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

SIMPLE SUMMARY: Leiomyosarcomas are aggressive diseases mainly treated by surgical resection with or without conventional chemotherapy. Despite efforts to stratify patients, no targeted therapy nor immunotherapy has shown a major therapeutic effect. The oncogenesis of leiomyosarcoma is poorly understood, and its understanding would allow the detection of their weaknesses. By integrating large-scale data, we identified two specifically deregulated pathways involved in differentiation/proliferation switch (MYOCD/SRF and E2F1/RB1) in a subgroup of well-differentiated vascular smooth muscle cell-derived cells leiomyosarcomas. Targeting MYOCD/SRF interaction with a specific inhibitor decreased the viability of a cell line derived from this tumor subgroup, which makes this pathway a potential therapeutic target. 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.