Distinct Cellular Origins and Differentiation Process Account for Distinct Oncogenic and Clinical Behaviors of Leiomyosarcomas
Author:
Darbo ElodieORCID, Pérot Gaëlle, Darmusey Lucie, Le Guellec Sophie, Leroy Laura, Gaston Laëtitia, Desplat Nelly, Thébault NoémieORCID, 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-YvesORCID, Chibon FrédéricORCID
Abstract
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.
Funder
Institut Nationale du Cancer Claudius Regaud Institute
Subject
Cancer Research,Oncology
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