Biology subjects

Blay, J.-Y.

Publications and source records attributed to Blay, J.-Y..

6 recordsLinked to original sources

bioRxiv2026

Routine FFPE sections support clinically compatible single-nucleus transcriptomics across six human cancer types

Tumor cellular composition--including malignant cell states, immune populations, and stromal populations--is increasingly recognized as a determinant of therapeutic response and resistance to anti-cancer agents, yet comprehensive cellular profiling remains largely confined to research settings. Here, we present a clinically compatible sample-to-report workflow for tumor composition profiling from routine formalin-fixed paraffin-embedded (FFPE) clinical specimens. By combining low-input single-nucleus RNA sequencing with foundation model- based automated cell annotation, this workflow enables prospective sample-by-sample analysis without dedicated research material or cohort-based processing. Across 116 clinical specimens representing six cancer types, we generated reproducible measurements of cellular composition and cell-type-specific gene expression, demonstrated high technical reproducibility, and showed concordance with pathological assessment of immune infiltration. The workflow was similarly applicable to archival FFPE material and ultra-low-input biopsy specimens. Together, these findings establish a practical framework for routine single-cell profiling from standard pathology specimens and open the perspective of prospective evaluation of cellular composition as a clinical biomarker in precision oncology.

cancer biology↗

bioRxiv2023

BMP2 and BMP7 cooperate with H3.3K27M to promote quiescence and invasiveness in pediatric diffuse midline gliomas

Pediatric diffuse midline gliomas (pDMG) are an aggressive type of childhood cancer with a fatal outcome. Their major epigenetic determinism has become clear, notably with the identification of K27M mutations in histone H3. However, the synergistic oncogenic mechanisms that induce and maintain tumor cell phenotype have yet to be deciphered. In 20 to 30% of cases, these tumors have an altered BMP signaling pathway with an oncogenic mutation on the BMP type I receptor ALK2, encoded by ACVR1. However, the potential impact of the BMP pathway in tumors non-mutated for ACVR1 is less clear. By integrating bulk, single-cell and spatial transcriptomic data, we show here that the BMP signaling pathway is activated at similar levels between ACVR1 wild-type and mutant tumors and identify BMP2 and BMP7 as putative activators of the pathway in a specific subpopulation of cells. By using both pediatric isogenic glioma lines genetically modified to overexpress H3.3K27M and patients-derived DIPG cell lines, we demonstrate that BMP2/7 synergizes with H3.3K27M to induce a transcriptomic rewiring associated with a quiescent but invasive cell state. These data suggest a generic oncogenic role for the BMP pathway in gliomagenesis of pDMG and pave the way for specific targeting of downstream effectors mediating the K27M/BMP crosstalk.

cancer biology↗

bioRxiv2023

Alterations of the TGFb-sequestration complex member ADAMTSL1 levels are associated with muscular defects and rhabdomyosarcoma aggressiveness

Rhabdomyosarcoma (RMS) is the most frequent form of paediatric soft-tissue sarcoma and remains a medical challenge, holding in failure current therapeutic strategies. RMS shares histological features with cells of the muscle lineage and this cancer is thought to arise from malignant transformation of myogenic precursors. It has been proposed that RMS and myogenesis could represent the "Jekyll and Hyde" of skeletal muscle. The underlying idea is that some early steps of myogenic differentiation are blocked in RMS, and that understanding how the normal process has gone awry could help to decipher the biological underpinnings of tumorigenesis and tumor escape. It is widely agreed that extracellular matrix (ECM) interferes in skeletal muscle regeneration and that defects in ECM components are clinically significant. The challenge is now to decipher actors and mechanisms responsible for the transmission of signals to muscle cells and the subsequent alterations that could be associated with RMS. Using an original transgenic mice model, we show here that ADAMTSL1 is involved in skeletal muscle regeneration. As previously reported for other members of its family, ADAMTSL1 is part of the TGF-{beta}-ECM-sequestering complex and likely positively regulates TGF-{beta}-pathway activity. Last, we observed that ADAMTSL1 expression behaves as a strong prognostic factor in the aggressive fusion-positive RMS and correlates with a neural-like phenotype of tumor cells, resulting from gain of SMAD2/3/4 targets.

cancer biology↗

bioRxiv2022

Fusion-negative Rhabdomyosarcoma 3D-organoids as an innovative model to predict resistance to cell death inducers

Rhabdomyosarcoma (RMS) is the main form of soft-tissue sarcoma in children and adolescents. For 20 years, and despite international clinical trials, its cure rate has not really improved, and remains stuck at 20% in case of relapse. The definition of new effective therapeutic combinations is hampered by the lack of reliable models, which complicate the transposition of promising results obtained in pre-clinical studies into efficient solutions for young patients. Inter-patient heterogeneity, particularly in the so-called fusion-negative group (FNRMS), adds an additional level of difficulty in optimizing the clinical management of children and adolescents with RMS. Here, we describe an original 3D-organoid model derived from relapsed FNRMS and show that it finely mimics the characteristics of the original tumor, including inter- and intra-tumoral heterogeneity. Moreover, we have established the proof-of-concept of their preclinical potential by re-evaluating the therapeutic opportunities of targeting apoptosis in FNRMS from a streamlined approach based on the exploitation of bulk and single-cell omics data.

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↗