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Come work with us at Guardant R&D! Yupeng and his team are absolutely amazing!
Come work with us at Guardant R&D! Yupeng and his team are absolutely amazing!
Aimé par Maximilien Grandclaudon
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Last week, Jason Silvers, our CFO, was recognized at the Boston Business Journal's 2024 CFO of the Year awards. This accolade honors chief financial…
Last week, Jason Silvers, our CFO, was recognized at the Boston Business Journal's 2024 CFO of the Year awards. This accolade honors chief financial…
Aimé par Maximilien Grandclaudon
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One-of-a-kind opportunity to impact cancer patients' lives by leading the Oncology Data Science group at Novartis Science. The role can be based in…
One-of-a-kind opportunity to impact cancer patients' lives by leading the Oncology Data Science group at Novartis Science. The role can be based in…
Aimé par Maximilien Grandclaudon
Expérience et formation
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Publications
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RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition
Nature Communications
The RNF43_p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43_p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43_p.G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43659mut…
The RNF43_p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43_p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43_p.G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43659mut isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43659mut may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers.
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PD-L1 and ICOSL discriminate human Secretory and Helper dendritic cells in cancer, allergy and autoimmunity
Nature Communications
Here we show, by using 16 different stimuli in vitro that activated DCs in human blood are phenotypically and functionally dichotomous, and pure cultures of type 2 conventional dendritic cells acquire these states (termed Secretory and Helper) upon appropriate stimuli. PD-L1highICOSLlow Secretory DCs produce large amounts of inflammatory cytokines and chemokines but induce very low levels of T helper (Th) cytokines following co-culturing with T cells. Conversely, PD-L1lowICOSLhigh Helper DCs…
Here we show, by using 16 different stimuli in vitro that activated DCs in human blood are phenotypically and functionally dichotomous, and pure cultures of type 2 conventional dendritic cells acquire these states (termed Secretory and Helper) upon appropriate stimuli. PD-L1highICOSLlow Secretory DCs produce large amounts of inflammatory cytokines and chemokines but induce very low levels of T helper (Th) cytokines following co-culturing with T cells. Conversely, PD-L1lowICOSLhigh Helper DCs produce low levels of secreted factors but induce high levels and a broad range of Th cytokines. Secretory DCs bear a single-cell transcriptomic signature indicative of mature migratory LAMP3+ DCs associated with cancer and inflammation. Secretory DCs are linked to good prognosis in head and neck squamous cell carcinoma, and to response to checkpoint blockade in Melanoma
Other authorsSee publication -
The PD-L1/4-1BB bispecific Antibody-Anticalin fusion protein PRS-344/S095012 elicits strong T-cell stimulation in a tumor-localized manner
Clin Cancer Res .
Purpose: While patients responding to checkpoint blockade often achieve remarkable clinical responses, there is still significant unmet need due to resistant or refractory tumors. A combination of checkpoint blockade with further T-cell stimulation mediated by 4-1BB agonism may increase response rates and durability of response. A bispecific molecule that blocks the PD-1/PD-L1 axis and localizes 4-1BB co-stimulation to a PD-L1-positive tumor microenvironment (TME) or tumor draining lymph nodes…
Purpose: While patients responding to checkpoint blockade often achieve remarkable clinical responses, there is still significant unmet need due to resistant or refractory tumors. A combination of checkpoint blockade with further T-cell stimulation mediated by 4-1BB agonism may increase response rates and durability of response. A bispecific molecule that blocks the PD-1/PD-L1 axis and localizes 4-1BB co-stimulation to a PD-L1-positive tumor microenvironment (TME) or tumor draining lymph nodes could maximize antitumor immunity and increase the therapeutic window beyond what has been reported for anti-4-1BB monoclonal antibodies (mAbs).
Experimental design: We generated and characterized the PD-L1/4-1BB bispecific molecule PRS-344/S095012 for target binding and functional activity in multiple relevant in vitro assays. Transgenic mice expressing human 4-1BB were transplanted with human PD-L1-expressing murine MC38 cells to assess in vivo antitumoral activity.
Results: PRS-344/S095012 bound to its targets with high affinity and efficiently blocked the PD-1/PD-L1 pathway, and PRS-344/S095012-mediated 4-1BB co-stimulation was strictly PD-L1 dependent. We demonstrated a synergistic effect of both pathways on T-cell stimulation with the bispecific PRS-344/S095012 being more potent than the combination of mAbs. PRS-344/S095012 augmented CD4+ and CD8+ T cells effector functions and enhanced antigen-specific T-cell stimulation. Finally, PRS-344/S095012 demonstrated strong antitumoral efficacy in an anti-PD-L1 resistant mouse model in which soluble 4-1BB was detected as an early marker for 4-1BB agonist activity.
