Aurélien de Reyniès

• PhD, HDR
• La Ligue contre le cancer

Background Epithelial ovarian cancer (EOC) is a leading cause of cancer mortality in women, often diagnosed at advanced stages. While first-line treatments improve survival, relapses remain common, with 5-year survival rates below 40%. Circulating tumor DNA (ctDNA) is a promising biomarker for non-invasive EOC detection and monitoring. It may help...

PURPOSE The objective of this work was to establish prognostic models in stage III colon cancer (CC) on the basis of transcriptomic signatures of the tumor microenvironment (TME) and cell cycle from the PETACC-8 (training set) and IDEA-France (validation set) trials. PATIENTS AND METHODS 3'RNA sequencing was performed in 1,733 patients from the PE...

We evaluate deconvolution methods, which infer levels of immune infiltration from bulk expression of tumor samples, through a community-wide DREAM Challenge. We assess six published and 22 community-contributed methods using in vitro and in silico transcriptional profiles of admixed cancer and healthy immune cells. Several published methods predict...

Patients with EGFR-mutated non-small cell lung cancer (NSCLC) benefit from treatment with tyrosine kinase inhibitors (TKI) targeting EGFR. Despite improvements in patient care, especially with the 3rd generation TKI osimertinib, disease relapse is observed in all patients. Among the various processes involved in TKI resistance, epithelial-to-mesenc...

Background Microsatellite instability (MSI) due to mismatch repair deficiency (dMMR) is common in colorectal cancer (CRC). These cancers are associated with somatic coding events, but the noncoding pathophysiological impact of this genomic instability is yet poorly understood. Here, we perform an analysis of coding and noncoding MSI events at the d...

Background The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrPC, which represents a candidate therapeutic target. How PrPC is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrPC expression and to s...

New therapeutic approaches are needed to improve the prognosis of Glioblastoma (GBM) patients. With the objective of identifying alternative oncogenic mechanisms to abnormally activated EGFR signaling, one of the most common oncogenic mechanisms in GBM, we performed a comparative analysis of gene expression profiles in a series of 54 human GBM samp...

PURPOSE No biomarker capable of improving selection and monitoring of patients with rectal cancer managed by watch-and-wait (W&W) strategy is currently available. Prognostic performance of the Immunoscore biopsy (IS B ) was recently suggested in a preliminary study. METHODS This international validation study included 249 patients with clinical co...

Purpose: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10-40% of patients with MSI mCRC will experience a primary resistance to ICI. Experimental design: In 2 cohorts of patients with MSI mCRC treated with ICI (explorato...

Purpose: Microsatellite instability (MSI) is currently the only predictive biomarker of efficacy of immune checkpoint inhibitors (ICI) in metastatic colorectal cancers (mCRC). However, 10-40% of patients with MSI mCRC will experience a primary resistance to ICI. Experimental design: In 2 cohorts of patients with MSI mCRC treated with ICI (explor...

Background: Molecular understanding of muscle-invasive (MIBC) and non-muscle-invasive (NMIBC) bladder cancer is currently based primarily on transcriptomic and genomic analyses. Objective: To conduct proteogenomic analyses to gain insights into bladder cancer (BC) heterogeneity and identify underlying processes specific to tumor subgroups and th...

Background: Mismatch repair deficient (dMMR) tumors displaying microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). However, a proportion of patients with dMMR/MSI mCRC exhibit resistance to ICI. Identificat...

Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced-stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that com...

Colorectal cancer (CRC) is the third most common cancer worldwide and represents the third leading cause of cancer deaths. Robust postoperative prediction of CRC patient prognosis may prove useful to better stratify patients, guide therapeutic choices and improve clinical trial designs. Deep learning-based analysis of whole slide images (WSI) has r...

Background: Renal medullary carcinoma (RMC) and collecting duct carcinoma (CDC) are rare entities with a poor outcome. First-line metastatic treatment is based on gemcitabine + platinum chemotherapy (GC) regimen but retrospective data suggest enhanced anti-tumour activity with the addition of bevacizumab. Therefore, we performed a prospective asse...

