Portrait of Sébastien Lemieux

Sébastien Lemieux

Associate Academic Member
Associate Professor, Université de Montréal, Department of Computer Science and Operations Research and Department of Biochemistry and Molecular Medicine
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Biography

Sébastien Lemieux trained as a microbiologist but turned to bioinformatics in 1997, completing his MSc and PhD at Université de Montréal under the supervision of François Major. After obtaining his PhD in 2002, he headed to the private sector for postdoctoral training at Elitra Canada (now Merck & Co) under the supervision of Bo Jiang. There he acquired skills in sequence analysis and the analysis of DNA microarray data, as well as in the integration of experimental data with computational techniques.

Lemieux joined Université de Montréal in 2005, first at the Institute for Research in Immunology and Cancer (IRIC). In 2018, he was appointed associate professor in the Department of Biochemistry and Molecular Medicine of the Faculty of Medicine.

Current Students

Matthew Scicluna
PhD - Université de Montréal
Principal supervisor :
Julie Hussin
matthew.scicluna@mila.quebec
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Publications

Transposable elements regulate thymus development and function
Jean-David Larouche
Céline M. Laumont
Assya Trofimov
Krystel Vincent
Leslie Hesnard
Sylvie Brochu
Caroline Côté
Juliette Humeau
Eric Bonneil
Joël Lanoix
Chantal Durette
Patrick Gendron
Jean-Philippe Laverdure
Ellen R. Richie
Sébastien Lemieux
Pierre Thibault
Claude Perreault
2024-02-01
bioRxiv (preprint)
doi.org
Identification of Acute Myeloid Leukemia Cell Surface Therapeutic Targets Using Single Cell RNA Sequencing Supported By Surface Proteomics
Véronique Lisi
Banafsheh Khakipoor
Azer Farah
Marie-Eve Bordeleau
Éric Audemard
Arnaud Metois
Louis Theret
Jean-Francois Spinella
Jalila Chagraoui
Ossama Moujaber
Laure Mallinger
Isabel Boivin
Nadine Mayotte
Azadeh Hajmirza
Eric Bonneil
Francois Béliveau
Albert Feghali
Geneviève Boucher
Patrick Gendron
Frederic Barabe … (see 6 more)
Sébastien Lemieux
Guillaume Richard-Carpentier
Josée Hébert
Philippe Roux
Guy Sauvageau
Vincent-Philippe Lavallee
Background: Acute myeloid leukemia (AML) comprises diverse genomic subgroups and remains hard to treat in most patients. Despite breakthrou… (see more)ghs in the therapeutic arsenal in recent years, clinical usage of therapeutic antibodies or chimeric antigen receptor T (CAR-T) cells has been lagging in contrast to other hematological malignancies. In fact, CD33 represents the only antibody-based strategy approved for this disease to date, highlighting the need to identify new promising targets. AML cells span a wide range of aberrant myeloid differentiation programs, complexifying the identification, by bulk genomics, of targets expressed in the most immature leukemic cells. Aims and Methods: To identify the expression landscape of surface proteins in immature leukemic cells, we performed single-cell RNA sequencing (scRNA-seq, 10x 3' Reagent Kits) of primary human AML cells from 20 specimens of the Leucegene cohort enriched in intermediate and adverse genetic backgrounds ( KMT2A-rearranged n=5, chromosome 5 and/or 7 deletions (abn5/7, n=5) complex karyotype (n=4), NPM1/DNMT3A/FLT3-ITD triple-mutant (n=3) and others (n=3)). A Random Forest classifier was developed to unbiasedly classify AML cells into distinct differentiation stages using normal bone marrow-derived scRNA-seq data from the Human Cell Atlas (HCA) consortium. Genes were scored based on their probability of coding for proteins expressed at the cell surface using the SPAT algorithm developed by our group (https://doi.org/10.1101/2023.07.07.547075), retaining high score ones. To validate surface expression, we concomitantly analyzed the surface proteome (hereafter named surfaceome) of 100 primary human AML samples from the Leucegene cohort, including all 20 samples profiled by scRNA-seq. Results: After quality control, we profiled and characterized 103 690 high quality cells (mean of 5185 cells/sample). We trained a Random Forest classifier to annotate cells in a two step process, first identifying plasma cells based on a restricted list of genes abundantly expressed in these cells and subsequently assigning the remaining cells to one of 33 cell types. We performed a five-fold cross validation of the model and subsequently determined the accuracy of our classifier to be 92% on the test subset of the HCA data. Applied to our AML cell collection, a total of 35 053 cells (34%) were unbiasedly classified as Hematopoietic Stem Cell (HSC)-like, corresponding to the most phenotypically immature leukemic cells in each patient sample (ranging from 4 to 74 %). Accordingly, HSC-like AML cells preferentially express genes associated with normal HSCs, such as