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1. PrPC controls epithelial-to-mesenchymal transition in EGFR-mutated NSCLC: implications for TKI resistance and patient follow-up

Author

Lailler, Claire, Didelot, Audrey, Garinet, Simon, Berthou, Hugo, Sroussi, Marine, de Reyniès, Aurélien, Dedhar, Shoukat, Martin-Lannerée, Séverine, Fabre, Elizabeth, Le Pimpec-Barthes, Françoise, Perrier, Alexandre, Poindessous, Virginie, Mansuet-Lupo, Audrey, Djouadi, Fatima, Launay, Jean-Marie, Laurent-Puig, Pierre, Blons, Hélène, and Mouillet-Richard, Sophie

Published
2024
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2. Author Correction: Community assessment of methods to deconvolve cellular composition from bulk gene expression

Author

White, Brian S., de Reyniès, Aurélien, Newman, Aaron M., Waterfall, Joshua J., Lamb, Andrew, Petitprez, Florent, Lin, Yating, Yu, Rongshan, Guerrero-Gimenez, Martin E., Domanskyi, Sergii, Monaco, Gianni, Chung, Verena, Banerjee, Jineta, Derrick, Daniel, Valdeolivas, Alberto, Li, Haojun, Xiao, Xu, Wang, Shun, Zheng, Frank, Yang, Wenxian, Catania, Carlos A., Lang, Benjamin J., Bertus, Thomas J., Piermarocchi, Carlo, Caruso, Francesca P., Ceccarelli, Michele, Yu, Thomas, Guo, Xindi, Bletz, Julie, Coller, John, Maecker, Holden, Duault, Caroline, Shokoohi, Vida, Patel, Shailja, Liliental, Joanna E., Simon, Stockard, Saez-Rodriguez, Julio, Heiser, Laura M., Guinney, Justin, and Gentles, Andrew J.

Published
2024
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3. Community assessment of methods to deconvolve cellular composition from bulk gene expression

Author

White, Brian S., de Reyniès, Aurélien, Newman, Aaron M., Waterfall, Joshua J., Lamb, Andrew, Petitprez, Florent, Lin, Yating, Yu, Rongshan, Guerrero-Gimenez, Martin E., Domanskyi, Sergii, Monaco, Gianni, Chung, Verena, Banerjee, Jineta, Derrick, Daniel, Valdeolivas, Alberto, Li, Haojun, Xiao, Xu, Wang, Shun, Zheng, Frank, Yang, Wenxian, Catania, Carlos A., Lang, Benjamin J., Bertus, Thomas J., Piermarocchi, Carlo, Caruso, Francesca P., Ceccarelli, Michele, Yu, Thomas, Guo, Xindi, Bletz, Julie, Coller, John, Maecker, Holden, Duault, Caroline, Shokoohi, Vida, Patel, Shailja, Liliental, Joanna E., Simon, Stockard, Saez-Rodriguez, Julio, Heiser, Laura M., Guinney, Justin, and Gentles, Andrew J.

Published
2024
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4. Microsatellite instability at U2AF-binding polypyrimidic tract sites perturbs alternative splicing during colorectal cancer initiation

Author

Jonchère, Vincent, Montémont, Hugo, Le Scanf, Enora, Siret, Aurélie, Letourneur, Quentin, Tubacher, Emmanuel, Battail, Christophe, Fall, Assane, Labreche, Karim, Renault, Victor, Ratovomanana, Toky, Buhard, Olivier, Jolly, Ariane, Le Rouzic, Philippe, Feys, Cody, Despras, Emmanuelle, Zouali, Habib, Nicolle, Rémy, Cervera, Pascale, Svrcek, Magali, Bourgoin, Pierre, Blanché, Hélène, Boland, Anne, Lefèvre, Jérémie, Parc, Yann, Touat, Mehdi, Bielle, Franck, Arzur, Danielle, Cueff, Gwennina, Le Jossic-Corcos, Catherine, Quéré, Gaël, Dujardin, Gwendal, Blondel, Marc, Le Maréchal, Cédric, Cohen, Romain, André, Thierry, Coulet, Florence, de la Grange, Pierre, de Reyniès, Aurélien, Fléjou, Jean-François, Renaud, Florence, Alentorn, Agusti, Corcos, Laurent, Deleuze, Jean-François, Collura, Ada, and Duval, Alex

Published
2024
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5. Wnt, glucocorticoid and cellular prion protein cooperate to drive a mesenchymal phenotype with poor prognosis in colon cancer

Author

Mouillet-Richard, Sophie, Gougelet, Angélique, Passet, Bruno, Brochard, Camille, Le Corre, Delphine, Pitasi, Caterina Luana, Joubel, Camille, Sroussi, Marine, Gallois, Claire, Lavergne, Julien, Castille, Johan, Vilotte, Marthe, Daniel-Carlier, Nathalie, Pilati, Camilla, de Reyniès, Aurélien, Djouadi, Fatima, Colnot, Sabine, André, Thierry, Taieb, Julien, Vilotte, Jean-Luc, Romagnolo, Béatrice, and Laurent-Puig, Pierre

Published
2024
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6. Community assessment of methods to deconvolve cellular composition from bulk gene expression

Author

Brian S. White, Aurélien de Reyniès, Aaron M. Newman, Joshua J. Waterfall, Andrew Lamb, Florent Petitprez, Yating Lin, Rongshan Yu, Martin E. Guerrero-Gimenez, Sergii Domanskyi, Gianni Monaco, Verena Chung, Jineta Banerjee, Daniel Derrick, Alberto Valdeolivas, Haojun Li, Xu Xiao, Shun Wang, Frank Zheng, Wenxian Yang, Carlos A. Catania, Benjamin J. Lang, Thomas J. Bertus, Carlo Piermarocchi, Francesca P. Caruso, Michele Ceccarelli, Thomas Yu, Xindi Guo, Julie Bletz, John Coller, Holden Maecker, Caroline Duault, Vida Shokoohi, Shailja Patel, Joanna E. Liliental, Stockard Simon, Tumor Deconvolution DREAM Challenge consortium, Julio Saez-Rodriguez, Laura M. Heiser, Justin Guinney, and Andrew J. Gentles

Subjects
Science
Abstract

Abstract 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 most cell types well, though they either were not trained to evaluate all functional CD8+ T cell states or do so with low accuracy. Several community-contributed methods address this gap, including a deep learning-based approach, whose strong performance establishes the applicability of this paradigm to deconvolution. Despite being developed largely using immune cells from healthy tissues, deconvolution methods predict levels of tumor-derived immune cells well. Our admixed and purified transcriptional profiles will be a valuable resource for developing deconvolution methods, including in response to common challenges we observe across methods, such as sensitive identification of functional CD4+ T cell states.