Background Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. Patients and methods To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we performed a comprehensive...

Objectifs Les sous-types moléculaires du carcinoma urothélial pourraient avoir un impact sur la réponse à la chimiothérapie néo-adjuvante dans le cancer de la vessie infiltrant le muscle. Les données de la littérature demeurent actuellement contradictoires. En utilisant la classification de consensus sur les différents sous-types moléculaires, nous...

Background Bladder cancer (BCa) is more common in men and presents differences in molecular subtypes based on sex. Fibroblast growth factor receptor 3 (FGFR3) mutations are enriched in the luminal papillary muscle-invasive BCa (MIBC) and non-MIBC subtypes. Objective To determine whether FGFR3 mutations initiate BCa and impact BCa male sex bias. D...

The cellular prion protein PrPC partners with caveolin-1 (CAV1) in neurodegenerative diseases but whether this interplay occurs in cancer has never been investigated. By leveraging patient and cell line datasets, we uncover a molecular link between PrPC and CAV1 across cancer. Using cell-based assays, we show that PrPC regulates the expression of a...

Background Muscle-invasive bladder cancer (MIBC) and upper urinary tract urothelial carcinoma (UTUC) are molecularly heterogeneous. Despite chemotherapies, immunotherapies, or anti-fibroblast growth factor receptor (FGFR) treatments, these tumors are still of a poor outcome. Our objective was to develop a bank of patient-derived xenografts (PDXs) r...

Objective: New therapeutic approaches are needed to improve the prognosis of glioblastoma (GBM) patients. Methods: With the objective of identifying alternative oncogenic mechanisms to abnormally activated epidermal growth factor receptor (EGFR) signalling, one of the most common oncogenic mechanisms in GBM, we performed a comparative analysis o...

Context: Polymerase epsilon (POLE) gene missense hotspot mutations can generate pathogenic (p) proofreading defects resulting in hypermutated genomic profiles. Aim: Determine the prevalence, genomic consequences and immunotherapy sensitivity of advanced POLE mutated tumors according to mutation site, primary tumor and tumor mutational burden (TMB)....

Deconvolution methods infer levels of immune and stromal infiltration from bulk expression of tumor samples. These methods allow projection of characteristics of the tumor microenvironment, known to affect patient outcome and therapeutic response, onto the millions of bulk transcriptional profiles in public databases, many focused on uniquely valua...

Tumors with microsatellite instability (MSI) represent a paradigm for the success of immune checkpoint inhibitor (ICI)-based immunotherapy, particularly in patients with metastatic colorectal cancer (mCRC). To date however, tools for predicting efficacy of these new therapies are lacking. Here we combined high-throughput DNA and RNA sequencing of t...

Background Muscle-invasive bladder cancer (MIBC) and upper urinary tract urothelial carcinoma (UTUC) are molecularly heterogeneous. Despite chemotherapies, immunotherapies or anti-FGFR treatments, these tumors are still of poor outcome. Our objective was to develop a bank of patient-derived xenografts (PDXs) recapitulating molecular heterogeneity o...

Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response t...

Primary central nervous system lymphoma (PCNSL) is a distinct extranodal lymphoma presenting with limited stage disease but variable response rates to treatment despite homogenous pathological presentation. The likely underlying molecular heterogeneity and its clinical impact is poorly understood. We performed a comprehensive genome-wide analysis o...

The presence of intratumoral tertiary lymphoid structures (TLS) is associated with positive clinical outcomes and responses to immunotherapy in cancer. Here, we used spatial transcriptomics to examine the nature of B cell responses within TLS in renal cell carcinoma (RCC). B cells were enriched in TLS, and therein, we could identify all B cell matu...

The prognostication of metastatic pancreatic adenocarcinoma (mPDAC) patients remains uncertain, mainly based on carbohydrate antigen 19-9 (CA19-9), with limited utility. Circulating tumour DNA (ctDNA) has been suggested as a prognostic factor, but its added value has been poorly explored. The objective was to determine whether ctDNA is an independe...

