ORCID Profile
0000-0003-2433-9837
Current Organisations
KU Leuven
,
VIB
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Publisher: Springer Science and Business Media LLC
Date: 23-01-2018
Publisher: Elsevier BV
Date: 02-2009
Publisher: Rockefeller University Press
Date: 21-07-2021
DOI: 10.1084/JEM.20210571
Abstract: The ability to adapt to environmental stress, including therapeutic insult, contributes to tumor evolution and drug resistance. In suboptimal conditions, the integrated stress response (ISR) promotes survival by d ening cytosolic translation. We show that ISR-dependent survival also relies on a concomitant up-regulation of mitochondrial protein synthesis, a vulnerability that can be exploited using mitoribosome-targeting antibiotics. Accordingly, such agents sensitized to MAPK inhibition, thus preventing the development of resistance in BRAFV600E melanoma models. Additionally, this treatment compromised the growth of melanomas that exhibited elevated ISR activity and resistance to both immunotherapy and targeted therapy. In keeping with this, pharmacological inactivation of ISR, or silencing of ATF4, rescued the antitumoral response to the tetracyclines. Moreover, a melanoma patient exposed to doxycycline experienced complete and long-lasting response of a treatment-resistant lesion. Our study indicates that the repurposing of mitoribosome-targeting antibiotics offers a rational salvage strategy for targeted therapy in BRAF mutant melanoma and a therapeutic option for NRAS-driven and immunotherapy-resistant tumors.
Publisher: Elsevier BV
Date: 08-2021
Publisher: Springer Science and Business Media LLC
Date: 03-2013
DOI: 10.1038/CDD.2013.12
Publisher: Springer Science and Business Media LLC
Date: 08-10-2020
Publisher: Springer Science and Business Media LLC
Date: 11-11-2021
DOI: 10.1038/S43018-021-00264-Y
Abstract: Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a 'MitoScore' signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies.
Publisher: Springer Science and Business Media LLC
Date: 22-07-2012
DOI: 10.1038/NM.2863
Publisher: Elsevier BV
Date: 02-2018
Publisher: Informa UK Limited
Date: 11-03-2014
DOI: 10.4161/CC.28474
Publisher: Oxford University Press (OUP)
Date: 11-03-2009
DOI: 10.1093/NAR/GKP112
Publisher: American Society for Clinical Investigation
Date: 23-11-2015
DOI: 10.1172/JCI82534
Publisher: Springer Science and Business Media LLC
Date: 02-02-2023
Publisher: Springer Science and Business Media LLC
Date: 04-2018
DOI: 10.1038/S41586-018-0040-3
Abstract: In cancer, the epithelial-to-mesenchymal transition (EMT) is associated with tumour stemness, metastasis and resistance to therapy. It has recently been proposed that, rather than being a binary process, EMT occurs through distinct intermediate states. However, there is no direct in vivo evidence for this idea. Here we screen a large panel of cell surface markers in skin and mammary primary tumours, and identify the existence of multiple tumour subpopulations associated with different EMT stages: from epithelial to completely mesenchymal states, passing through intermediate hybrid states. Although all EMT subpopulations presented similar tumour-propagating cell capacity, they displayed differences in cellular plasticity, invasiveness and metastatic potential. Their transcriptional and epigenetic landscapes identify the underlying gene regulatory networks, transcription factors and signalling pathways that control these different EMT transition states. Finally, these tumour subpopulations are localized in different niches that differentially regulate EMT transition states.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2023
DOI: 10.1038/S41586-023-06199-X
Abstract: Most clinically applied cancer immunotherapies rely on the ability of CD8 + cytolytic T cells to directly recognize and kill tumour cells 1–3 . These strategies are limited by the emergence of major histocompatibility complex (MHC)-deficient tumour cells and the formation of an immunosuppressive tumour microenvironment 4–6 . The ability of CD4 + effector cells to contribute to antitumour immunity independently of CD8 + T cells is increasingly recognized, but strategies to unleash their full potential remain to be identified 7–10 . Here, we describe a mechanism whereby a small number of CD4 + T cells is sufficient to eradicate MHC-deficient tumours that escape direct CD8 + T cell targeting. The CD4 + effector T cells preferentially cluster at tumour invasive margins where they interact with MHC-II + CD11c + antigen-presenting cells. We show that T helper type 1 cell-directed CD4 + T cells and innate immune stimulation reprogramme the tumour-associated myeloid cell network towards interferon-activated antigen-presenting and iNOS-expressing tumouricidal effector phenotypes. Together, CD4 + T cells and tumouricidal myeloid cells orchestrate the induction of remote inflammatory cell death that indirectly eradicates interferon-unresponsive and MHC-deficient tumours. These results warrant the clinical exploitation of this ability of CD4 + T cells and innate immune stimulators in a strategy to complement the direct cytolytic activity of CD8 + T cells and natural killer cells and advance cancer immunotherapies.