Published
2024
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7. Microsatellite instability at U2AF-binding polypyrimidic tract sites perturbs alternative splicing during colorectal cancer initiation

Author

Vincent Jonchère, Hugo Montémont, Enora Le Scanf, Aurélie Siret, Quentin Letourneur, Emmanuel Tubacher, Christophe Battail, Assane Fall, Karim Labreche, Victor Renault, Toky Ratovomanana, Olivier Buhard, Ariane Jolly, Philippe Le Rouzic, Cody Feys, Emmanuelle Despras, Habib Zouali, Rémy Nicolle, Pascale Cervera, Magali Svrcek, Pierre Bourgoin, Hélène Blanché, Anne Boland, Jérémie Lefèvre, Yann Parc, Mehdi Touat, Franck Bielle, Danielle Arzur, Gwennina Cueff, Catherine Le Jossic-Corcos, Gaël Quéré, Gwendal Dujardin, Marc Blondel, Cédric Le Maréchal, Romain Cohen, Thierry André, Florence Coulet, Pierre de la Grange, Aurélien de Reyniès, Jean-François Fléjou, Florence Renaud, Agusti Alentorn, Laurent Corcos, Jean-François Deleuze, Ada Collura, and Alex Duval

Subjects
Colorectal cancer, Mismatch repair deficiency, Microsatellite instability, Whole-exome and RNA sequencing, Alternative splicing, Polypyrimidine U2AF binding site, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract 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 different steps of colorectal tumorigenesis using whole exome sequencing and search for associated splicing events via RNA sequencing at the bulk-tumor and single-cell levels. Results Our results demonstrate that MSI leads to hundreds of noncoding DNA mutations, notably at polypyrimidine U2AF RNA-binding sites which are endowed with cis-activity in splicing, while higher frequency of exon skipping events are observed in the mRNAs of MSI compared to non-MSI CRC. At the DNA level, these noncoding MSI mutations occur very early prior to cell transformation in the dMMR colonic crypt, accounting for only a fraction of the exon skipping in MSI CRC. At the RNA level, the aberrant exon skipping signature is likely to impair colonic cell differentiation in MSI CRC affecting the expression of alternative exons encoding protein isoforms governing cell fate, while also targeting constitutive exons, making dMMR cells immunogenic in early stage before the onset of coding mutations. This signature is characterized by its similarity to the oncogenic U2AF1-S34F splicing mutation observed in several other non-MSI cancer. Conclusions Overall, these findings provide evidence that a very early RNA splicing signature partly driven by MSI impairs cell differentiation and promotes MSI CRC initiation, far before coding mutations which accumulate later during MSI tumorigenesis.

Published
2024
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8. Wnt, glucocorticoid and cellular prion protein cooperate to drive a mesenchymal phenotype with poor prognosis in colon cancer

Author

Sophie Mouillet-Richard, Angélique Gougelet, Bruno Passet, Camille Brochard, Delphine Le Corre, Caterina Luana Pitasi, Camille Joubel, Marine Sroussi, Claire Gallois, Julien Lavergne, Johan Castille, Marthe Vilotte, Nathalie Daniel-Carlier, Camilla Pilati, Aurélien de Reyniès, Fatima Djouadi, Sabine Colnot, Thierry André, Julien Taieb, Jean-Luc Vilotte, Béatrice Romagnolo, and Pierre Laurent-Puig

Subjects
Colon cancer, Prion protein, Wnt-β-catenin, Glucocorticoid receptor, Molecular classification, Medicine
Abstract

Abstract 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 shed light on the gene regulatory networks linked to PrPC. Methods We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients. Results In silico analyses combined with cell-based assays identified the Wnt-β-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrPC and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrPC, β-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence. Conclusions An unleashed PrPC-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.

Published
2024
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9. Author Correction: Community assessment of methods to deconvolve cellular composition from bulk gene expression

Author

Brian S. White, Aurélien de Reyniès, Aaron M. Newman, Joshua J. Waterfall, Andrew Lamb, Florent Petitprez, Yating Lin, Rongshan Yu, Martin E. Guerrero-Gimenez, Sergii Domanskyi, Gianni Monaco, Verena Chung, Jineta Banerjee, Daniel Derrick, Alberto Valdeolivas, Haojun Li, Xu Xiao, Shun Wang, Frank Zheng, Wenxian Yang, Carlos A. Catania, Benjamin J. Lang, Thomas J. Bertus, Carlo Piermarocchi, Francesca P. Caruso, Michele Ceccarelli, Thomas Yu, Xindi Guo, Julie Bletz, John Coller, Holden Maecker, Caroline Duault, Vida Shokoohi, Shailja Patel, Joanna E. Liliental, Stockard Simon, Tumor Deconvolution DREAM Challenge consortium, Julio Saez-Rodriguez, Laura M. Heiser, Justin Guinney, and Andrew J. Gentles

Subjects
Science
Published
2024
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10. Proteogenomic Characterization of Bladder Cancer Reveals Sensitivity to Apoptosis Induced by Tumor Necrosis Factor–related Apoptosis-inducing Ligand in FGFR3-mutated Tumors

Author

Groeneveld, Clarice S., Sanchez-Quiles, Virginia, Dufour, Florent, Shi, Mingjun, Dingli, Florent, Nicolle, Rémy, Chapeaublanc, Elodie, Poullet, Patrick, Jeffery, Daniel, Krucker, Clémentine, Maillé, Pascale, Vacherot, Francis, Vordos, Dimitri, Benhamou, Simone, Lebret, Thierry, Micheau, Olivier, Zinovyev, Andrei, Loew, Damarys, Allory, Yves, de Reyniès, Aurélien, Bernard-Pierrot, Isabelle, and Radvanyi, François

