A5024722868- Protein Degradation and Inhibitors
- Sarcoma Diagnosis and Treatment
- Cancer-related gene regulation
- Cancer-related molecular mechanisms research
- Ubiquitin and proteasome pathways
- RNA modifications and cancer
- Genomics and Chromatin Dynamics
- Epigenetics and DNA Methylation
- CAR-T cell therapy research
- Histone Deacetylase Inhibitors Research
- FOXO transcription factor regulation
- RNA Interference and Gene Delivery
- Peptidase Inhibition and Analysis
- Cancer Cells and Metastasis
- Virus-based gene therapy research
- Muscle Physiology and Disorders
- Cancer Genomics and Diagnostics
- Acute Lymphoblastic Leukemia research
- MicroRNA in disease regulation
- DNA Repair Mechanisms
- Cell Adhesion Molecules Research
- Cancer-related Molecular Pathways
- Cancer, Hypoxia, and Metabolism
- Heat shock proteins research
- CRISPR and Genetic Engineering
National Cancer Institute
2019-2025
University of Rome Tor Vergata
2022-2024
Bambino Gesù Children's Hospital
2016-2024
National Institutes of Health
2019-2024
Istituti di Ricovero e Cura a Carattere Scientifico
2015-2024
University of Bologna
2011-2015
Istituto Dermopatico dell'Immacolata
2015
Abstract Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3–FOXO1. The mechanisms which PAX3–FOXO1 dysregulates chromatin are unknown. We find reprograms cis-regulatory landscape inducing de novo super enhancers. uses enhancers to set up autoregulatory loops in collaboration with master factors MYOG, MYOD, MYCN. This enhancer circuitry consistent across cell lines primary tumors....
Abstract Identity determining transcription factors (TFs), or core regulatory (CR) TFs, are governed by cell-type specific super enhancers (SEs). Drugs to selectively inhibit CR circuitry of high interest for cancer treatment. In alveolar rhabdomyosarcoma, PAX3-FOXO1 activates SEs induce the expression other providing a model system studying cell addiction transcription. Using chemical genetics, systematic screening matter biological outcome, here we report on screen epigenetic probes able...
Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting are lacking. Here, we screen 62,643 compounds using engineered cell line that monitors transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm inhibition of multiple KDMs with highest...
Since the histone modifying enzymes EZH2 and HDACs control a number of epigenetic-dependent carcinogenic pathways, we designed first-in-class dual EZH2/HDAC inhibitor 5 displaying (sub)micromolar inhibition against both targets. When tested in several cancer cell lines, hybrid impaired viability at low micromolar level leukemia U937 rhabdomyosarcoma RH4 cells provided G1 arrest, apoptotic induction, increased differentiation, associated with an increase acetyl-H3 acetyl-α-tubulin decrease...
Periodontitis is linked to the onset and progression of oral squamous cell carcinoma (OSCC), an epidemiologically frequent clinically aggressive malignancy. In this context, Fusobacterium (F.) nucleatum Porphyromonas (P.) gingivalis, two bacteria that cause periodontitis, are found in OSCC tissues as well premalignant lesions, where they exert pro-tumorigenic activities. Since present also endodontic diseases, playing a role their pathogenesis, here we analyze literature searching for...
Rhabdomyosarcoma (RMS) is an aggressive pediatric malignancy of the muscle, that includes Fusion Positive (FP)-RMS harboring PAX3/7-FOXO1 and Negative (FN)-RMS commonly with RAS pathway mutations. RMS express myogenic master transcription factors MYOD MYOG yet are unable to terminally differentiate. Here, we report SNAI2 highly expressed in FN-RMS, oncogenic, blocks differentiation, promotes growth. activates via super enhancers striped 3D contact architecture. Genome wide chromatin binding...
