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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Published in:bioRxiv
Main Authors: Darbo, Elodie, Pérot, Gaëlle, Darmusey, Lucie, Sophie Le Guellec, 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, Jean-Michel Coindre, Blay, Jean-Yves, Chibon, Frédéric
Format: Paper
Language:English
Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 03.01.2023
Cold Spring Harbor Laboratory
Edition:1.5
Subjects:
Cancer Biology
Chemotherapy
Fibroblasts
Gene expression
Genomes
Genomics
Medical prognosis
Metastases
Muscle contraction
Smooth muscle
Transcription
Tumorigenesis
Tumors
leiomyosarcoma
differentiation
transcriptional regulation
oncogenesis
bioinformatics
ISSN:2692-8205, 2692-8205
Online Access:Get full text
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Summary: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 modulation 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.Competing Interest StatementThe authors have declared no competing interest.Footnotes* Some figures have been updated. The text has been modified. Results and conclusions remain unchanged.
Bibliography:SourceType-Working Papers-1
ObjectType-Working Paper/Pre-Print-1
content type line 50
Competing Interest Statement: The authors have declared no competing interest.
ISSN:2692-8205
2692-8205
DOI:10.1101/2020.10.23.352336