Published
2024
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11. Basal/squamous and mixed subtype bladder cancers present poor outcomes after neoadjuvant chemotherapy in the VESPER trial

Author

Pignot, G., Fendler, J.P., Guy, L., Verhoest, G., Mottet, N., Doerfler, A., Abadie-Lacourtoisie, S., Azzouzi, A., Mongiat, P., Geoffrois, L., Eschwege, P., Di Fiore, F., Roubaud, G., Hoepffner, J.L., Barthelemy, P., Lang, H., Voog, E., Mandron, E., Tourani, J.M., Serrrate, C., Colau, A., Saldana, C., de La Taille, A., Nguyen, T., Kleinclauss, F., Loriot, Y., Irani, J., Eymard, J.C., Larre, S., Huillard, O., Zerbib, M., Rolland, F., Rigaud, J., Houede, N., Droupy, S., Malouf, G., Roupret, M., Vieillot, S., Letang, N., Lharidon, T., Gaschignard, N., Hilgers, W., Davin, J.L., Groeneveld, C.S., Pfister, C., Culine, S., Harter, V., Krucker, C., Fontugne, J., Dixon, V., Sirab, N., Bernard-Pierrot, I., de Reyniès, A., Radvanyi, F., and Allory, Y.

Published
2024
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12. Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer

Author

Robertson, A. Gordon, Meghani, Khyati, Cooley, Lauren Folgosa, McLaughlin, Kimberly A., Fall, Leigh Ann, Yu, Yanni, Castro, Mauro A. A., Groeneveld, Clarice S., de Reyniès, Aurélien, Nazarov, Vadim I., Tsvetkov, Vasily O., Choy, Bonnie, Raggi, Daniele, Marandino, Laura, Montorsi, Francesco, Powles, Thomas, Necchi, Andrea, and Meeks, Joshua J.

Published
2023
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13. Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer

Author

A. Gordon Robertson, Khyati Meghani, Lauren Folgosa Cooley, Kimberly A. McLaughlin, Leigh Ann Fall, Yanni Yu, Mauro A. A. Castro, Clarice S. Groeneveld, Aurélien de Reyniès, Vadim I. Nazarov, Vasily O. Tsvetkov, Bonnie Choy, Daniele Raggi, Laura Marandino, Francesco Montorsi, Thomas Powles, Andrea Necchi, and Joshua J. Meeks

Subjects
Science
Abstract

Abstract 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 combined transcriptional and genetic profiling with digital spatial profiling. We identify five distinctive genetic and transcriptomic programs and validate these in an independent neoadjuvant CPI trial to identify the features of response or resistance to CPI. By modeling the regulatory network, we identify the histone demethylase KDM5B as a repressor of tumor immune signaling pathways in one resistant subtype (S1, Luminal-excluded) and demonstrate that inhibition of KDM5B enhances immunogenicity in FGFR3-mutated BCa cells. Our study identifies signatures associated with response to CPI that can be used to molecularly stratify patients and suggests therapeutic alternatives for subtypes with poor response to neoadjuvant immunotherapy.

Published
2023
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14. Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability

Author

Ratovomanana, T., Nicolle, R., Cohen, R., Diehl, A., Siret, A., Letourneur, Q., Buhard, O., Perrier, A., Guillerm, E., Coulet, F., Cervera, P., Benusiglio, P., Labrèche, K., Colle, R., Collura, A., Despras, E., Le Rouzic, P., Renaud, F., Cros, J., Alentorn, A., Touat, M., Ayadi, M., Bourgoin, P., Prunier, C., Tournigand, C., Fouchardière, C. de la, Tougeron, D., Jonchère, V., Bennouna, J., de Reynies, A., Fléjou, J.-F., Svrcek, M., André, T., and Duval, A.

Published
2023
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15. Gemcitabine plus platinum-based chemotherapy in combination with bevacizumab for kidney metastatic collecting duct and medullary carcinomas: Results of a prospective phase II trial (BEVABEL-GETUG/AFU24)

Author

Thibault, Constance, Fléchon, Aude, Albiges, Laurence, Joly, Charlotte, Barthelemy, Philippe, Gross-Goupil, Marine, Chevreau, Christine, Coquan, Elodie, Rolland, Frédéric, Laguerre, Brigitte, Gravis, Gwenaelle, Pécuchet, Nicolas, Elaidi, Réza-Thierry, Timsit, Marc-Olivier, Brihoum, Meryem, Auclin, Edouard, de Reyniès, Aurélien, Allory, Yves, and Oudard, Stéphane

Published
2023
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16. Molecular and clinical diversity in primary central nervous system lymphoma

Author

Hernández-Verdin, I., Kirasic, E., Wienand, K., Mokhtari, K., Eimer, S., Loiseau, H., Rousseau, A., Paillassa, J., Ahle, G., Lerintiu, F., Uro-Coste, E., Oberic, L., Figarella-Branger, D., Chinot, O., Gauchotte, G., Taillandier, L., Marolleau, J.-P., Polivka, M., Adam, C., Ursu, R., Schmitt, A., Barillot, N., Nichelli, L., Lozano-Sánchez, F., Ibañez-Juliá, M.-J., Peyre, M., Mathon, B., Abada, Y., Charlotte, F., Davi, F., Stewart, C., de Reyniès, A., Choquet, S., Soussain, C., Houillier, C., Chapuy, B., Hoang-Xuan, K., and Alentorn, A.

