Menée sur des levures à fission, cette étude identifie un mécanisme qui, à l'occasion du redémarrage de fourches bloquées dans la réplication de l'ADN, contribue à des réarrangements chromosomiques massifs impliqués dans le développement du cancer

Recombination-restarted replication makes inverted chromosome fusions at inverted repeats

Mizuno, Ken 'Ichi ; Miyabe, Izumi ; Schalbetter, Stephanie A. ; Carr, Antony M. ; Murray, Johanne M.

Impediments to DNA replication are known to induce gross chromosomal rearrangements (GCRs) and copy-number variations (CNVs). GCRs and CNVs underlie human genomic disorders and are a feature of cancer. During cancer development, environmental factors and oncogene-driven proliferation promote replication stress. Resulting GCRs and CNVs are proposed to contribute to cancer development and therapy resistance. When stress arrests replication, the replisome remains associated with the fork DNA [...]

Cet article passe en revue les travaux récents ayant mis en évidence des anomalies moléculaires associées à l'hétérogénéité phénotypique des syndromes myélodysplasiques

The genetic basis of phenotypic heterogeneity in myelodysplastic syndromes

Raza, Azra ; Galili, Naomi

Myelodysplastic syndromes (MDS) are malignant clonal disorders of haematopoietic stem cells and their microenvironment, affecting older individuals (median age ~70 years). Unique features that are associated with MDS — but which are not necessarily present in every patient with MDS — include excessive apoptosis in maturing clonal cells, a pro-inflammatory bone marrow microenvironment, specific chromosomal abnormalities, abnormal ribosomal protein biogenesis, the presence of uniparental disomy, [...]

Menée sur des échantillons de tissus tumoraux et de tissus sains prélevés sur 101 patients atteints d'un cancer du poumon non à petites cellules de stade I-II, cette étude identifie un ensemble de gènes spécifiquement méthylés dans les tumeurs, notamment les gènes HOXA2 et HOXA10

Genome-Wide CpG Island Methylation Analyses in Non-Small Cell Lung Cancer Patients

Heller, Gerwin ; Babinsky, Valerie N. ; Ziegler, Barbara ; Weinzierl, Marlene ; Noll, Christian ; Altenberger, Corinna ; Müllauer, Leonhard ; Dekan, Gerhard ; Grin, Yuliya ; Lang, György ; End-Pfützenreuter, Adelheid ; Steiner, Irene ; Zehetmayer, Sonja ; Döme, Balazs ; Arns, Britt-Madeleine ; Fong, Kwun M. ; Wright, Casey M. ; Yang, Ian A. ; Klepetko, Walter ; Posch, Martin ; Zielinski, Christoph C. ; Zöchbauer-Müller, Sabine

DNA methylation is part of the epigenetic gene regulation complex which is relevant for the pathogenesis of cancer. We performed a genome-wide search for methylated CpG islands in tumors and corresponding non-malignant lung tissue samples of 101 stage I-III non-small cell lung cancer (NSCLC) patients by combining methylated DNA immunoprecipitation and microarray analysis (MeDIP-chip). Overall, we identified 2414 genomic positions differentially methylated between tumor and non-malignant lung [...]

Menée sur 14 patientes atteintes d'un cancer métastatique du sein triplement négatif, cette étude dresse le catalogue des altérations génomiques présentes dans ces tumeurs, notamment des altérations suggérant l'intérêt d'une thérapie ciblée

Genome and transcriptome sequencing in prospective refractory metastatic triple negative breast cancer uncovers therapeutic vulnerabilities

Craig, David W ; O'Shaughnessy, Joyce A. ; Kiefer, Jeffrey A ; Aldrich, Jessica ; Sinari, Shripad ; Moses, Tracy M ; Wong, Shukmei ; Dinh, Jennifer ; Christoforides, Alexis ; Blum, Joanne L. ; Aitelli, Cristi L ; Osborne, Cynthia R ; Izatt, Tyler ; Kurdoglu, Ahmet ; Baker, Angela ; Koeman, Julie ; Barbacioru, Catalin ; Sakarya, Onur ; De La Vega, Francisco M. ; Siddiqui, Asim ; Hoang, Linh ; Billings, Paul R ; Salhia, Bodour ; Tolcher, Anthony W ; Trent, Jeffrey M ; Mousses, Spyro ; Von Hoff, Daniel D ; Carpten, John D

Triple negative breast cancer (TNBC) is characterized by the absence of expression of estrogen receptor, progesterone receptor, and HER-2. Thirty percent of patients recur after first line treatment, and metastatic TNBC (mTNBC) has a poor prognosis with median survival of one year. Here, we present initial analyses of whole genome and transcriptome sequencing data from 14 prospective metastatic mTNBC. We have cataloged the collection of somatic genomic alterations in these advanced tumors; [...]

Cet article passe en revue les travaux récents sur la génomique des médulloblastomes

Medulloblastomics: the end of the beginning

Northcott, Paul A. ; Jones, David T. W. ; Kool, Marcel ; Robinson, Giles W. ; Gilbertson, Richard J. ; Cho, Yoon-Jae ; Pomeroy, Scott L. ; Korshunov, Andrey ; Lichter, Peter ; Taylor, Michael D. ; Pfister, Stefan M.