CD34, FAM30A, and SPINK2, and globally lack expression of mature lineages defining genes, further validating our classifier. The proportion of HSC-like cells varied among AML subgroups, and was lowest in KMT2A-r AML (median 19%) and highest in abn5/7 samples (46%). Integration of our AML atlas using Harmony algorithm preserved differentiation hierarchies across samples, with most cell types, including HSC-like cells, occupying a defined area in the low dimensional embedding. To identify new surface antigens specifically expressed in immature leukemic cells, we compared the high (≥8) SPAT score gene expression profile of AML HSC-like cells with that of normal HSC cells (HCA), and identified 60 genes significantly overexpressed in AML immature cells. Of those, 39 genes were also detected at the protein level by the surfaceome analysis, supporting their predicted expression at the cell surface in AML samples. 59% of these 39 genes (n=23) were detected in over 80% of the specimens analyzed by the surfaceome, and thus are nearly universally expressed in our AML cohort. To identify targets of therapies that could be repurposed, we next evaluated the relevance of our findings by querying the Thera-SAbDab database. Most interestingly, 8 of the 39 AML specific HSC markers are targeted by therapeutic antibodies FDA-approved or in clinical trials for the treatment of AML (n=4, IL3RA, FLT3, CD37 and TNFRSF10B) or other indications (n = 4). Conclusion Our genetically diverse AML single-cell atlas, supported by mass spectrometry, enables the identification of both subset-specific and pan-AML surface protein genes. These represent potential targets for antibody based strategy development or therapy repurposing in AML.
2023-11-28
Blood (published)
doi.org
Pepid: a Highly Modifiable, Bioinformatics-Oriented Peptide Search Engine
Jeremie Zumer
Sébastien Lemieux
2023-11-02
bioRxiv (preprint)
doi.org
Mining Mass Spectra for Peptide Facts
Jeremie Zumer
Sébastien Lemieux
The current mainstream software for peptide-centric tandem mass spectrometry data analysis can be categorized as either database-driven, whi… (see more)ch rely on a library of mass spectra to identify the peptide associated with novel query spectra, or de novo sequencing-based, which aim to find the entire peptide sequence by relying only on the query mass spectrum. While the first paradigm currently produces state-of-the-art results in peptide identification tasks, it does not inherently make use of information present in the query mass spectrum itself to refine identifications. Meanwhile, de novo approaches attempt to solve a complex problem in one go, without any search space constraints in the general case, leading to comparatively poor results. In this paper, we decompose the de novo problem into putatively easier subproblems, and we show that peptide identification rates of database-driven methods may be improved in terms of peptide identification rate by solving one such subsproblem without requiring a solution for the complete de novo task. We demonstrate this using a de novo peptide length prediction task as the chosen subproblem. As a first prototype, we show that a deep learning-based length prediction model increases peptide identification rates in the ProteomeTools dataset as part of an Pepid-based identification pipeline. Using the predicted information to better rank the candidates, we show that combining ideas from the two paradigms produces clear benefits in this setting. We propose that the next generation of peptide-centric tandem mass spectrometry identification methods should combine elements of these paradigms by mining facts “de novo; about the peptide represented in a spectrum, while simultaneously limiting the search space with a peptide candidates database.
2023-11-01
bioRxiv (preprint)
doi.org
BamQuery: a proteogenomic tool to explore the immunopeptidome and prioritize actionable tumor antigens
Maria-Virginia Ruiz Cuevas
Marie-Pierre Hardy
Jean-David Larouche
Anca Apavaloaei
Eralda Kina
Krystel Vincent
Patrick Gendron
Jean-Philippe Laverdure
Chantal Durette
Pierre Thibault
Sébastien Lemieux
Claude Perreault
Grégory Ehx
2023-08-15
Genome Biology (published)
doi.org
Toward computing attributions for dimensionality reduction techniques
Matthew Scicluna
Jean-Christophe Grenier
Raphael Poujol
Sébastien Lemieux
Julie Hussin
2023-08-03
Bioinformatics Advances (published)
doi.org
Abstract 2987: BamQuery: a new proteogenomic tool to explore the immunopeptidome and prioritize actionable tumor antigens
Maria-Virginia Ruiz Cuevas
Marie-Pierre Hardy
Jean-David Larouche
Anca Apavaloaei
Eralda Kina
Krystel Vincent
Patrick Gendron
Jean-Philippe Laverdure
Chantal Durette
Pierre Thibault
Sébastien Lemieux
Claude Perreault
Grégory Ehx