Core regulatory transcription factors (CR TFs) establish enhancers with logical ordering during embryogenesis and development. Here we report that in fusion-positive rhabdomyosarcoma, a cancer of the muscle lineage, chief oncogene PAX3-FOXO1 is driven by translocated FOXO1 super enhancer (SE) restricted to late stage myogenesis. Using chromatin conformation capture techniques, demonstrate extensive cis-regulatory domain interacts PAX3. Furthermore, RNA sequencing immunoprecipitation data...
Rhabdomyosarcoma (RMS) is a pediatric soft tissue sarcoma arising from myogenic precursors that have lost their capability to differentiate into skeletal muscle. The polycomb-group protein EZH2 Lys27 histone H3 methyltransferase regulates the balance between cell proliferation and differentiation by epigenetically silencing muscle-specific genes. often over-expressed in several human cancers acting as an oncogene. We previously reported inhibition induces cycle arrest followed of RMS cells...
Oral squamous cell carcinoma (OSCC) is a rapidly progressive cancer that often develops resistance against DNA damage inducers, such as radiotherapy and chemotherapy, which are still the standard of care regimens for this tumor. Thus, identification biomarkers capable monitoring clinical progression OSCC its responsiveness to therapy strongly required. To meet need, here we have employed Whole Genome Sequencing RNA-seq data from cohort 316 patients retrieved TCGA Pan-Cancer Atlas analyze...
Abstract BACKGROUND: Oncogenic fusion genes are attractive therapeutic targets due to their tumor-specific expression and driver roles in cancer. PAX3::FOXO1 (P3F) is the dominant oncogenic of fusion-positive rhabdomyosarcoma (FP-RMS) with no current targeted therapy. METHOD: HiBiT tag, an 11 amino acid peptide NanoLuc luciferase, was inserted into C-terminal end endogenous P3F using CRISPR. Western used for tag validation. RNA-seq ChIP-seq were assess transcriptomics DNA binding...
One of the critical events that regulates muscle cell differentiation is replacement lamin B receptor (LBR)-tether with A/C (LMNA)-tether to remodel transcription and induce differentiation-specific genes. Here, we report localization activity LBR-tether are crucially dependent on muscle-specific chaperone HSPB3 depletion prevents differentiation. We further show binds LBR in nucleoplasm maintains it a dynamic state, thus promoting myogenic genes, including genes extracellular matrix....
Hepatocellular carcinoma (HCC) is one of the most common and lethal malignant tumours worldwide. Sorafenib (SOR) effective single-drug systemic therapy against advanced HCC, but identification novel combination regimens for a continued improvement in overall survival big challenge. Recent studies highlighted crucial role focal adhesion kinase (FAK) HCC growth. The aim this study was to investigate antitumor effects three different FAK inhibitors (FAKi), alone or with SOR, using vitro vivo...
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. About 25% RMS expresses fusion oncoproteins such as PAX3/PAX7-FOXO1 (fusion-positive, FP) while fusion-negative (FN)-RMS harbors RAS mutations. Radiotherapy (RT) plays a crucial role in local control but metastatic often radio-resistant. HDAC inhibitors (HDACi) radio-sensitize different cancer cells types. Thus, we evaluated MS-275 (Entinostat), Class I and IV HDACi, combination with RT on vitro vivo. reversibly...
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood. Recently, we demonstrated overexpression of both DNA methyltransferase 3A (DNMT3A) and 3B (DNMT3B) RMS tumour biopsies cell lines compared to normal skeletal muscle. Radiotherapy may often fail due abnormal expression some molecules able drive resistance mechanisms. The aim this study was analyse involvement DNMT3A DNMT3B radioresistance RMS. RNA interference experiments against DNMT3A/3B were performed embryonal...
Although progress in children, adults, ALL still carries a dismal outcome. Here, we explored the vitro and vivo activity of PF-00477736 (Pfizer), potent, selective ATP-competitive small-molecule inhibitor checkpoint kinase 1 (Chk1) with lower efficacy 2 (Chk2). The effectiveness as single agent B-/T-ALL was evaluated studies agent. compound terms cytotoxicity, induction apoptosis, changes gene protein expression assessed using different cell lines. Finally, action leukemic mouse generated by...