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
INSERM U1218 ACTION, Institut Bergonié, 33000 Bordeaux, France.
CNRS UMR5800, LaBRI, 33400 Talence, France.
Cancers (Basel). 2023 Jan 15;15(2):534. doi: 10.3390/cancers15020534.
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 alteration, could explain how hLMS balance this uncommon interplay between differentiation and aggressiveness.
平滑肌肉瘤（LMS）是一种极具侵袭性的疾病，已被描述为一种转录相对一致的高分化肿瘤亚组，且与较差的生存率相关。由此产生的问题是，分化和肿瘤进展这两个明显相互拮抗的过程是如何共存并导致肿瘤恶性的。我们首先在三个独立队列中鉴定出转录最均一的LMS亚组，我们将其命名为“hLMS”。多组学数据整合和功能分析表明，hLMS起源于血管平滑肌细胞，并表明hLMS转录程序既反映了由MYOCD/SRF调控网络控制的平滑肌收缩活动的调节，也反映了由E2F/RB1途径控制的细胞周期活动的激活。我们提出，血管平滑肌细胞的表型可塑性与MYOCD/SRF途径扩增（这对hLMS存活至关重要）、PTEN缺失和改变同时存在，可以解释hLMS如何平衡这种分化与侵袭性之间罕见的相互作用。
