Nature Communications (Dec 2023)
MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting
- Silvia Pomella,
- Matteo Cassandri,
- Lucrezia D’Archivio,
- Antonella Porrazzo,
- Cristina Cossetti,
- Doris Phelps,
- Clara Perrone,
- Michele Pezzella,
- Antonella Cardinale,
- Marco Wachtel,
- Sara Aloisi,
- David Milewski,
- Marta Colletti,
- Prethish Sreenivas,
- Zoë S. Walters,
- Giovanni Barillari,
- Angela Di Giannatale,
- Giuseppe Maria Milano,
- Cristiano De Stefanis,
- Rita Alaggio,
- Sonia Rodriguez-Rodriguez,
- Nadia Carlesso,
- Christopher R. Vakoc,
- Enrico Velardi,
- Beat W. Schafer,
- Ernesto Guccione,
- Susanne A. Gatz,
- Ajla Wasti,
- Marielle Yohe,
- Myron Ignatius,
- Concetta Quintarelli,
- Janet Shipley,
- Lucio Miele,
- Javed Khan,
- Peter J. Houghton,
- Francesco Marampon,
- Berkley E. Gryder,
- Biagio De Angelis,
- Franco Locatelli,
- Rossella Rota
Affiliations
- Silvia Pomella
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Matteo Cassandri
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Lucrezia D’Archivio
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Antonella Porrazzo
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Cristina Cossetti
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Doris Phelps
- Greehey Children’s Cancer Research Institute (GCCRI), UT Health Science Center
- Clara Perrone
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Michele Pezzella
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Antonella Cardinale
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Marco Wachtel
- Department of Oncology and Children’s Research Center, University Children’s Hospital
- Sara Aloisi
- Department of Genetics and Genome Sciences, Case Western Reserve University
- David Milewski
- Oncogenomics Section, Genetics Branch, National Cancer Institute, NIH,
- Marta Colletti
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Prethish Sreenivas
- Greehey Children’s Cancer Research Institute (GCCRI), UT Health Science Center
- Zoë S. Walters
- Sarcoma Molecular Pathology, Divisions of Molecular Pathology, The Institute of Cancer Research
- Giovanni Barillari
- Department of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata
- Angela Di Giannatale
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Giuseppe Maria Milano
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Cristiano De Stefanis
- Histology-Core Facility, Bambino Gesu’ Children’s Hospital, IRCCS
- Rita Alaggio
- Department of Pathology Unit, Department of Laboratories, Bambino Gesù Children’s Hospital, IRCCS
- Sonia Rodriguez-Rodriguez
- Department of Stem Cell and Regenerative Medicine, City of Hope National Medical Center
- Nadia Carlesso
- Department of Stem Cell and Regenerative Medicine, City of Hope National Medical Center
- Christopher R. Vakoc
- Cold Spring Harbor Laboratory
- Enrico Velardi
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Beat W. Schafer
- Department of Oncology and Children’s Research Center, University Children’s Hospital
- Ernesto Guccione
- Center for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai
- Susanne A. Gatz
- Institute of Cancer and Genomic Sciences, University of Birmingham
- Ajla Wasti
- Children and Young People’s Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research
- Marielle Yohe
- Laboratory of Cell and Developmental Signaling, National Cancer Institute, NIH
- Myron Ignatius
- Greehey Children’s Cancer Research Institute (GCCRI), UT Health Science Center
- Concetta Quintarelli
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Janet Shipley
- Sarcoma Molecular Pathology, Divisions of Molecular Pathology, The Institute of Cancer Research
- Lucio Miele
- Department of Genetics, Louisiana State University Health Sciences Center
- Javed Khan
- Oncogenomics Section, Genetics Branch, National Cancer Institute, NIH,
- Peter J. Houghton
- Greehey Children’s Cancer Research Institute (GCCRI), UT Health Science Center
- Francesco Marampon
- Department of Radiological Oncological and Pathological Sciences, Sapienza University of Rome
- Berkley E. Gryder
- Department of Genetics and Genome Sciences, Case Western Reserve University
- Biagio De Angelis
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Franco Locatelli
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- Rossella Rota
- Department of Hematology and Oncology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, IRCCS
- DOI
- https://doi.org/10.1038/s41467-023-44130-0
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 23
Abstract
Abstract Rhabdomyosarcomas (RMS) are pediatric mesenchymal-derived malignancies encompassing PAX3/7-FOXO1 Fusion Positive (FP)-RMS, and Fusion Negative (FN)-RMS with frequent RAS pathway mutations. RMS express the master myogenic transcription factor MYOD that, whilst essential for survival, cannot support differentiation. Here we discover SKP2, an oncogenic E3-ubiquitin ligase, as a critical pro-tumorigenic driver in FN-RMS. We show that SKP2 is overexpressed in RMS through the binding of MYOD to an intronic enhancer. SKP2 in FN-RMS promotes cell cycle progression and prevents differentiation by directly targeting p27Kip1 and p57Kip2, respectively. SKP2 depletion unlocks a partly MYOD-dependent myogenic transcriptional program and strongly affects stemness and tumorigenic features and prevents in vivo tumor growth. These effects are mirrored by the investigational NEDDylation inhibitor MLN4924. Results demonstrate a crucial crosstalk between transcriptional and post-translational mechanisms through the MYOD-SKP2 axis that contributes to tumorigenesis in FN-RMS. Finally, NEDDylation inhibition is identified as a potential therapeutic vulnerability in FN-RMS.