Published
2023
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18. Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer

Author

Meylan, Maxime, Petitprez, Florent, Becht, Etienne, Bougoüin, Antoine, Pupier, Guilhem, Calvez, Anne, Giglioli, Ilenia, Verkarre, Virginie, Lacroix, Guillaume, Verneau, Johanna, Sun, Chen-Ming, Laurent-Puig, Pierre, Vano, Yann-Alexandre, Elaïdi, Reza, Méjean, Arnaud, Sanchez-Salas, Rafaël, Barret, Eric, Cathelineau, Xavier, Oudard, Stephane, Reynaud, Claude-Agnès, de Reyniès, Aurélien, Sautès-Fridman, Catherine, and Fridman, Wolf Herman

Published
2022
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19. DECONbench: a benchmarking platform dedicated to deconvolution methods for tumor heterogeneity quantification

Author

Clémentine Decamps, Alexis Arnaud, Florent Petitprez, Mira Ayadi, Aurélia Baurès, Lucile Armenoult, HADACA consortium, Sergio Escalera, Isabelle Guyon, Rémy Nicolle, Richard Tomasini, Aurélien de Reyniès, Jérôme Cros, Yuna Blum, and Magali Richard

Subjects
Benchmarking platform, Deconvolution, Transcriptome, DNA methylation, Omics integration, Cellular heterogeneity, Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Quantification of tumor heterogeneity is essential to better understand cancer progression and to adapt therapeutic treatments to patient specificities. Bioinformatic tools to assess the different cell populations from single-omic datasets as bulk transcriptome or methylome samples have been recently developed, including reference-based and reference-free methods. Improved methods using multi-omic datasets are yet to be developed in the future and the community would need systematic tools to perform a comparative evaluation of these algorithms on controlled data. Results We present DECONbench, a standardized unbiased benchmarking resource, applied to the evaluation of computational methods quantifying cell-type heterogeneity in cancer. DECONbench includes gold standard simulated benchmark datasets, consisting of transcriptome and methylome profiles mimicking pancreatic adenocarcinoma molecular heterogeneity, and a set of baseline deconvolution methods (reference-free algorithms inferring cell-type proportions). DECONbench performs a systematic performance evaluation of each new methodological contribution and provides the possibility to publicly share source code and scoring. Conclusion DECONbench allows continuous submission of new methods in a user-friendly fashion, each novel contribution being automatically compared to the reference baseline methods, which enables crowdsourced benchmarking. DECONbench is designed to serve as a reference platform for the benchmarking of deconvolution methods in the evaluation of cancer heterogeneity. We believe it will contribute to leverage the benchmarking practices in the biomedical and life science communities. DECONbench is hosted on the open source Codalab competition platform. It is freely available at: https://competitions.codalab.org/competitions/27453 .

Published
2021
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20. Molecular Subtypes and Gene Expression Signatures as Prognostic Features in Fully Resected Clear Cell Renal Cell Carcinoma: A Tailored Approach to Adjuvant Trials

Author

Roussel, Eduard, Verbiest, Annelies, Kinget, Lisa, Boeckx, Bram, Zucman-Rossi, Jessica, Couchy, Gabrielle, Caruso, Stefano, Job, Sylvie, de Reyniès, Aurélien, De Wever, Liesbeth, Baldewijns, Marcella, Van Poppel, Hendrik, Joniau, Steven, Lambrechts, Diether, Albersen, Maarten, and Beuselinck, Benoit

Published
2021
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21. Performance of Next-Generation Sequencing for the Detection of Microsatellite Instability in Colorectal Cancer With Deficient DNA Mismatch Repair

Author

Ratovomanana, Toky, Cohen, Romain, Svrcek, Magali, Renaud, Florence, Cervera, Pascale, Siret, Aurélie, Letourneur, Quentin, Buhard, Olivier, Bourgoin, Pierre, Guillerm, Erell, Dorard, Coralie, Nicolle, Remy, Ayadi, Mira, Touat, Mehdi, Bielle, Franck, Sanson, Marc, Le Rouzic, Philippe, Buisine, Marie-Pierre, Piessen, Guillaume, Collura, Ada, Fléjou, Jean-François, de Reyniès, Aurélien, Coulet, Florence, Ghiringhelli, François, André, Thierry, Jonchère, Vincent, and Duval, Alex

Published
2021
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22. A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression

Author

Jing Liu, Daniela Ottaviani, Meriem Sefta, Céline Desbrousses, Elodie Chapeaublanc, Rosario Aschero, Nanor Sirab, Fabiana Lubieniecki, Gabriela Lamas, Laurie Tonon, Catherine Dehainault, Clément Hua, Paul Fréneaux, Sacha Reichman, Narjesse Karboul, Anne Biton, Liliana Mirabal-Ortega, Magalie Larcher, Céline Brulard, Sandrine Arrufat, André Nicolas, Nabila Elarouci, Tatiana Popova, Fariba Némati, Didier Decaudin, David Gentien, Sylvain Baulande, Odette Mariani, Florent Dufour, Sylvain Guibert, Céline Vallot, Livia Lumbroso-Le Rouic, Alexandre Matet, Laurence Desjardins, Guillem Pascual-Pasto, Mariona Suñol, Jaume Catala-Mora, Genoveva Correa Llano, Jérôme Couturier, Emmanuel Barillot, Paula Schaiquevich, Marion Gauthier-Villars, Dominique Stoppa-Lyonnet, Lisa Golmard, Claude Houdayer, Hervé Brisse, Isabelle Bernard-Pierrot, Eric Letouzé, Alain Viari, Simon Saule, Xavier Sastre-Garau, François Doz, Angel M. Carcaboso, Nathalie Cassoux, Celio Pouponnot, Olivier Goureau, Guillermo Chantada, Aurélien de Reyniès, Isabelle Aerts, and François Radvanyi

Subjects
Science
Abstract

Retinoblastoma is the most frequent intraocular paediatric malignancy whose molecular basis remains poorly understood. Here, the authors perform multi-omic analysis and identify two subtypes; one in a cone differentiated state and one more aggressive showing cone dedifferentiation and expressing neuronal markers.

Published
2021
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24. A transcriptomic signature to predict adjuvant gemcitabine sensitivity in pancreatic adenocarcinoma

Author

Nicolle, R., Gayet, O., Duconseil, P., Vanbrugghe, C., Roques, J., Bigonnet, M., Blum, Y., Elarouci, N., Armenoult, L., Ayadi, M., de Reyniès, A., Puleo, F., Augustin, J., Emile, J.F., Svrcek, M., Arsenijevic, T., Hammel, P., Giovannini, M., Grandval, P., Dahan, L., Moutardier, V., Gilabert, M., Van Laethem, J.L., Bachet, J.B., Cros, J., Iovanna, J., and Dusetti, N.J.