The division of medulloblastoma into different subgroups by microarray expression profiling has dramatically changed our perspective of this malignant childhood brain tumour. Now, the availability of next-generation sequencing and complementary high-density genomic technologies has unmasked novel driver mutations in each medulloblastoma subgroup. The implications of these findings for the management of patients are readily apparent, pinpointing previously unappreciated diagnostic and [...]

Cet article passe en revue les travaux récents sur le rôle de micro-ARNs dans la régulation du métabolisme des cellules cancéreuses

Roles of microRNA on cancer cell metabolism

Chen, Bing ; Li, Hongbin ; Zeng, Xiao ; Yang, Pengbo ; Liu, Xinyu ; Zhao, Xia ; Liang, Shufang

Advanced studies of microRNAs (miRNAs) have revealed their manifold biological functions, including control of cell proliferation, cell cycle and cell death. However, it seems that their roles as key regulators of metabolism have drawn more and more attention in the recent years. Cancer cells display increased metabolic autonomy in comparison to non-transformed cells, taking up nutrients and metabolizing them in pathways that support growth and proliferation. MiRNAs regulate cell metabolic [...]

Menée à l'aide d'un modèle murin transgénique, cette étude met en évidence un mécanisme par lequel, en perturbant l'activité transcriptionnelle liée au proto-oncogène Bcl6, le micro-ARN 155 favorise la prolifération des cellules leucémiques

miR-155 targets histone deacetylase 4 (HDAC4) and impairs transcriptional activity of B-cell lymphoma 6 (BCL6) in the Eµ-miR-155 transgenic mouse model

Sandhu, Sukhinder K. ; Volinia, Stefano ; Costinean, Stefan ; Galasso, Marco ; Neinast, Reid ; Santhanam, Ramasamy ; Parthun, Mark R. ; Perrotti, Danilo ; Marcucci, Guido ; Garzon, Ramiro ; Croce, Carlo M.

Multiple studies have established that microRNAs (miRNAs) are involved in the initiation and progression of cancer. Notably, miR-155 is one of the most overexpressed miRNAs in several solid and hematological malignancies. Ectopic miR-155 expression in mice B cells (Eμ-miR-155 transgenic mice) has been shown to induce pre–B-cell proliferation followed by high-grade lymphoma/leukemia. Loss of miR-155 in mice resulted in impaired immunity due to defective T-cell–mediated immune response. Here we [...]

Menée in vitro, in vivo et à partir d'échantillons tumoraux prélevés sur des patients atteints d'un mélanome métastatique, cette étude analyse le rôle joué par des mutations du gène suppresseur de tumeurs Nf1, en coopération avec des mutations du gène BRAF, dans la mélanogenèse et l'apparition d'une résistance thérapeutique

Elucidating distinct roles for NF1 in melanomagenesis

Maertens, Ophelia ; Johnson, Bryan ; Hollstein, Pablo ; Frederick, Dennie T. ; Cooper, Zachary A. ; Messaien, Ludwine ; Bronson, Roderick T. ; McMahon, Martin ; Granter, Scott ; Flaherty, Keith T. ; Wargo, Jennifer A. ; Marais, Richard ; Cichowski, Karen

BRAF mutations play a well-established role in melanomagenesis; however, without additional genetic alterations tumor development is restricted by oncogene-induced senescence (OIS). Here we show that mutations in the NF1 tumor suppressor gene cooperate with BRAF mutations in melanomagenesis by preventing OIS. In a genetically engineered mouse model, Nf1 mutations suppress Braf-induced senescence, promote melanocyte hyperproliferation, and enhance melanoma development. Nf1 mutations function by [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant l'expression du facteur de transcription Oct-1, STAT3 favorise la prolifération cellulaire et réduit l'apoptose dans les cellules de carcinome épidermoïde de l'œsophage

STAT3 is involved in esophageal carcinogenesis through regulation of Oct-1

Wang, Zhipeng ; Zhu, Shaojun ; Shen, Min ; Liu, Juanjuan ; Wang, Meng ; Li, Chen ; Wang, Yukun ; Deng, Anmei ; Mei, Qibing

The transcription factor signal transducer and activator of transcription 3 (STAT3) contributes to cell proliferation, apoptosis, and motility in human cancer cells. We aim to elucidate the function of STAT3 in esophageal carcinogenesis process and molecular mechanisms. We showed that hyperactivated STAT3 in esophageal carcinogenesis tissues correlated with the overexpression of octamer transcription factor-1 (Oct-1). High STAT3 phosphorylation correlated with shorter survival compared to low [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant l'expression du gène AMPKα1, le micro-ARN 148b joue un rôle de suppresseur de tumeurs dans le cancer du pancréas

MiR-148b functions as a tumor suppressor in pancreatic cancer by targeting AMPKα1

Zhao, Gang ; Zhang, Jungang ; Liu, Yang ; Qin, Qi ; Wang, Bo ; Tian, Kui ; Liu, Lin ; Li, Xiang ; Niu, Yi ; Deng, Shi-chang ; Wang, Chun-you

MicroRNAs are small non-coding RNAs that participate in a variety of biological processes, and dysregulation of miRNA is always associated with cancer development and progression. Aberrant expression of miR-148b has been found in some types of cancer, but its expression and potential biological role in pancreatic cancer are still largely unknown. In this study, our data showed that miR-148b was significantly downregulated in 48 pairs of human pancreatic cancer tissues and five cell lines. [...]

