Biology subjects

Chibon, F.

Publications and source records attributed to Chibon, F..

5 recordsLinked to original sources

bioRxiv2026

Alternative Lengthening of Telomeres and CINSARC are interconnected toward non-translocation-related sarcomas progression

Alternative lengthening of telomeres (ALT) is a telomere elongation mechanism activated during oncogenesis and primarily acting in tumors of mesenchymal origin. Although the proteins involved in the machinery enabling ALT to elongate telomeres are becoming better understood, the underlying biology of this mechanism remains unclear. In the present study, we took advantage of a fully characterized cohort of 98 leiomyosarcomas (LMS) from the French Sarcoma Group to further our understanding of the ALT mechanism. We first compared the transcriptomic profiles of ALT+ and TERT+ LMS and demonstrated a strong enrichment of the CINSARC signature in ALT+ tumors. The establishment of an ALT+-related signature in these LMS confirmed the close association between CINSARC and ALT in two additional cohorts of non-translocation-related sarcomas. In vitro mesenchymal models of spontaneous ALT induction showed increased CINSARC expression following acquisition of the ALT mechanism. Conversely, ALT inactivation, through BLM inhibition, led to decreased CINSARC expression. These results establish CINSARC as a new hallmark of the ALT mechanism in non-translocation-related sarcomas and demonstrate the association of a cellular biological process with the CINSARC prognostic signature, namely the ALT mechanism.

cancer biology↗

bioRxiv2025

Breaking the redundancy: TAZ outperforms YAP1 in GIST progression

BackgroundGastrointestinal stromal tumors (GIST) are mainly caused by gain-of-function mutations in KIT or PDGFRA genes and are the most common neoplasms of the digestive tract. Imatinib (IM), a tyrosine kinase inhibitor (TKI) targeting these oncogenic drivers, has considerably improved patient outcomes, although resistance remains a major challenge. The transcriptional co-activators YAP1 and TAZ, downstream effectors of the Hippo pathway, have emerged as potential oncogenic drivers in various cancers, including GIST. However, their specific roles in KIT-dependent tumor development remain unclear. MethodsWe used WRAP5-based nanoparticles loaded with specifically designed siRNA to selectively silence YAP1 and/or TAZ proteins in KIT-dependent IM-sensitive GIST cell lines. This nucleic acid delivery system enabled efficient and specific knockdown without cytotoxicity. We assessed the impact on cell proliferation, migration, and gene expression, focusing on YAP1/TAZ targets CYR61 and CTGF. ResultsTAZ silencing resulted in a substantial reduction in GIST-T1 cell proliferation and migration, whereas YAP1 knockdown was comparatively limited. This finding was consistent with an increased TAZ expression in GIST patients, which was associated with shorter progression-free survival and an increased tendency for metastasis development. A slight additive effect was observed upon a combined YAP1/TAZ silencing in the migration assay, suggesting a more complex regulation between these two proteins. CYR61 and CTGF expressions were predominantly regulated by TAZ, though a stronger downregulation was observed upon dual knockdown in a subset of GIST cell lines with differential YAP1 and TAZ basal expression. Finally, CYR61 seemed to be more implicated in cell proliferation inhibition, which is further supported by the correlation between high CYR61 expression and poor prognosis in the GIST patients. ConclusionOur results highlight the central regulatory function of TAZ-CYR61 axis in oncogenic processes in KIT-dependent GIST, with a modest contribution from YAP1. Targeting TAZ, alone or in combination with YAP1, may represent a promising therapeutic approach, particularly in the context of tumor heterogeneity.

cancer biology↗

bioRxiv2023

A metabolic crosstalk between liposarcoma and muscle sustains tumor growth

Dedifferentiated (DD-LPS) and Well-differentiated (WD-LPS) liposarcoma are characterized by a systematic amplification of the MDM2 oncogene. We recently demonstrated that p53-independent metabolic functions of chromatin-bound MDM2 (C-MDM2) are exacerbated in LPS and mediate an addiction to serine metabolism in order to sustain tumor growth. Here, we show that metabolic cooperation between LPS and distant muscle, which raise serine and glycine blood levels, is essential for LPS tumor growth. By releasing IL-6, tumor influence distant muscle to upregulate their serine synthesis machinery. Blocking IL-6 secretion or treating LPS cells with FDA approved IL-6 inhibitor, decreased serine production and impaired tumor proliferation. These data reveal IL-6 as a central tumorkine in metabolic crosstalk between tissues and identifies IL-6 as a plausible treatment for LPS patients.

cancer biology↗

bioRxiv2020

SRF-MYOCD axis is the targetable driver of a well differentiated aggressive subtype 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 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.

cancer biology↗

bioRxiv2020

ATRX alteration contributes to tumor growth and immune escape in pleomorphic sarcomas

Whole genome and transcriptome sequencing of a cohort of 67 leiomyosarcomas revealed ATRX to be one of the most frequently mutated genes in leiomyosarcomas after TP53 and RB1. While its function is well described in the alternative lengthening of telomeres mechanism, we wondered whether its alteration could have complementary effects on sarcoma oncogenesis. ATRX alteration is associated with the down-expression of genes linked to differentiation in leiomyosarcomas, and to immunity in an additional cohort of 60 poorly differentiated sarcomas. In vitro and in vivo models showed that ATRX loss increases tumor growth rate and immune escape by decreasing the immunity load of active mast cells in sarcoma tumors. These data indicate that an alternative to unsuccessful targeting of the adaptive immune system in sarcoma could be to target the innate system. This might lead to a better outcome for sarcoma patients in terms of ATRX status.

cancer biology↗