Published
2021
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25. An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer

Author

Sia Viborg Lindskrog, Frederik Prip, Philippe Lamy, Ann Taber, Clarice S. Groeneveld, Karin Birkenkamp-Demtröder, Jørgen Bjerggaard Jensen, Trine Strandgaard, Iver Nordentoft, Emil Christensen, Mateo Sokac, Nicolai J. Birkbak, Lasse Maretty, Gregers G. Hermann, Astrid C. Petersen, Veronika Weyerer, Marc-Oliver Grimm, Marcus Horstmann, Gottfrid Sjödahl, Mattias Höglund, Torben Steiniche, Karin Mogensen, Aurélien de Reyniès, Roman Nawroth, Brian Jordan, Xiaoqi Lin, Dejan Dragicevic, Douglas G. Ward, Anshita Goel, Carolyn D. Hurst, Jay D. Raman, Joshua I. Warrick, Ulrika Segersten, Danijel Sikic, Kim E. M. van Kessel, Tobias Maurer, Joshua J. Meeks, David J. DeGraff, Richard T. Bryan, Margaret A. Knowles, Tatjana Simic, Arndt Hartmann, Ellen C. Zwarthoff, Per-Uno Malmström, Núria Malats, Francisco X. Real, and Lars Dyrskjøt

Subjects
Science
Abstract

Multiple molecular profiling methods are required to study urothelial non-muscle-invasive bladder cancer (NMIBC) due to its heterogeneity. Here the authors integrate multi-omics data of 834 NMIBC patients, identifying a molecular subgroup associated with multiple alterations and worse outcomes.

Published
2021
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26. Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer

Author

Nicolle, Rémy, Blum, Yuna, Duconseil, Pauline, Vanbrugghe, Charles, Brandone, Nicolas, Poizat, Flora, Roques, Julie, Bigonnet, Martin, Gayet, Odile, Rubis, Marion, Elarouci, Nabila, Armenoult, Lucile, Ayadi, Mira, de Reyniès, Aurélien, Giovannini, Marc, Grandval, Philippe, Garcia, Stephane, Canivet, Cindy, Cros, Jérôme, Bournet, Barbara, Buscail, Louis, Moutardier, Vincent, Gilabert, Marine, Iovanna, Juan, and Dusetti, Nelson

Published
2020
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27. A Consensus Molecular Classification of Muscle-invasive Bladder Cancer

Author

Aine, Mattias, Al-Ahmadie, Hikmat, Allory, Yves, Bellmunt, Joaquim, Bernard-Pierrot, Isabelle, Black, Peter C., Castro, Mauro A.A., Chan, Keith S., Choi, Woonyoung, Czerniak, Bogdan, Dinney, Colin P., Dyrskjøt, Lars, Eriksson, Pontus, Fontugne, Jacqueline, Gibb, Ewan A., Groeneveld, Clarice S., Hartmann, Arndt, Hoadley, Katherine A., Höglund, Mattias, Kamoun, Aurélie, Kardos, Jordan, Kim, Jaegil, Kim, William Y., Kwiatkowski, David J., Lebret, Thierry, Lerner, Seth P., Liedberg, Fredrik, Malats, Núria, McConkey, David J., Mo, Qianxing, Powles, Thomas, Radvanyi, François, Real, Francisco X., de Reyniès, Aurélien, Robertson, A. Gordon, Siefker-Radtke, Arlene, Sirab, Nanor, Seiler, Roland, Sjödahl, Gottfrid, Taber, Ann, Weinstein, John, and Zlotta, Alexandre

Published
2020
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29. The murine Microenvironment Cell Population counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations in murine samples using gene expression

Author

Florent Petitprez, Sacha Levy, Cheng-Ming Sun, Maxime Meylan, Christophe Linhard, Etienne Becht, Nabila Elarouci, David Tavel, Lubka T. Roumenina, Mira Ayadi, Catherine Sautès-Fridman, Wolf H. Fridman, and Aurélien de Reyniès

Subjects
Immune composition, Heterogeneous tissue, Tumor microenvironment, Immune checkpoint blockade, Alzheimer’s disease, Medicine, Genetics, QH426-470
Abstract

Abstract 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 method based on highly specific transcriptomic markers that accurately quantify 16 immune and stromal murine cell populations. We validated mMCP-counter with flow cytometry data and showed that mMCP-counter outperforms existing methods. We showed that mMCP-counter scores are predictive of response to immune checkpoint blockade in cancer mouse models and identify early immune impacts of Alzheimer’s disease.

Published
2020
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30. B cells are associated with survival and immunotherapy response in sarcoma

Author

Petitprez, Florent, de Reyniès, Aurélien, Keung, Emily Z., Chen, Tom Wei-Wu, Sun, Cheng-Ming, Calderaro, Julien, and Jeng, Yung-Ming

Subjects
Sarcoma -- Care and treatment -- Patient outcomes, Immunotherapy -- Patient outcomes, B cells -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes.sup.1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely.sup.3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8.sup.+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases. Immune profiling of the tumour microenvironment of soft-tissue sarcoma identifies a group of patients with high levels of B-cell infiltration and tertiary lymphoid structures that have improved survival and a high response rate to immune checkpoint blockade therapy., Author(s): Florent Petitprez [sup.1] [sup.2] [sup.3] [sup.4] , Aurélien de Reyniès [sup.4] , Emily Z. Keung [sup.5] , Tom Wei-Wu Chen [sup.6] [sup.7] [sup.8] [sup.9] , Cheng-Ming Sun [sup.1] [sup.2] [...]

Published
2020
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31. A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression

Author

Liu, Jing, Ottaviani, Daniela, Sefta, Meriem, Desbrousses, Céline, Chapeaublanc, Elodie, Aschero, Rosario, Sirab, Nanor, Lubieniecki, Fabiana, Lamas, Gabriela, Tonon, Laurie, Dehainault, Catherine, Hua, Clément, Fréneaux, Paul, Reichman, Sacha, Karboul, Narjesse, Biton, Anne, Mirabal-Ortega, Liliana, Larcher, Magalie, Brulard, Céline, Arrufat, Sandrine, Nicolas, André, Elarouci, Nabila, Popova, Tatiana, Némati, Fariba, Decaudin, Didier, Gentien, David, Baulande, Sylvain, Mariani, Odette, Dufour, Florent, Guibert, Sylvain, Vallot, Céline, Rouic, Livia Lumbroso-Le, Matet, Alexandre, Desjardins, Laurence, Pascual-Pasto, Guillem, Suñol, Mariona, Catala-Mora, Jaume, Llano, Genoveva Correa, Couturier, Jérôme, Barillot, Emmanuel, Schaiquevich, Paula, Gauthier-Villars, Marion, Stoppa-Lyonnet, Dominique, Golmard, Lisa, Houdayer, Claude, Brisse, Hervé, Bernard-Pierrot, Isabelle, Letouzé, Eric, Viari, Alain, Saule, Simon, Sastre-Garau, Xavier, Doz, François, Carcaboso, Angel M., Cassoux, Nathalie, Pouponnot, Celio, Goureau, Olivier, Chantada, Guillermo, de Reyniès, Aurélien, Aerts, Isabelle, and Radvanyi, François

