Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant

IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions

Molecular Pathways to Initiation and Progression in Gliomas

Gliomas are the most common primary adult brain tumors. Despite current treatment, including surgery radio- and chemotherapy, these tumors continue to progress and recur with a more aggressive and resistant phenotype. Recurrence is believed to be, in no small part, due to the presence within the tumors of Brain Tumor Initiating Cells (BTICs). These cells have stem-like properties, are resistant to therapeutic effort and demonstrate enhanced tumorigenic potential. The key molecular alterations sustaining growth and therapeutic resistance in gliomas are now well described. However, targeted therapies have so far failed to make significant impact in the clinic, perhaps due to the heterogeneity and rapid evolution characteristic of these tumors. A better understanding of the players driving recurrence and the molecular pathways to initiation and progression in gliomas is hence essential to developing novel therapeutic strategies and improve clinical outcome. Isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation is found in grade II-III astrocytomas, oligodendrogliomas and in secondary glioblastomas (GBMs), but is completely absent from primary GBMs, thus reflecting a different origin and evolution. In the first section of this thesis, we study the IDH1/2 mutation in glioma and its contradictory roles during tumor initiation and progression. More specifically, we show that the IDH1/2 mutation is directly involved in downregulating glycolytic genes such as LDHA. We also report the selection of large chr2 deletions resulting in the loss of either the IDH1 wild-type or mutant allele. Although essential during initiation, we argue that the IDH1/2 mutation may be a limiting factor of tumor progression at later stages of tumorigenesis. Often considered a different disease, primary GBMs are the most aggressive and lethal primary brain tumors. In the second section of this thesis, we focus on these tumors through the study of primary GBM-derived BTICs. We report the existence of distinct precursor states (stem-like and progenitor-like) in BTICs predictive of survival and associated with GBM subtypes. Further, we highlight a STAT3-driven EMT-like process in progenitor-like BTICs, which may drive the progression towards more aggressive and resistant recurrent GBM

Discours de M. Chesnelong,..., président de l'assemblée générale des comités catholiques de France : [discours] prononcé dans la séance du 19 mai 1873

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Le Béarn / Charles Chesnelong

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Patrick O'Quin : [discours prononcés à ses obsèques par MM. Laforgue, H. d'Astis, Ch. Chesnelong]

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Hyperpolarized 13C MR imaging detects no lactate production in mutant IDH1 gliomas: Implications for diagnosis and response monitoring

Metabolic imaging of brain tumors using 13C Magnetic Resonance Spectroscopy (MRS) of hyperpolarized [1-13C] pyruvate is a promising neuroimaging strategy which, after a decade of preclinical success in glioblastoma (GBM) models, is now entering clinical trials in multiple centers. Typically, the presence of GBM has been associated with elevated hyperpolarized [1-13C] lactate produced from [1-13C] pyruvate, and response to therapy has been associated with a drop in hyperpolarized [1-13C] lactate. However, to date, lower grade gliomas had not been investigated using this approach. The most prevalent mutation in lower grade gliomas is the isocitrate dehydrogenase 1 (IDH1) mutation, which, in addition to initiating tumor development, also induces metabolic reprogramming. In particular, mutant IDH1 gliomas are associated with low levels of lactate dehydrogenase A (LDHA) and monocarboxylate transporters 1 and 4 (MCT1, MCT4), three proteins involved in pyruvate metabolism to lactate. We therefore investigated the potential of 13C MRS of hyperpolarized [1-13C] pyruvate for detection of mutant IDH1 gliomas and for monitoring of their therapeutic response. We studied patient-derived mutant IDH1 glioma cells that underexpress LDHA, MCT1 and MCT4, and wild-type IDH1 GBM cells that express high levels of these proteins. Mutant IDH1 cells and tumors produced significantly less hyperpolarized [1-13C] lactate compared to GBM, consistent with their metabolic reprogramming. Furthermore, hyperpolarized [1-13C] lactate production was not affected by chemotherapeutic treatment with temozolomide (TMZ) in mutant IDH1 tumors, in contrast to previous reports in GBM. Our results demonstrate the unusual metabolic imaging profile of mutant IDH1 gliomas, which, when combined with other clinically available imaging methods, could be used to detect the presence of the IDH1 mutation in vivo

Precursor States of Brain Tumor Initiating Cell Lines Are Predictive of Survival in Xenografts and Associated with Glioblastoma Subtypes

In glioblastoma multiforme (GBM), brain-tumor-initiating cells (BTICs) with cancer stem cell characteristics have been identified and proposed as primordial cells responsible for disease initiation, recurrence, and therapeutic resistance. However, the extent to which individual, patient-derived BTIC lines reflect the heterogeneity of GBM remains poorly understood. Here we applied a stem cell biology approach and compared self-renewal, marker expression, label retention, and asymmetric cell division in 20 BTIC lines. Through cluster analysis, we identified two subgroups of BTIC lines with distinct precursor states, stem- or progenitor-like, predictive of survival after xenograft. Moreover, stem and progenitor transcriptomic signatures were identified, which showed a strong association with the proneural and mesenchymal subtypes, respectively, in the TCGA cohort. This study proposes a different framework for the study and use of BTIC lines and provides precursor biology insights into GBM