Publisher: Elsevier BV
Date: 08-2018
DOI: 10.1016/J.CELL.2018.06.025
Abstract: Many patients with advanced cancers achieve dramatic responses to a panoply of therapeutics yet retain minimal residual disease (MRD), which ultimately results in relapse. To gain insights into the biology of MRD, we applied single-cell RNA sequencing to malignant cells isolated from BRAF mutant patient-derived xenograft melanoma cohorts exposed to concurrent RAF/MEK-inhibition. We identified distinct drug-tolerant transcriptional states, varying combinations of which co-occurred within MRDs from PDXs and biopsies of patients on treatment. One of these exhibited a neural crest stem cell (NCSC) transcriptional program largely driven by the nuclear receptor RXRG. An RXR antagonist mitigated accumulation of NCSCs in MRD and delayed the development of resistance. These data identify NCSCs as key drivers of resistance and illustrate the therapeutic potential of MRD-directed therapy. They also highlight how gene regulatory network architecture reprogramming may be therapeutically exploited to limit cellular heterogeneity, a key driver of disease progression and therapy resistance.
Publisher: Springer Science and Business Media LLC
Date: 14-11-2018
DOI: 10.1038/S41467-018-06951-2
Abstract: BRAF inhibitors target the BRAF-V600E/K mutated kinase, the driver mutation found in 50% of cutaneous melanoma. They give unprecedented anti-tumor responses but acquisition of resistance ultimately limits their clinical benefit. The master regulators driving the expression of resistance-genes remain poorly understood. Here, we demonstrate that the Aryl hydrocarbon Receptor (AhR) transcription factor is constitutively activated in a subset of melanoma cells, promoting the dedifferentiation of melanoma cells and the expression of BRAFi-resistance genes. Typically, under BRAFi pressure, death of BRAFi-sensitive cells leads to an enrichment of a small subpopulation of AhR-activated and BRAFi-persister cells, responsible for relapse. Also, differentiated and BRAFi-sensitive cells can be redirected towards an AhR-dependent resistant program using AhR agonists. We thus identify Resveratrol, a clinically compatible AhR-antagonist that abrogates deleterious AhR sustained-activation. Combined with BRAFi, Resveratrol reduces the number of BRAFi-resistant cells and delays tumor growth. We thus propose AhR-impairment as a strategy to overcome melanoma resistance.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2023
Publisher: American Association for Cancer Research (AACR)
Date: 15-07-2020
DOI: 10.1158/0008-5472.CAN-19-2373
Abstract: ZEB2 function exerts opposing behaviors in melanoma by promoting proliferation and expansion and conversely inhibiting invasiveness, which could be of future clinical relevance.
Publisher: Elsevier BV
Date: 07-2000
DOI: 10.1016/S1074-7613(00)00005-4
Abstract: Many receptors activate phospholipase Cgamma1 or -gamma2. To assess the role of PLCgamma2, we derived enzyme-deficient mice. The mice are viable but have decreased mature B cells, a block in pro-B cell differentiation, and B1 B cell deficiency. IgM receptor-induced Ca2+ flux and proliferation to B cell mitogens are absent. IgM, IgG2a, and IgG3 levels are reduced, and T cell-independent antibody production is absent. The similarity to Btk- or Blnk-deficient mice demonstrates that PLCgamma2 is downstream in Btk/Blnk signaling. FcRgamma signaling is also defective, resulting in a loss of collagen-induced platelet aggregation, mast cell FcepsilonR function, and NK cell FcgammaRIII and 2B4 function. The results define a signal transduction pathway broadly utilized by immunoglobulin superfamily receptors.
Publisher: Public Library of Science (PLoS)
Date: 24-07-2014
No related grants have been discovered for Jean-Christophe Marine.