Menée sur 55 patients pédiatriques atteints d'une leucémie lymphoblastique aiguë, cette étude met en évidence le rôle joué par la chimiothérapie dans l'évolution clonale au cours de la récidive, puis identifie des mécanismes par lesquels des mutations RAS peuvent favoriser la sensibilité ou la résistance à la chimiothérapie

Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia

Oshima, Koichi ; Khiabanian, Hossein ; da Silva-Almeida, Ana C. ; Tzoneva, Gannie ; Abate, Francesco ; Ambesi-Impiombato, Alberto ; Sanchez-Martin, Marta ; Carpenter, Zachary ; Penson, Alex ; Perez-Garcia, Arianne ; Eckert, Cornelia ; Nicolas, Concepción ; Balbin, Milagros ; Sulis, Maria Luisa ; Kato, Motohiro ; Koh, Katsuyoshi ; Paganin, Maddalena ; Basso, Giuseppe ; Gastier-Foster, Julie M. ; Devidas, Meenakshi ; Loh, Mignon L. ; Kirschner-Schwabe, Renate ; Palomero, Teresa ; Rabadan, Raul ; Ferrando, Adolfo A.

Although multiagent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die because of chemorefractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape at relapse in pediatric ALL cases. These analyses identified numerous relapse-associated mutated genes intertwined in chemotherapy resistance-related protein complexes. In this context, RAS-MAPK [...]

A partir d'échantillons tumoraux prélevés sur 42 patients atteints d'un mésothéliome malin, cette étude dresse le catalogue des anomalies génomiques identifiées dans les tumeurs

Genomic Landscape of Malignant Mesotheliomas

Kato, Shumei ; Tomson, Brett N. ; Buys, Timon P. H. ; Elkin, Sheryl K. ; Carter, Jennifer L. ; Kurzrock, Razelle

Understanding the genomic landscape of malignant mesothelioma may identify novel molecular drivers of this ultra-rare disease, which can lead to an expanded roster of targeted therapies and clinical trial options for patients with mesothelioma. We examined the molecular profiles of 42 patients with malignant mesothelioma (including pleural, peritoneal, and pericardial) that were referred by clinicians to be tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory using [...]

Menée à l'aide d'une technique de séquençage de l'exome entier sur des échantillons tumoraux prélevés sur 135 patients atteints d'un carcinome du rhinopharynx, cette étude identifie de multiples mutations induisant la perte de fonction de plusieurs gènes impliqués dans la régulation de la voie de signalisation NF-kappaB

Whole-exome sequencing identifies multiple loss-of-function mutations of NF-kappaB pathway regulators in nasopharyngeal carcinoma

Zheng, Hong ; Dai, Wei ; Cheung, Arthur Kwok Leung ; Ko, Josephine Mun Yee ; Kan, Rebecca ; Wong, Bonnie Wing Yan ; Leong, Merrin Man Long ; Deng, Mingdan ; Kwok, Tommy Chin Tung ; Chan, Jimmy Yu-Wai ; Kwong, Dora Lai-Wan ; Lee, Anne Wing-Mui ; Ng, Wai Tong ; Ngan, Roger Kai Cheong ; Yau, Chun Chung ; Tung, Stewart ; Lee, Victor Ho-Fun ; Lam, Ka-on ; Kwan, Chung Kong ; Li, Wing Sum ; Yau, Stephen ; Chan, Kwok-Wah ; Lung, Maria Li

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a unique geographical distribution. The genomic abnormalities leading to NPC pathogenesis remain unclear. In total, 135 NPC tumors were examined to characterize the mutational landscape using whole-exome sequencing and targeted resequencing. An APOBEC cytidine deaminase mutagenesis signature was revealed in the somatic mutations. Noticeably, multiple loss-of-function mutations were identified in several NF-κB signaling negative [...]

Cet article passe en revue les travaux récents sur des mécanismes par lesquels le métabolisme lipidique, notamment la synthèse des acides gras, favorise le développement et la progression d'une tumeur

The multifaceted roles of fatty acid synthesis in cancer

Rohrig, Florian ; Schulze, Almut

Lipid metabolism, in particular the synthesis of fatty acids (FAs), is an essential cellular process that converts nutrients into metabolic intermediates for membrane biosynthesis, energy storage and the generation of signalling molecules. This Review explores how different aspects of FA synthesis promote tumorigenesis and tumour progression. FA synthesis has received substantial attention as a potential target for cancer therapy, but strategies to target this process have not yet translated [...]