Cet article passe en revue les travaux récents sur le rôle de la signalisation Notch dans les sarcomes des tissus mous chez les enfants

Notch signaling in pediatric soft tissue sarcomas

Rota, Rossella ; Ciarapica, Roberta ; Miele, Lucio ; Locatelli, Franco

Pediatric soft tissue sarcomas are rare tumors of childhood, frequently characterized by specific chromosome translocations. Despite improvements in treatment, their clinical management is often challenging due to the low responsiveness of metastatic forms and aggressive variants to conventional therapeutic approaches, which leads to poor overall survival. It is widely thought that soft tissue sarcomas derive from mesenchymal progenitor cells that, during embryonic life, have developed [...]

Cet article passe en revue les travaux récents sur l'enchaînement des interactions entre les cellules tumorales, qui s'échappent de la tumeur primitive, et divers types cellulaires au long du parcours dans l'organisme conduisant à la formation de métastases à distance

The Initial Hours of Metastasis: The Importance of Cooperative Host-Tumor Cell Interactions during Hematogenous Dissemination

Labelle, Myriam ; Hynes, Richard O.

Tumor cells transit from the primary tumor via the blood circulation to form metastases in distant organs. During this process, tumor cells encounter a number of environmental challenges and stimuli that profoundly impact their metastatic potential. Here, we review the cooperative and dynamic host–tumor cell interactions that support and promote the hematogenous dissemination of cancer cells to sites of distant metastasis. In particular, we discuss what is known about the cross-talk occurring [...]

Menée in vitro et sur des échantillons tumoraux prélevés sur des patients atteints d'un mélanome métastatique, cette étude met en évidence un mécanisme par lequel, en régulant l'expression de l'alipoprotéine ApoE, trois micro-ARNs favorisent le processus métastatique

Convergent Multi-miRNA Targeting of ApoE Drives LRP1/LRP8-Dependent Melanoma Metastasis and Angiogenesis

Pencheva, Nora ; Tran, Hien ; Buss, Colin ; Huh, Doowon ; Drobnjak, Marija ; Busam, Klaus ; Tavazoie, Sohail F

Through in vivo selection of human cancer cell populations, we uncover a convergent and cooperative miRNA network that drives melanoma metastasis. We identify miR-1908, miR-199a-5p, and miR-199a-3p as endogenous promoters of metastatic invasion, angiogenesis, and colonization in melanoma. These miRNAs convergently target apolipoprotein E (ApoE) and the heat shock factor DNAJA4. Cancer-secreted ApoE suppresses invasion and metastatic endothelial recruitment (MER) by engaging melanoma cell LRP1 [...]

A partir de l'analyse de biopsies de tumeurs primitives et de métastases osseuses, cette étude met en évidence le rôle joué par un transporteur ATP-dépendant, ABCC5, dans le processus métastatique d'un cancer du sein

ABCC5 supports osteoclast formation and promotes breast cancer metastasis to bone

Mourskaia, Anna ; Amir, Eitan ; Dong, Zhifeng ; Tiedemann, Kerstin ; Cory, Sean ; Omeroglu, Atilla ; Bertos, Nicholas ; Ouellet, Veronique ; Clemons, Mark ; Scheffer, George ; Park, Morag ; Hallett, Michael ; Komarova, Svetlana ; Siegel, Peter

INTRODUCTION:Bone is the most common site of breast cancer metastasis and complications associated with bone metastases can lead to a significantly decreased patient quality of life. Thus, it is essential to gain a better understanding of the molecular mechanisms that underlie the emergence and growth of breast cancer skeletal metastases. METHODS:To search for novel molecular mediators that influence breast cancer bone metastasis, we generated gene expression profiles from laser capture [...]

Cet article passe en revue l'intérêt des modèles in vitro de la matrice extracellulaire pour étudier les processus de l'angiogenèse tumorale

Engineering Approaches for Investigating Tumor Angiogenesis: Exploiting the Role of the Extracellular Matrix

Hielscher, Abigail C. ; Gerecht, Sharon

A major paradigm shift in cancer research is the emergence of multidisciplinary approaches to investigate complex cell behaviors, to elucidate regulatory mechanisms and to identify therapeutic targets. Recently, efforts are focused on the engineering of complex in vitro models, which more accurately recapitulate the growth and progression of cancer. These strategies have proven vital for investigating and targeting the events that control tumor angiogenesis. In this review, we explore how the [...]