Distinct Cellular Origins and Differentiation Process Account for Distinct Oncogenic and Clinical Behaviors of Leiomyosarcomas

In leiomyosarcoma (LMS), a very aggressive disease, a relatively transcriptionally uniform subgroup of well-differentiated tumors has been described and is associated with poor survival. The question raised how differentiation and tumor progression, two apparently antagonist processes, coexist and a...

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Vydáno v:Cancers Ročník 15; číslo 2; s. 534
Hlavní autoři: Darbo, Elodie, Pérot, Gaëlle, Darmusey, Lucie, Le Guellec, Sophie, Leroy, Laura, Gaston, Laëtitia, Desplat, Nelly, Thébault, Noémie, Merle, Candice, Rochaix, Philippe, Valentin, Thibaud, Ferron, Gwenaël, Chevreau, Christine, Bui, Binh, Stoeckle, Eberhard, Ranchere-Vince, Dominique, Méeus, Pierre, Terrier, Philippe, Piperno-Neumann, Sophie, Collin, Françoise, De Pinieux, Gonzague, Duffaud, Florence, Coindre, Jean-Michel, Blay, Jean-Yves, Chibon, Frédéric
Médium: Journal Article
Jazyk:angličtina
Vydáno: Switzerland MDPI AG 15.01.2023
MDPI
Témata:
Cancer
Cell activation
Cell cycle
Cell differentiation
Chemotherapy
E2F1 protein
Gene expression
Genomes
Immunotherapy
Life Sciences
Malignancy
Medical prognosis
Metastasis
Muscle contraction
Patients
Phenotypic plasticity
PTEN protein
Sarcoma
Smooth muscle
Therapeutic targets
Transcription
Tumorigenesis
Tumors
United States > US
leiomyosarcoma
differentiation
transcriptional regulation
bioinformatics
oncogenesis
ISSN:2072-6694, 2072-6694
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Popis
Shrnutí:In leiomyosarcoma (LMS), a very aggressive disease, a relatively transcriptionally uniform subgroup of well-differentiated tumors has been described and is associated with poor survival. The question raised how differentiation and tumor progression, two apparently antagonist processes, coexist and allow tumor malignancy. We first identified the most transcriptionally homogeneous LMS subgroup in three independent cohorts, which we named ‘hLMS’. The integration of multi-omics data and functional analysis suggests that hLMS originate from vascular smooth muscle cells and show that hLMS transcriptional program reflects both modulations of smooth muscle contraction activity controlled by MYOCD/SRF regulatory network and activation of the cell cycle activity controlled by E2F/RB1 pathway. We propose that the phenotypic plasticity of vascular smooth muscle cells coupled with MYOCD/SRF pathway amplification, essential for hLMS survival, concomitant with PTEN absence and RB1 alteration, could explain how hLMS balance this uncommon interplay between differentiation and aggressiveness.
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Current address: INSERM U1312, BoRdeaux Institute of onCology, 33076 Bordeaux, France.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers15020534