Published
2021
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32. An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer

Author

Lindskrog, Sia Viborg, Prip, Frederik, Lamy, Philippe, Taber, Ann, Groeneveld, Clarice S., Birkenkamp-Demtröder, Karin, Jensen, Jørgen Bjerggaard, Strandgaard, Trine, Nordentoft, Iver, Christensen, Emil, Sokac, Mateo, Birkbak, Nicolai J., Maretty, Lasse, Hermann, Gregers G., Petersen, Astrid C., Weyerer, Veronika, Grimm, Marc-Oliver, Horstmann, Marcus, Sjödahl, Gottfrid, Höglund, Mattias, Steiniche, Torben, Mogensen, Karin, de Reyniès, Aurélien, Nawroth, Roman, Jordan, Brian, Lin, Xiaoqi, Dragicevic, Dejan, Ward, Douglas G., Goel, Anshita, Hurst, Carolyn D., Raman, Jay D., Warrick, Joshua I., Segersten, Ulrika, Sikic, Danijel, van Kessel, Kim E. M., Maurer, Tobias, Meeks, Joshua J., DeGraff, David J., Bryan, Richard T., Knowles, Margaret A., Simic, Tatjana, Hartmann, Arndt, Zwarthoff, Ellen C., Malmström, Per-Uno, Malats, Núria, Real, Francisco X., and Dyrskjøt, Lars

Published
2021
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33. The cellular prion protein controls the mesenchymal-like molecular subtype and predicts disease outcome in colorectal cancer

Author

Le Corre, Delphine, Ghazi, Alexandre, Balogoun, Ralyath, Pilati, Camilla, Aparicio, Thomas, Martin-Lannerée, Séverine, Marisa, Laetitia, Djouadi, Fatima, Poindessous, Virginie, Crozet, Carole, Emile, Jean-François, Mulot, Claire, Le Malicot, Karine, Boige, Valérie, Blons, Hélène, de Reynies, Aurélien, Taieb, Julien, Ghiringhelli, François, Bennouna, Jaafar, Launay, Jean-Marie, Laurent-Puig, Pierre, and Mouillet-Richard, Sophie

Published
2019
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34. PrPCcontrols epithelial-to-mesenchymal transition in EGFR-mutated NSCLC: implications for TKI resistance and patient follow-up

Author

Lailler, Claire, Didelot, Audrey, Garinet, Simon, Berthou, Hugo, Sroussi, Marine, de Reyniès, Aurélien, Dedhar, Shoukat, Martin-Lannerée, Séverine, Fabre, Elizabeth, Le Pimpec-Barthes, Françoise, Perrier, Alexandre, Poindessous, Virginie, Mansuet-Lupo, Audrey, Djouadi, Fatima, Launay, Jean-Marie, Laurent-Puig, Pierre, Blons, Hélène, and Mouillet-Richard, Sophie

Abstract

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-mesenchymal transition (EMT) is far from being fully characterized. We hypothesized that the cellular prion protein PrPCcould be involved in EMT and EGFR-TKI resistance in NSCLC. Using 5 independent lung adenocarcinoma datasets, including our own cohort, we document that the expression of the PRNPgene encoding PrPCis associated with EMT. By manipulating the levels of PrPCin different EGFR-mutated NSCLC cell lines, we firmly establish that the expression of PrPCis mandatory for cells to maintain or acquire a mesenchymal phenotype. Mechanistically, we show that PrPCoperates through an ILK-RBPJ cascade, which also controls the expression of EGFR. Our data further demonstrate that PrPClevels are elevated in EGFR-mutated versus wild-type tumours or upon EGFR activation in vitro. In addition, we provide evidence that PRNPlevels increase with TKI resistance and that reducing PRNPexpression sensitizes cells to osimertinib. Finally, we found that plasma PrPClevels are increased in EGFR-mutated NSCLC patients from 2 independent cohorts and that their longitudinal evolution mirrors that of disease. Altogether, these findings define PrPCas a candidate driver of EMT-dependent resistance to EGFR-TKI in NSCLC. They further suggest that monitoring plasma PrPClevels may represent a valuable non-invasive strategy for patient follow-up and warrant considering PrPC-targeted therapies for EGFR-mutated NSCLC patients with TKI failure.

Published
2024
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36. Integrated molecular characterization of chondrosarcoma reveals critical determinants of disease progression

Author

Rémy Nicolle, Mira Ayadi, Anne Gomez-Brouchet, Lucile Armenoult, Guillaume Banneau, Nabila Elarouci, Matthias Tallegas, Anne-Valérie Decouvelaere, Sébastien Aubert, Françoise Rédini, Béatrice Marie, Corinne Labit-Bouvier, Nicolas Reina, Marie Karanian, Louis-Romée le Nail, Philippe Anract, François Gouin, Frédérique Larousserie, Aurélien de Reyniès, and Gonzague de Pinieux

Subjects
Science
Abstract

Chondrosarcomas are heterogenous tumours of the bone cartilage and have highly variable prognoses. Here, the authors perform a multi-omics analysis, revealing molecular features that can stratify clinical outcomes.

Published
2019
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37. Dissecting heterogeneity in malignant pleural mesothelioma through histo-molecular gradients for clinical applications

Author

Yuna Blum, Clément Meiller, Lisa Quetel, Nabila Elarouci, Mira Ayadi, Danisa Tashtanbaeva, Lucile Armenoult, François Montagne, Robin Tranchant, Annie Renier, Leanne de Koning, Marie-Christine Copin, Paul Hofman, Véronique Hofman, Henri Porte, Françoise Le Pimpec-Barthes, Jessica Zucman-Rossi, Marie-Claude Jaurand, Aurélien de Reyniès, and Didier Jean

Subjects
Science
Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive form of cancer. Here, the authors show MPM is heterogeneously composed of epithelioid and sarcomatoid components and their proportions associate with prognosis and could inform therapeutic strategies.