Basal/Squamous (Ba/Sq) subtype represents an intrinsic and robust group in the consensus molecular classification of muscle-invasive bladder cancer (MIBC), with poor outcome and controversial chemosensitivity. We aimed to investigate the spectrum of intratumor heterogeneity (ITH) in Ba/Sq subtype. First, we validated a 29 gene NanoString codeset to...

Background: Quantification of tumor heterogeneity is essential to better understand cancer progression and to adapt therapeutic treatments to patient specificities. Bioin- formatic tools to assess the different cell populations from single-omic datasets as bulk transcriptome or methylome samples have been recently developed, including refer- ence-b...

Retinoblastoma is the most frequent intraocular malignancy in children, originating from a maturing cone precursor in the developing retina. Little is known on the molecular basis underlying the biological and clinical behavior of this cancer. Here, using multi-omics data, we demonstrate the existence of two retinoblastoma subtypes. Subtype 1, of e...

Background FGFR3 mutations are among the most frequent genetic alterations in bladder cancer and are enriched in the luminal papillary subtype of muscle-invasive tumors (MIBC) and luminal-like classes 1 and 3 of non-MIBC. To study their oncogenic properties in vivo, we developed here a genetically engineered mouse (GEM) model expressing the most fr...

MicroAbstract : Trials with adjuvant anti-angiogenic therapy failed to demonstrate significant benefit in high-risk, resected clear-cell renal cell carcinoma. We show that molecular subtypes and angiogenesis-related gene expression are associated with disease-free and overall survival. Clinically high-risk tumors are infrequently angiogenic but can...

Purpose: The consensus molecular subtypes (CMS) represent a significant advance in the understanding of intertumor heterogeneity in colon cancer. Intratumor heterogeneity (ITH) is the new frontier for refining prognostication and understanding treatment resistance. This study aims at deciphering the transcriptomic ITH of colon cancer and understan...

Metastatic clear-cell renal cell carcinoma (m-ccRCC) is characterized by increased hypoxia-induced factor (HIF)-2α and vascular endothelial growth factor receptor (VEGFR)-dependent angiogenesis through loss of function of the von Hippel–Lindau protein. VEGFR tyrosine kinase inhibitors (VEGFR-TKIs) are a cornerstone of m-ccRCC treatment, and new tre...

Introduction Immune checkpoint inhibitors (ICIs) have proved to be an effective treatment for up to 40% of muscle-invasive bladder cancer (MIBC), but there is still a need for better performing biomarkers allowing to improve prediction of response to ICI. Response to immunotherapy in soft-tissue sarcoma, melanoma and renal cell carcinoma have been...

Background & Aims Next generation sequencing (NGS) was recently approved by the FDA to detect microsatellite instability (MSI) arising from defective mismatch repair (dMMR) in patients with metastatic colorectal cancer (mCRC) prior to treatment with immune checkpoint inhibitors (ICI). In this study, we aimed to evaluate and improve the performance...

Context: The number of prognostic markers for clear cell renal cell carcinoma (ccRCC) has been increasing regularly over the last 15 years, without being integrated and compared. Objective: Our goal was to perform a review of prognostic markers for ccRCC to lay the ground for their use in the clinics. Evidence Acquisition: PubMed database was searc...

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and dise...

Cadherins form a large and pleiotropic superfamily of membranous proteins sharing Ca²⁺-binding repeats. While the importance of classic cadherins such as E- or N-cadherin for tumorigenesis is acknowledged, there is much less information about other cadherins that are merely considered as tissue-specific adhesion molecules. Here, we focused on the a...

The CMS4 mesenchymal subtype of colorectal cancer (CRC) is associated with poor prognosis and resistance to treatment. The cellular prion protein PrPC is overexpressed in CMS4 tumors and controls the expression of a panel of CMS4-specific genes in CRC cell lines. Here, we sought to investigate PrPC downstream pathways that may underlie its role in...