A partir de données issues du projet "The Cancer Genome Atlas", puis menée in vitro et validée sur deux cohortes de patients atteints d'un glioblastome, cette étude identifie le rôle joué par l'annexine 2 dans la formation d'une tumeur mésenchymateuse

Integrative Modeling Reveals Annexin A2-mediated Epigenetic Control of Mesenchymal Glioblastoma

Kling, Teresia ; Ferrarese, Roberto ; hAilín, Darren Ó ; Johansson, Patrik ; Heiland, Dieter Henrik ; Dai, Fangping ; Vasilikos, Ioannis ; Weyerbrock, Astrid ; Jörnsten, Rebecka ; Carro, Maria Stella ; Nelander, Sven

Glioblastomas are characterized by transcriptionally distinct subtypes, but despite possible clinical relevance, their regulation remains poorly understood. The commonly used molecular classification systems for GBM all identify a subtype with high expression of mesenchymal marker transcripts, strongly associated with invasive growth. We used a comprehensive data-driven network modeling technique (augmented sparse inverse covariance selection, aSICS) to define separate genomic, epigenetic, and [...]

Cet article passe en revue les travaux récents sur les mécanismes induisant des changements de concentration de certains métabolites dans les cellules cancéreuses

Altered metabolite levels in cancer: implications for tumour biology and cancer therapy

Sullivan, Lucas B. ; Gui, Dan Y. ; Heiden, Matthew G. Vander

Altered cell metabolism is a characteristic feature of many cancers. Aside from well-described changes in nutrient consumption and waste excretion, altered cancer cell metabolism also results in changes to intracellular metabolite concentrations. Increased levels of metabolites that result directly from genetic mutations and cancer-associated modifications in protein expression can promote cancer initiation and progression. Changes in the levels of specific metabolites, such as [...]

Menée à l'aide de modèles murins de cancer du pancréas, cette étude met en évidence des mécanismes par lesquels la signalisation TGFbeta favorise la formation de métastases dans le foie et le poumon

Mutant p53 Together with TGFbeta Signaling Influence Organ-Specific Hematogenous Colonization Patterns of Pancreatic Cancer

Zhong, Yi ; Macgregor-Das, Anne M ; Saunders, Tyler ; Whittle, Martin ; Makohon-Moore, Alvin ; Kohutek, Zachary ; Poling, Justin ; Herbst, Brian ; Javier, Breanna ; Cope, Leslie ; Leach, Steven D ; Hingorani, Sunil R ; Iacobuzio-Donahue, Christine A

Purpose: TP53 and the TGFβ pathway are major mediators of pancreatic cancer metastasis. The mechanisms by which they cause hematogenous metastasis have not been fully explored. Experimental Design: KPC (LSL-KRASG12D/+;LSL-Trp53R172H/+; Ptf1aCre/+) mice were generated and the frequency and morphology of organ-specific hematogenous metastases compared to that seen in KPTC and KTC littermates (Tgfbr2+/-). Key findings were validated in primary cells from each genotype and samples of human [...]

Menée in vitro et à l'aide de données portant sur 664 patientes atteintes d'un cancer du sein, cette étude met en évidence des mécanismes par lesquels, via la signalisation Jagged1/Notch1, la protéine BRD4 favorise le processus métastatique d'un cancer du sein triplement négatif

BRD4 regulates breast cancer dissemination through Jagged1/Notch1 signaling

Andrieu, Guillaume ; Tran, Anna H. ; Strissel, Katherine J. ; Denis, Gerald V.

The Bromodomain and ExtraTerminal (BET) proteins are epigenetic 'readers' of acetylated histones in chromatin and have been identified as promising therapeutic targets in diverse cancers. However, it remains unclear how individual family members participate in cancer progression, and small molecule inhibitors such as JQ1 can target functionally independent BET proteins. Here we report a signaling pathway involving BRD4 and the ligand/receptor pair Jagged1/Notch1 that sustains triple-negative [...]

A partir de données issues du projet "The Cancer Genome Atlas", puis menée in vitro et in vivo sur des modèles de cancer du sein, cette étude met en évidence des mécanismes suggérant que la signalisation LIFR-STAT3 favorise la dormance des cellules cancéreuses disséminées dans les os

Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow

Johnson, Rachelle W. ; Finger, Elizabeth C. ; Olcina, Monica M. ; Vilalta, Marta ; Aguilera, Todd ; Miao, Yu ; Merkel, Alyssa R. ; Johnson, Joshua R. ; Sterling, Julie A. ; Wu, Joy Y. ; Giaccia, Amato J.

Breast cancer cells frequently home to the bone marrow, where they may enter a dormant state before forming a bone metastasis. Several members of the interleukin-6 (IL-6) cytokine family are implicated in breast cancer bone colonization, but the role for the IL-6 cytokine leukaemia inhibitory factor (LIF) in this process is unknown. We tested the hypothesis that LIF provides a pro-dormancy signal to breast cancer cells in the bone. In breast cancer patients, LIF receptor (LIFR) levels are lower [...]