Conclusions: The PD-L1/4-1BB bispecific PRS-344/S095012 efficiently combines checkpoint blockade with a tumor-localized 4-1BB mediated stimulation burst to antigen-specific T cells, more potent than the combination of mAbs, supporting the advancement of PRS-344/S095012 towards clinical development.Other authorsSee publication -
YAP1 and PRDM14 converge to promote cell survival and tumorigenesis
Dev Cell
The transcriptional co-activator YAP1 oncogene is the downstream effector of the Hippo pathway, which regulates tissue homeostasis, organ size, regeneration, and tumorigenesis. Multiple cancers are dependent on sustained expression of YAP1 for cell proliferation, survival, and tumorigenesis, but the molecular basis of this oncogene dependency is not well understood. To identify genes that can functionally substitute for YAP1, we performed a genome-scale genetic rescue screen in YAP1-dependent…
The transcriptional co-activator YAP1 oncogene is the downstream effector of the Hippo pathway, which regulates tissue homeostasis, organ size, regeneration, and tumorigenesis. Multiple cancers are dependent on sustained expression of YAP1 for cell proliferation, survival, and tumorigenesis, but the molecular basis of this oncogene dependency is not well understood. To identify genes that can functionally substitute for YAP1, we performed a genome-scale genetic rescue screen in YAP1-dependent colon cancer cells expressing an inducible YAP1-specific shRNA. We found that the transcription factor PRDM14 rescued cell proliferation and tumorigenesis upon YAP1 suppression in YAP1-dependent cells, xenografts, and colon cancer organoids. YAP1 and PRDM14 individually activated the transcription of calmodulin 2 (CALM2) and a glucose transporter SLC2A1 upon YAP1 suppression, and CALM2 or SLC2A1 expression was required for the rescue of YAP1 suppression. Together, these findings implicate PRDM14-mediated transcriptional upregulation of CALM2 and SLC2A1 as key components of oncogenic YAP1 signaling and dependency.
Other authors -
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A multivariate modeling framework to quantify immune checkpoint context-dependent stimulation on T cells
Cell Discov
Cells receive, and adjust to, various stimuli, which function as part of complex microenvironments forming their "context". The possibility that a given context impacts the response to a given stimulus defines "context-dependency" and it explains large parts of the functional variability of physiopathological and pharmacological stimuli. Currently, there is no framework to analyze and quantify context-dependency over multiple contexts and cellular response outputs. We established an…
Cells receive, and adjust to, various stimuli, which function as part of complex microenvironments forming their "context". The possibility that a given context impacts the response to a given stimulus defines "context-dependency" and it explains large parts of the functional variability of physiopathological and pharmacological stimuli. Currently, there is no framework to analyze and quantify context-dependency over multiple contexts and cellular response outputs. We established an experimental system including a stimulus of interest, applied to an immune cell type in several contexts. We studied the function of OX40 ligand (OX40L) on T helper (Th) cell differentiation, in 4 molecular (Th0, Th1, Th2, and Th17) and 11 dendritic cell (DC) contexts (monocyte-derived DC and cDC2 conditions). We measured 17 Th output cytokines in 302 observations, and developed a statistical modeling strategy to quantify OX40L context-dependency. This revealed highly variable context-dependency, depending on the output cytokine and context type itself. Among molecular contexts, Th2 was the most influential on OX40L function. Among DC contexts, the DC type rather than the activating stimuli was dominant in controlling OX40L context-dependency. This work mathematically formalizes the complex determinants of OX40L functionality, and provides a unique framework to decipher and quantify the context-dependent variability of any biomolecule or drug function.
Other authorsSee publication -
Interplay between SMAD2 and STAT5A is a critical determinant of IL-17A/IL-17F differential expression
Molecular Biomedicine
Our model analysis points to the transcription factors NFAT2A, STAT5A and SMAD2 as key regulators of the differential expression of IL-17A and IL-17F, with STAT5A controlling IL-17F expression, and an interplay of NFAT2A, STAT5A and SMAD2 controlling IL-17A expression. We experimentally observed that the production of IL-17A was correlated with an increase of SMAD2 transcription, and the expression of IL-17F correlated with an increase of BLIMP-1 transcription, together with an increase of…
Our model analysis points to the transcription factors NFAT2A, STAT5A and SMAD2 as key regulators of the differential expression of IL-17A and IL-17F, with STAT5A controlling IL-17F expression, and an interplay of NFAT2A, STAT5A and SMAD2 controlling IL-17A expression. We experimentally observed that the production of IL-17A was correlated with an increase of SMAD2 transcription, and the expression of IL-17F correlated with an increase of BLIMP-1 transcription, together with an increase of STAT5A expression (mRNA), as predicted by our model. Interestingly, RORγt presumably plays a more determinant role in IL-17A expression as compared to IL-17F expression. In conclusion, we propose the first mechanistic model accounting for the differential expression of IL-17A and F in Th cells, providing a basis to design novel therapeutic interventions in auto-immune and inflammatory diseases.