Published
2019
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38. Recurrent activating mutations of PPARγ associated with luminal bladder tumors

Author

Natacha Rochel, Clémentine Krucker, Laure Coutos-Thévenot, Judit Osz, Ruiyun Zhang, Elodie Guyon, Wayne Zita, Séverin Vanthong, Oscar Alba Hernandez, Maxime Bourguet, Kays Al Badawy, Florent Dufour, Carole Peluso-Iltis, Syrine Heckler-Beji, Annick Dejaegere, Aurélie Kamoun, Aurélien de Reyniès, Yann Neuzillet, Sandra Rebouissou, Claire Béraud, Hervé Lang, Thierry Massfelder, Yves Allory, Sarah Cianférani, Roland H. Stote, François Radvanyi, and Isabelle Bernard-Pierrot

Subjects
Science
Abstract

Activation of the PPARγ/RXRα pathway in luminal bladder cancers has mainly been linked to PPARG gene amplifications and activating point mutations in RXRα. Here, the authors identify recurrent PPARγ mutations with similar effects and elucidate the structural basis for this mutational PPARγ activation.

Published
2019
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39. Gemcitabine plus platinum-based chemotherapy in combination with bevacizumab for kidney metastatic collecting duct and medullary carcinomas: Results of a prospective phase II trial (BEVABEL-GETUG/AFU24)

Author

Constance Thibault, Aude Fléchon, Laurence Albiges, Charlotte Joly, Philippe Barthelemy, Marine Gross-Goupil, Christine Chevreau, Elodie Coquan, Frédéric Rolland, Brigitte Laguerre, Gwenaelle Gravis, Nicolas Pécuchet, Réza-Thierry Elaidi, Marc-Olivier Timsit, Meryem Brihoum, Edouard Auclin, Aurélien de Reyniès, Yves Allory, and Stéphane Oudard

Subjects
Cancer Research, Oncology
Published
2023
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40. Review of Prognostic Expression Markers for Clear Cell Renal Cell Carcinoma

Author

Florent Petitprez, Mira Ayadi, Aurélien de Reyniès, Wolf H. Fridman, Catherine Sautès-Fridman, and Sylvie Job

Subjects
prognostic markers, clear cell renal cell carcinoma (ccRCC), multivariate analysis, independent datasets, cox models, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

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 searched to identify RNA and protein markers whose expression level was reported as associated with survival of ccRCC patients. Relevant studies were selected through cross-reading by two readers.Evidence Synthesis: We selected 249 studies reporting an association with prognostic of either single markers or multiple-marker models. Altogether, these studies were based on a total of 341 distinct markers and 13 multiple-marker models. Twenty percent of these markers were involved in four biological pathways altered in ccRCC: cell cycle, angiogenesis, hypoxia, and immune response. The main genes (VHL, PBRM1, BAP1, and SETD2) involved in ccRCC carcinogenesis are not the most relevant for assessing survival.Conclusion: Among single markers, the most validated markers were KI67, BIRC5, TP53, CXCR4, and CA9. Of the multiple-marker models, the most famous model, ClearCode34, has been highly validated on several independent datasets, but its clinical utility has not yet been investigated.Patient Summary: Over the years, the prognosis studies have evolved from single markers to multiple-marker models. Our review highlights the highly validated prognostic markers and multiple-marker models and discusses their clinical utility for better therapeutic care.

Published
2021
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41. Stratification of Pancreatic Ductal Adenocarcinomas Based on Tumor and Microenvironment Features

Author

Puleo, Francesco, Nicolle, Rémy, Blum, Yuna, Cros, Jérôme, Marisa, Laetitia, Demetter, Pieter, Quertinmont, Eric, Svrcek, Magali, Elarouci, Nabila, Iovanna, Juan, Franchimont, Denis, Verset, Laurine, Galdon, Maria Gomez, Devière, Jacques, de Reyniès, Aurélien, Laurent-Puig, Pierre, Van Laethem, Jean-Luc, Bachet, Jean-Baptiste, and Maréchal, Raphaël

Published
2018
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43. Polymorphisms in the Von Hippel–Lindau Gene Are Associated With Overall Survival in Metastatic Clear-Cell Renal-Cell Carcinoma Patients Treated With VEGFR Tyrosine Kinase Inhibitors

Author

Verbiest, Annelies, Lambrechts, Diether, Van Brussel, Thomas, Couchy, Gabrielle, Wozniak, Agnieszka, Méjean, Arnaud, Lerut, Evelyne, Oudard, Stéphane, Verkarre, Virginie, Job, Sylvie, de Reynies, Aurélien, Machiels, Jean-Pascal, Patard, Jean-Jacques, Zucman-Rossi, Jessica, and Beuselinck, Benoit

Published
2018
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46. Identification of Positively and Negatively Selected Driver Gene Mutations Associated With Colorectal Cancer With Microsatellite Instability

Author

Jonchere, Vincent, Marisa, Laetitia, Greene, Malorie, Virouleau, Alain, Buhard, Olivier, Bertrand, Romane, Svrcek, Magali, Cervera, Pascale, Goloudina, Anastasia, Guillerm, Erell, Coulet, Florence, Landman, Samuel, Ratovomanana, Toky, Job, Sylvie, Ayadi, Mira, Elarouci, Nabila, Armenoult, Lucile, Merabtene, Fatiha, Dumont, Sylvie, Parc, Yann, Lefèvre, Jérémie H., André, Thierry, Fléjou, Jean-François, Guilloux, Agathe, Collura, Ada, de Reyniès, Aurélien, and Duval, Alex

Published
2018
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47. Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer

Author

Rémy Nicolle, Yuna Blum, Pauline Duconseil, Charles Vanbrugghe, Nicolas Brandone, Flora Poizat, Julie Roques, Martin Bigonnet, Odile Gayet, Marion Rubis, Nabila Elarouci, Lucile Armenoult, Mira Ayadi, Aurélien de Reyniès, Marc Giovannini, Philippe Grandval, Stephane Garcia, Cindy Canivet, Jérôme Cros, Barbara Bournet, Vincent Moutardier, Marine Gilabert, Juan Iovanna, Nelson Dusetti, and Louis Buscail

Subjects
Pancreatic cancer, Transcriptomic signature, Chemosensitivity prediction, Prognostic, Translational medicine, Precision medicine, Medicine, Medicine (General), R5-920
Abstract

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 gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n = 598) of resected tumours; ii/ 60 advanced tumours obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumours. Findings: A unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumours (e.g. 308 consecutive resected PDAC, uHR=0.321 95% CI [0.207–0.5] and 60 locally-advanced or metastatic PDAC, uHR=0.308 95% CI [0.113–0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumour response: -0.67, p-value < 0.001). Interpretation: PAMG unify all PDAC pre-existing classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient. Funding: Project funding was provided by INCa (Grants number 2018–078 and 2018–079, BACAP BCB INCa_6294), Canceropole PACA, DGOS (labellisation SIRIC), Amidex Foundation, Fondation de France, INSERM and Ligue Contre le Cancer.

Published
2020
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48. The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies

Author

Florent Petitprez, Maxime Meylan, Aurélien de Reyniès, Catherine Sautès-Fridman, and Wolf H. Fridman

Subjects
tumor microenvironment, immunotherapy, immune checkpoint blockade, response, prediction, Immunologic diseases. Allergy, RC581-607
Abstract

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 reinvigorate an efficacious antitumoral immune response. In addition to tumor cell intrinsic biomarkers, increasing data pinpoint the importance of the TME in guiding patient selection and combination therapies. Here, we review recent efforts in determining how various components of the TME can influence response and resistance to ICB. Although a large body of evidence points to the extent and functional orientation of the T cell infiltrate as important in therapy response, recent studies also confirm a role for other components of the TME, such as B cells, myeloid lineage cells, cancer-associated fibroblasts, and vasculature. If the ultimate goal of curative cancer therapies is to induce a long-term memory T cell response, the other components of the TME may positively or negatively modulate the induction of efficient antitumor immunity. The emergence of novel high-throughput methods for analyzing the TME, including transcriptomics, has allowed tremendous developments in the field, with the expansion of patient cohorts, and the identification of TME-based markers of therapy response. Together, these studies open the possibility of including TME-based markers for selecting patients that are likely to respond to specific therapies, and pave the way to personalized medicine in oncology.

Published
2020
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49. Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes

Author

Gwen Lomberk, Yuna Blum, Rémy Nicolle, Asha Nair, Krutika Satish Gaonkar, Laetitia Marisa, Angela Mathison, Zhifu Sun, Huihuang Yan, Nabila Elarouci, Lucile Armenoult, Mira Ayadi, Tamas Ordog, Jeong-Heon Lee, Gavin Oliver, Eric Klee, Vincent Moutardier, Odile Gayet, Benjamin Bian, Pauline Duconseil, Marine Gilabert, Martin Bigonnet, Stephane Garcia, Olivier Turrini, Jean-Robert Delpero, Marc Giovannini, Philippe Grandval, Mohamed Gasmi, Veronique Secq, Aurélien De Reyniès, Nelson Dusetti, Juan Iovanna, and Raul Urrutia

Subjects
Science
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a complex disease and its underlying epigenomic heterogeneity is not fully understood. Here, the authors utilize patient-derived PDAC xenografts to define the epigenomic landscape of PDAC, highlighting chromatin states linked to differing disease aggressiveness and survival.

Published
2018
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50. Identification of Positively and Negatively Selected Driver Gene Mutations Associated With Colorectal Cancer With Microsatellite InstabilitySummary

Author

Vincent Jonchere, Laetitia Marisa, Malorie Greene, Alain Virouleau, Olivier Buhard, Romane Bertrand, Magali Svrcek, Pascale Cervera, Anastasia Goloudina, Erell Guillerm, Florence Coulet, Samuel Landman, Toky Ratovomanana, Sylvie Job, Mira Ayadi, Nabila Elarouci, Lucile Armenoult, Fatiha Merabtene, Sylvie Dumont, Yann Parc, Jérémie H. Lefèvre, Thierry André, Jean-François Fléjou, Agathe Guilloux, Ada Collura, Aurélien de Reyniès, and Alex Duval

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Background & Aims: Recent studies have shown that cancers arise as a result of the positive selection of driver somatic events in tumor DNA, with negative selection playing only a minor role, if any. However, these investigations were concerned with alterations at nonrepetitive sequences and did not take into account mutations in repetitive sequences that have very high pathophysiological relevance in the tumors showing microsatellite instability (MSI) resulting from mismatch repair deficiency investigated in the present study. Methods: We performed whole-exome sequencing of 47 MSI colorectal cancers (CRCs) and confirmed results in an independent cohort of 53 MSI CRCs. We used a probabilistic model of mutational events within microsatellites, while adapting pre-existing models to analyze nonrepetitive DNA sequences. Negatively selected coding alterations in MSI CRCs were investigated for their functional and clinical impact in CRC cell lines and in a third cohort of 164 MSI CRC patients. Results: Both positive and negative selection of somatic mutations in DNA repeats was observed, leading us to identify the expected true driver genes associated with the MSI-driven tumorigenic process. Several coding negatively selected MSI-related mutational events (n = 5) were shown to have deleterious effects on tumor cells. In the tumors in which deleterious MSI mutations were observed despite the negative selection, they were associated with worse survival in MSI CRC patients (hazard ratio, 3; 95% CI, 1.1–7.9; P = .03), suggesting their anticancer impact should be offset by other as yet unknown oncogenic processes that contribute to a poor prognosis. Conclusions: The present results identify the positive and negative driver somatic mutations acting in MSI-driven tumorigenesis, suggesting that genomic instability in MSI CRC plays a dual role in achieving tumor cell transformation. Exome sequencing data have been deposited in the European genome–phenome archive (accession: EGAS00001002477). Keywords: Colorectal Cancer, Microsatellite Instability, Tumorigenic Process, Driver Gene Mutations, Positive and Negative Selection

Published
2018
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