MHC class I-associated peptides (MAPs), collectively referred to as the immunopeptidome, have a pivotal role in cancer immunosurveillance. W… (see more)hile MAPs were long thought to be solely generated by the degradation of canonical proteins, recent advances in the field of proteogenomics (genomically-informed proteomics) evidenced that ∼10% of them originate from allegedly noncoding genomic sequences. Among these sequences, endogenous retroelements (EREs) are under intense scrutiny as a possible source of actionable tumor antigens (TAs). With the increasing number of cancer-oriented immunopeptidomic and proteogenomic studies comes the need to accurately attribute an RNA expression level to each MAP identified by mass-spectrometry. Here, we introduce BamQuery (BQ), a computational tool to attribute an exhaustive RNA expression to MAPs of any genomic origin (exon, intron, UTR, intergenic) from bulk and single-cell RNA-sequencing data. By using BQ on large datasets of published MAPs identified by mass spectrometry, we show that many of them can arise from more than one genomic region. Indeed, 27% of MAPs reported as deriving from protein-coding exons (canonical MAPs) could also arise from non-canonical genomic regions, sometimes with greater probability, and 61% of non-canonical MAPs could arise from more than a single genomic origin (334 possible regions on average per non-canonical MAP; up to 35,343 for EREs). The consideration of all these origins evidenced an unsuspected high RNA expression in normal human tissues of (i) published neoantigens/TAs (mutated or not); (ii) MAPs derived from proteasomal splicing, supposedly not genomically templated, and (iii) MAPs derived from viruses. In particular, the high expression of candidate immunotherapeutic targets such as TAs highlights the relevance of BamQuery and the necessity of using it to validate such antigens before translating their usage in clinical trials. We also demonstrate that BamQuery can be used to directly identify safe and actionable TAs as well as to predict their immunogenicity through our freely accessible web portal (https://bamquery.iric.ca/search). Therefore, BQ could become an essential tool in any TA prioritization pipeline in the near future. Citation Format: Maria-Virginia Ruiz Cuevas, Marie-Pierre Hardy, Jean-David Larouche, Anca Apavaloaei, Eralda Kina, Krystel Vincent, Patrick Gendron, Jean-Philippe Laverdure, Chantal Durette, Pierre Thibault, Sebastien Lemieux, Claude Perreault, Gregory Ehx. BamQuery: a new proteogenomic tool to explore the immunopeptidome and prioritize actionable tumor antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2987.
2023-04-04
Cancer Research (published)
doi.org
Abstract 2993: Unmutated tumor antigens are abundant and contribute to tumor control in melanoma
Anca Apavaloaei
Qingchuan Zhao
Leslie Hesnard
Krystel Vincent
Marie-Pierre Hardy
Chantal Durette
Joël Lanoix
Jean-Philippe Laverdure
Jean-David Larouche
Maria-Virginia Ruiz Cuevas
Grégory Ehx
Sébastien Lemieux
Pierre Thibault
Claude Perreault
Recognition of MHC-I-associated tumor antigens (TAs) by CD8+ T cells is central to antitumor immunity. Owing to the elevated tumor mutationa… (see more)l burden (TMB) in melanoma, the marked efficacy of immune checkpoint blockade (ICB) has been attributed to the recognition of mutated TAs. However, recent reports showed that response to ICB in melanomas with low TMB is associated with CD8+ T-cell reactivity against melanocyte lineage-associated antigens (LSAs). Here, we systematically evaluated the contribution of all TA classes, i.e., mutated and unmutated, canonical and non-canonical, to the antigenic landscape of melanoma. We characterized the TAs from melanoma biopsies and patient-derived cell lines using proteogenomics. Out of 79450 MHC-I-associated peptides (MAPs) identified from 19 samples, we found 557 unmutated TAs classified as tumor-specific (TSA), tumor-associated (TAA), or LSAs. These TAs most often derived from annotated open-reading frames, followed by ncRNAs and intergenic regions. By contrast, only 6 MAPs were mutated and tumor-specific, which could be partially explained by a decreased expression of mutations within MAP-generating genomic regions. While the number of unmutated TAs with predicted presentation (TApres) in melanoma patients was similar between responders and non-responders pre-ICB, non-responders showed marks of inefficient antigen presentation. In consequence, only responders lost TApres upon treatment, in tandem with an expansion in tumor-infiltrating lymphocytes. These results reveal a previously underappreciated contribution of unmutated TAs to tumor control in melanoma and suggest that enhancing their recognition could improve the ICB efficacy in non-responders. Citation Format: Anca Apavaloaei, Qingchuan Zhao, Leslie Hesnard, Krystel Vincent, Marie-Pierre Hardy, Chantal Durette, Joël Lanoix, Jean-Philippe Laverdure, Jean-David Larouche, Maria Virginia Ruiz Cuevas, Grégory Ehx, Sébastien Lemieux, Pierre Thibault, Claude Perreault. Unmutated tumor antigens are abundant and contribute to tumor control in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2993.