Other authorsSee publication -
Dissection of intercellular communication using the transcriptome-based framework ICELLNET
Nature Communications
Cell-to-cell communication can be inferred from ligand-receptor expression in cell transcriptomic datasets. However, important challenges remain: global integration of cell-to-cell communication; biological interpretation; and application to individual cell population transcriptomic profiles. We develop ICELLNET, a transcriptomic-based framework integrating: 1) an original expert-curated database of ligand-receptor interactions accounting for multiple subunits expression; 2) quantification of…
Cell-to-cell communication can be inferred from ligand-receptor expression in cell transcriptomic datasets. However, important challenges remain: global integration of cell-to-cell communication; biological interpretation; and application to individual cell population transcriptomic profiles. We develop ICELLNET, a transcriptomic-based framework integrating: 1) an original expert-curated database of ligand-receptor interactions accounting for multiple subunits expression; 2) quantification of communication scores; 3) the possibility to connect a cell population of interest with 31 reference human cell types; and 4) three visualization modes to facilitate biological interpretation.
Other authorsSee publication -
T H cell diversity and response to dupilumab in patients with atopic dermatitis
J Allergy Clin Immunol
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A quantitative multivariate model of human dendritic cell-T helper cell communication
Cell
We developed a data-driven, computationally validated model capturing 56 already described and 290 potentially novel mechanisms of Th cell specification. By predicting context-dependent behaviors, we demonstrate a new function for IL-12p70 as an inducer of Th17 in an IL-1 signaling context. This work provides a unique resource to decipher the complex combinatorial rules governing DC-Th cell communication and guide their manipulation for vaccine design and immunotherapies.
Other authorsSee publication -
Model checking to assess T-helper cell plasticity
Frontiers in Bioengineering and Biotechnology
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Plus d’activités de Maximilien
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What does it take to build an AI-driven biotech in 2024? Our CEO Michael Nally will share his insight into this very topic as part of a panel…
What does it take to build an AI-driven biotech in 2024? Our CEO Michael Nally will share his insight into this very topic as part of a panel…
Aimé par Maximilien Grandclaudon
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Happy to share Owkin's major expansion into Germany 🇩🇪, Austria 🇦🇹 and Switzerland 🇨🇭 following partnerships with *nine hospitals* to bring…
Happy to share Owkin's major expansion into Germany 🇩🇪, Austria 🇦🇹 and Switzerland 🇨🇭 following partnerships with *nine hospitals* to bring…
Aimé par Maximilien Grandclaudon
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Introducing TLS Detect RUO – an AI research tool designed to detect the presence of tertiary lymphoid structures (TLS) across various tumor types…
Introducing TLS Detect RUO – an AI research tool designed to detect the presence of tertiary lymphoid structures (TLS) across various tumor types…
Aimé par Maximilien Grandclaudon
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Great opportunity to join Owkin as a ML-protein expert in the drug discovery field! Do not hesitate to reach out to me for more info!
Great opportunity to join Owkin as a ML-protein expert in the drug discovery field! Do not hesitate to reach out to me for more info!
Partagé par Maximilien Grandclaudon
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Every Summer, #TeamGenerate takes a well-deserved week off over the Fourth of July to rest and recharge for what’s next. This break allows us to…
Every Summer, #TeamGenerate takes a well-deserved week off over the Fourth of July to rest and recharge for what’s next. This break allows us to…
Aimé par Maximilien Grandclaudon
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I am thrilled to announce that I will be speaking at Optimize, the upcoming Trial Interactive Customer Summit, on the panel titled "Inspection War…
I am thrilled to announce that I will be speaking at Optimize, the upcoming Trial Interactive Customer Summit, on the panel titled "Inspection War…
Aimé par Maximilien Grandclaudon
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Our Head of Pathology, Katharina von Loga, will speak at the Sheffield Pathology conference on ‘Artificial intelligence in GI pathology: where are we…
Our Head of Pathology, Katharina von Loga, will speak at the Sheffield Pathology conference on ‘Artificial intelligence in GI pathology: where are we…
Aimé par Maximilien Grandclaudon
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🇨🇭 Owkin Senior Data Scientist, Nicolas Loiseau, will present our work on ‘FedECA: A Federated Control Arm Methods for Causal Inference in…
🇨🇭 Owkin Senior Data Scientist, Nicolas Loiseau, will present our work on ‘FedECA: A Federated Control Arm Methods for Causal Inference in…
Aimé par Maximilien Grandclaudon
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🇫🇷 Join our Senior Product Manager, Victor Aubert, alongside Celine Riou and Bertrand de Fürst, for a webinar hosted by Tribun Health on…
🇫🇷 Join our Senior Product Manager, Victor Aubert, alongside Celine Riou and Bertrand de Fürst, for a webinar hosted by Tribun Health on…
Aimé par Maximilien Grandclaudon