We previously reported MCP-counter and mMCP-counter, methods that allow precise estimation of the immune and stromal composition of human and murine samples from bulk transcriptomic data, but they were only distributed as R packages. Here, we report webMCP-counter, a user-friendly web interface to allow all users to use these methods, regardless of...

The chromosome translocations generating PAX3-FOXO1 and PAX7-FOXO1 chimeric proteins are the primary hallmarks of the paediatric fusion-positive alveolar subtype of Rhabdomyosarcoma (FP-RMS). Despite the ability of these transcription factors to remodel chromatin landscapes and promote the expression of tumour driver genes, they only inefficiently...

Objectifs Le score pronostique de CAPRA est clinicobiologique et permet d’estimer le risque de récidive d’un cancer de prostate (CaP) après traitement. Des récentes études préliminaires ont mis en évidence l’existence de sous-groupes moléculaires pronostiques dans les CaP. L’objectif de cette étude était d’évaluer le risque de récidive du CaP après...

Background Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients’ performance status and expected efficacy. The establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. Pa...

Benign adrenal tumors cover a spectrum of lesions with distinct morphology and steroid secretion. Current classification is empirical. Beyond a few driver mutations, pathophysiology is not well understood. Here, a pangenomic characterization of benign adrenocortical tumors is proposed, aiming at unbiased classification and new pathophysiological in...

Quantifying tissue-infiltrating immune and stromal cells provides clinically relevant information for various diseases. While numerous methods can quantify immune or stromal cells in human tissue samples from transcriptomic data, few are available for mouse studies. We introduce murine Microenvironment Cell Population counter (mMCP-counter), a meth...

GLI1 expression is broadly accepted as a marker of Hedgehog pathway activation in tumors. Efficacy of Hedgehog inhibitors is essentially limited to tumors bearing activating mutations of the pathway. GLI2, a critical Hedgehog effector, is necessary for GLI1 expression and is a direct transcriptional target of TGF-β/SMAD signaling. We examined the e...

As the catalog of oncogenic driver mutations is expanding, it becomes clear that alterations in a given gene might have different functions and should not be lumped into one class. The transcription factor GATA3 is a paradigm of this. We investigated the functions of the most common GATA3 mutation (X308_Splice) and five additional mutations, which...

Background: Muscle-invasive bladder cancers (MIBCs) constitute a heterogeneous group of tumors with poor outcome. Recently, MIBC molecular subtyping efforts from an international consortium led to the identification of six subtypes, improving prediction of clinical outcomes and treatment responses. FGFR3 alterations (mutations and translocations),...

Background A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient's care is the lack of molecular parameters characterizing tumours and allowing a personalized treatment. Methods Patient-derived xenografts (PDX) were obtained from 76 consecutive PDAC and classified according to their histology into five groups. A PDAC molecular gradi...

Stage T1 bladder cancers have the highest progression and recurrence rates of all non–muscle-invasive bladder cancers (NMIBCs). Most T1 cancers are treated with bacillus Calmette-Guérin (BCG), but many will progress or recur, and some T1 patients will die from bladder cancer. Particularly aggressive tumors could be treated with early cystectomy. To...

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we performed a large integrative multi-omics analysis of patients diagnosed with NMIBC (n=834). Transcriptomic analysis identified four classes (1, 2a, 2b and 3) reflecting tumor biology and...

Motivation Quantification of tumor heterogeneity is essential to better understand cancer progressionand to adapt therapeutic treatments to patient specificities. Results We present DECONbench, a web-based application to benchmark computational methods dedicated to quantify of cell-type heterogeneity in cancer. DECONbench includes benchmark datase...

The chromosome translocations generating PAX3FOXO1 and PAX7FOXO1 chimeric proteins are the primary hallmarks of the paediatric cancer, Alveolar Rhabdomyosarcoma (ARMS). Despite the ability of these transcription factors to remodel chromatin landscapes and promote the expression of tumour driver genes, they only inefficiently promote malignant trans...

