed: 31760795
DOI: 10.1177/0145561319890165 -
Oncogene Mar 2022Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar...
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures. Our validation studies for a CRISPR screen of 400 epigenetic targets identified SMARCA4 as a unique factor for long-term (but not short-term) tumor cell survival in ARMS. A SMARCA4/SMARCA2 protein degrader (ACBI-1) demonstrated similar long-term tumor cell dependence in vitro and in vivo. These results credential SMARCA4 as a tumor cell dependency factor and a therapeutic target in ARMS.
Topics: Biology; Child; DNA Helicases; Humans; Neoplasms; Nuclear Proteins; Rhabdomyosarcoma, Alveolar; Rhabdomyosarcoma, Embryonal; Transcription Factors
PubMed: 35094009
DOI: 10.1038/s41388-022-02205-0