2023-04-04
Cancer Research (published)
doi.org
Transposable elements regulate thymus development and function 1
Jean-David Larouche
Céline M. Laumont
Assya Trofimov
Krystel Vincent
Leslie Hesnard
Sylvie Brochu
Caroline Côté
Juliette Humeau
Eric Bonneil
Joël Lanoix
Chantal Durette
Patrick Gendron
Jean-Philippe Laverdure
Ellen Rothman Richie
Sébastien Lemieux
Pierre Thibault
Claude Perreault
21 Transposable elements (TE) are repetitive sequences representing ~45% of the human and mouse genomes 22 and are highly expressed by medul… (see more)lary thymic epithelial cells (mTEC). In this study, we investigated the 23 role of transposable elements (TE), which are highly expressed by medullary thymic epithelial cells 24 (mTEC), on T-cell development in the thymus. We performed multi-omic analyses of TEs in human and 25 mouse thymic cells to elucidate their role in T cell development. We report that TE expression in the 26 human thymus is high and shows extensive ageand cell lineage-related variations. TEs interact with 27 multiple transcription factors in all cell types of the human thymus. Two cell types express particularly 28 broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDC). In mTECs, TEs interact with 29 transcription factors essential for mTEC development and function (e.g., PAX1 and RELB) and generate 30 MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 31 regulate non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large 32 numbers of TEs that lead to the formation of dsRNA, triggering RIG-I and MDA5 signaling and 33 explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study illustrates the diversity of 34 interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic 35 cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. 36 Therefore, we propose that the orchestration of TE expression in thymic cells is critical to prevent 37 autoimmunity in vertebrates. 38
2023-01-01
(published)
www.semanticscholar.org
Transposable elements regulate thymus development and function 1
Jean-David Larouche
Céline M. Laumont
Assya Trofimov
Krystel Vincent
Leslie Hesnard
Sylvie Brochu
Caroline Côté
Juliette Humeau
Eric Bonneil
Joël Lanoix
Chantal Durette
Patrick Gendron
Jean-Philippe Laverdure
Ellen Rothman Richie
Sébastien Lemieux
Pierre Thibault
Claude Perreault
21 Transposable elements (TE) are repetitive sequences representing ~45% of the human and mouse genomes 22 and are highly expressed by medul… (see more)lary thymic epithelial cells (mTEC). In this study, we investigated the 23 role of transposable elements (TE), which are highly expressed by medullary thymic epithelial cells 24 (mTEC), on T-cell development in the thymus. We performed multi-omic analyses of TEs in human and 25 mouse thymic cells to elucidate their role in T cell development. We report that TE expression in the 26 human thymus is high and shows extensive ageand cell lineage-related variations. TEs interact with 27 multiple transcription factors in all cell types of the human thymus. Two cell types express particularly 28 broad TE repertoires: mTECs and plasmacytoid dendritic cells (pDC). In mTECs, TEs interact with 29 transcription factors essential for mTEC development and function (e.g., PAX1 and RELB) and generate 30 MHC-I-associated peptides implicated in thymocyte education. Notably, AIRE, FEZF2, and CHD4 31 regulate non-redundant sets of TEs in murine mTECs. Human thymic pDCs homogenously express large 32 numbers of TEs that lead to the formation of dsRNA, triggering RIG-I and MDA5 signaling and 33 explaining why thymic pDCs constitutively secrete IFN ɑ/β. This study illustrates the diversity of 34 interactions between TEs and the adaptive immune system. TEs are genetic parasites, and the two thymic 35 cell types most affected by TEs (mTEcs and pDCs) are essential to establishing central T-cell tolerance. 36 Therefore, we propose that the orchestration of TE expression in thymic cells is critical to prevent 37 autoimmunity in vertebrates. 38
2023-01-01
(published)
www.semanticscholar.org
Unified gene expression signature of novel NPM1 exon 5 mutations in acute myeloid leukemia
Véronique Lisi
Ève Blanchard
Michael Vladovsky
Éric Audemard
Albert Ferghaly
Sébastien Lemieux
Josée Hébert
Guy Sauvageau
Vincent-Philippe Lavallee
Visual Abstract
2022-09-02
Blood Advances (published)
doi.org
Proteogenomics and Differential Ion Mobility Enable the Exploration of the Mutational Landscape in Colon Cancer Cells
Zhaoguan Wu
Eric Bonneil
Michael Belford
Cornelia Boeser
Maria-Virginia Ruiz Cuevas
Sébastien Lemieux
Jean-Jacques Dunyach
Pierre Thibault
2022-08-22
Analytical Chemistry (published)
doi.org