Tumor cells constantly interact with their microenvironment, which comprises a variety of immune cells together with endothelial cells and fibroblasts. The composition of the tumor microenvironment (TME) has been shown to influence response to immune checkpoint blockade (ICB). ICB takes advantage of immune cell infiltration in the tumor to reinvigo...

Quantifying tissue-infiltrating immune and stromal cells provides clinically relevant information for various diseases, notably cancer. While numerous methods allow to quantify immune or stromal cells in human tissue samples based on transcriptomic data, very few are available for mouse studies. Here, we introduce murine Microenvironment Cell Popul...

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608...

PPARγ activation is a critical event in luminal muscle-invasive bladder cancer (MIBC) tumorigenesis, favoring both tumor cell growth and microenvironment modulation toward tumor immune escape. Conversely, the down-regulation of PPARγ activity in basal MIBC suggests tumor suppressive effects in this subgroup. Here, we report genetic, epigenetic and...

Background & aims: Intrahepatic cholangiocarcinoma (ICC) is asevere malignant tumor in which the standard therapies are mostly ineffective. The biological significance of the desmoplastic tumor microenvironment (TME) of ICC has been stressed, but was insufficiently taken into account in the search for classifications of ICC adapted to clinical tri...

Context Pheochromocytomas and paragangliomas (PPGL) are neuroendocrine tumors explained by germline or somatic mutations in about 70% of cases. Patients with SDHB mutations are at high risk of developing metastatic disease, yet no reliable tumor biomarkers are available to predict tumor aggressiveness. Objective We aimed at identifying long non-co...

Motivation Matrix factorization (MF) methods are widely used in order to reduce dimensionality of transcriptomic datasets to the action of few hidden factors (metagenes). MF algorithms have never been compared based on the between-datasets reproducibility of their outputs in similar independent datasets. Lack of this knowledge might have a crucial...

Chondrosarcomas are primary cancers of cartilaginous tissue with highly contrasting prognoses. These tumors are defined by recurrent mutations in the IDH genes and other genetic alterations including inactivation of CDKN2A and COL2A1; however, these have no clinical value. Here we use multi-omics molecular profiles from a series of cartilage tumors...

Background Soft tissue sarcomas (STS) form a group of rare cancers which accounts for around 1% of tumours. Although up to 15% of patients respond in immunotherapy trials, there are no biomarkers predicting response of STS to checkpoint blockade therapies yet. Methods We analysed transcriptomic data of 4 publicly available cohorts, accounting for...

Background Tumor pathologists classify tumors according to cell-level and tissue-level criteria, using molecular markers in addition to morphological patterns, as reported in WHO tumor classifications. Their work describes to some extent both inter-tumor and intra-tumor heterogeneity, but it is a tedious task with potential reproducibility issues....

Background: Muscle-invasive bladder cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, but the diversity of their subtype sets impedes their clinical application. Objective: To achieve an international consensus on MIBC molecular subtypes that reconciles the...

GLI1 expression is broadly accepted as a marker of Hedgehog pathway activation in tumors. Efficacy of Hedgehog inhibitors is essentially limited to tumors bearing activating mutations of the pathway. GLI2, a critical Hedgehog effector, is necessary for GLI1 expression and is a direct transcriptional target of TGF-β/SMAD signaling. We examined the e...

Background: Comprehensive transcriptomic analyses have shown that colorectal cancer (CRC) is heterogeneous and have led to the definition of molecular subtypes among which the stem-cell, mesenchymal-like group is associated with poor prognosis. The molecular pathways orchestrating the emergence of this subtype are incompletely understood. In line...

Introduction: Immune cell infiltration in solid tumors correlates with patient outcome and therapeutic response. While specific cell-type infiltration can be elucidated by single-cell transcriptomic techniques, these suffer biases and limitations of scale. To instead leverage existing large repositories of bulk gene expression data with clinical ou...

The management of locally advanced head and neck squamous cell carcinoma (HNSCC) with Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), achieves only moderate response rates, and clinical trials that evaluated EGFR-blockade with tyrosine kinase inhibitors (TKI) yielded disappointing results. Inter-tumor heterog...