Biologie

Aberrations chromosomiques

A partir d'échantillons tumoraux prélevés pendant une période de 5 ans sur un patient atteint d'un myélome multiple, cette étude de séquençage du génome entier met en évidence l'évolution des variants génomiques depuis le diagnostic jusqu'à la progression vers une leucémie secondaire

Whole genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution and clonal tides
• Blood, sous presse, 2012 (résumé)

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A partir d'échantillons tumoraux prélevés pendant une période de 5 ans sur un patient atteint d'un myélome multiple, cette étude de séquençage du génome entier met en évidence l'évolution des variants génomiques depuis le diagnostic jusqu'à la progression vers une leucémie secondaire

“Whole genome sequencing of multiple myeloma from diagnosis to plasma cell leukemia reveals genomic initiating events, evolution and clonal tides”

• Egan, Jan B.;Shi, Chang-Xin;Tembe, Waibhav;Christoforides, Alexis;Kurdoglu, Ahmet;Sinari, Shripad;Middha, Sumit;Asmann, Yan;Schmidt, Jessica;Braggio, Esteban;Keats, Jonathan J.;Fonseca, Rafael;Bergsagel, P. Leif;Craig, David W.;Carpten, John D.;Stewart, A. Keith

The longitudinal evolution of a myeloma genome from diagnosis to plasma cell leukemia has not previously been reported. We used whole genome sequencing (WGS) on four purified tumor samples and patient germline DNA drawn over a five year period in a t(4;14) multiple myeloma patient. Tumor samples were acquired at diagnosis, first relapse, second relapse and end-stage secondary plasma cell leukemia (sPCL). In addition to the t(4;14), all tumor time points also shared 10 common single nucleotide variants (SNV) on WGS comprising shared initiating events. Interestingly, we observed genomic sequence variants that waxed and waned with time in progressive tumors suggesting the presence of multiple independent, yet related clones at diagnosis that rose and fell in dominance. Five newly acquired SNV, including truncating mutations of RB1 and ZKSCAN3, were observed only in the final sPCL sample suggesting leukemic transformation events. This longitudinal WGS characterization of the natural ...

Mots clés : Myélome multiple et maladies immunoprolifératives; Biologie (Aberrations chromosomiques)

Menée initialement sur une cohorte de 20 patients (10 porteurs d'une mutation conférant une susceptibilité au syndrome de Lynch et 10 témoins), puis validée sur une cohorte de 109 patients (30 avec mutation, 79 témoins), cette étude identifie la présence d'un nouveau type de lésion du côlon spécifiquement associée au syndrome de Lynch

Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study
• The Lancet Oncology, sous presse, 2012 (résumé)

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Menée initialement sur une cohorte de 20 patients (10 porteurs d'une mutation conférant une susceptibilité au syndrome de Lynch et 10 témoins), puis validée sur une cohorte de 109 patients (30 avec mutation, 79 témoins), cette étude identifie la présence d'un nouveau type de lésion du côlon spécifiquement associée au syndrome de Lynch

“Prevalence of mismatch repair-deficient crypt foci in Lynch syndrome: a pathological study”

• Kloor, Matthias;Huth, Cathrin;Voigt, Anita Y.;Benner, Axel;Schirmacher, Peter;von Knebel Doeberitz, Magnus;Bläker, Hendrik

Lynch syndrome is an inherited tumour predisposition syndrome caused by germline mutations of DNA mismatch repair (MMR) genes. Mutation carriers have a high risk of developing colorectal cancer, but do not present with polyposis, a typical feature of other colorectal cancer syndromes such as familial adenomatous polyposis, in which polyposis reflects the high frequency of biallelicAPCgene inactivation. We asked whether in Lynch syndrome biallelic inactivation ofMMRgenes occurred at a similar frequency to that ofAPCgene, and whetherMMRinactivation resulted in detectable lesions within the intestinal mucosa. Resections done for small and large bowel cancer between January, 2002, and January, 2011, were retrieved. We systematically analysed non-tumorous mucosa from carriers of a Lynch syndrome mutation (set 1: ten patients) and control patients without Lynch syndrome (set 1: nine patients) for MMR protein expression (MLH1, MSH2, and EPCAM) with immunohistochemistry. We validated the ...
Lynch syndrome: new tales from the crypt
• The Lancet Oncology, sous presse, 2012 (commentaire en libre accès)

Détails

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Menée initialement sur une cohorte de 20 patients (10 porteurs d'une mutation conférant une susceptibilité au syndrome de Lynch et 10 témoins), puis validée sur une cohorte de 109 patients (30 avec mutation, 79 témoins), cette étude identifie la présence d'un nouveau type de lésion du côlon spécifiquement associée au syndrome de Lynch

“Lynch syndrome: new tales from the crypt”

• Boland, C. Richard

Mots clés : Colon-rectum; Biologie (Aberrations chromosomiques)

Oncogènes et suppresseurs de tumeurs

Menée à l'aide d'un modèle murin et d'échantillons tumoraux prélevés sur 74 patients atteints d'un ostéosarcome, cette étude montre que l'activité de la protéine kinase GSK-3 β favorise la croissance tumorale

Glycogen Synthase Kinase-3β, NF-κB Signaling, and Tumorigenesis of Human Osteosarcoma
• Journal of the National Cancer Institute, sous presse, 2012 (article en libre accès)

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Menée à l'aide d'un modèle murin et d'échantillons tumoraux prélevés sur 74 patients atteints d'un ostéosarcome, cette étude montre que l'activité de la protéine kinase GSK-3 β favorise la croissance tumorale

“Glycogen Synthase Kinase-3β, NF-κB Signaling, and Tumorigenesis of Human Osteosarcoma”

• Tang, Qing-Lian;Xie, Xian-Biao;Wang, Jin;Chen, Qiong;Han, An-Jia;Zou, Chang-Ye;Yin, Jun-Qiang;Liu, Da-Wei;Liang, Yi;Zhao, Zhi-Qiang;Yong, Bi-Cheng;Zhang, Ru-Hua;Feng, Qi-Sheng;Deng, Wu-Guo;Zhu, Xiao-Feng;Zhou, Binhua P.;Zeng, Yi-Xin;Shen, Jing-Nan;Kang, Tiebang

Background Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase, may function as a tumor suppressor or an oncogene, depending on the tumor type. We sought to determine the biological function of GSK-3β in osteosarcoma, a rare pediatric cancer for which the identification of new therapeutic targets is urgent.Methods We used cell viability assays, colony formation assays, and apoptosis assays to analyze the effects of altered GSK-3β expression in U2OS, MG63, SAOS2, U2OS/MTX300, and ZOS osteosarcoma cell lines. Nude mice (n = 5–8 mice per group) were injected with U2OS/MTX300, and ZOS cells to assess the role of GSK-3β in osteosarcoma growth in vivo and to evaluate the effects of inhibitors and/or anticancer drugs on tumor growth. We used an antibody array, polymerase chain reaction, western blotting, and a luciferase reporter assay to establish the effect of GSK-3β inhibition on the nuclear factor-κB (NF-κB) pathway. Immunochemistry was performed on primary ...
Can a Two-Faced Kinase be Exploited for Osteosarcoma?
• Journal of the National Cancer Institute, sous presse, 2012 (éditorial en libre accès)

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Menée à l'aide d'un modèle murin et d'échantillons tumoraux prélevés sur 74 patients atteints d'un ostéosarcome, cette étude montre que l'activité de la protéine kinase GSK-3 β favorise la croissance tumorale

“Can a Two-Faced Kinase be Exploited for Osteosarcoma?”

• Woodgett, James R

Mots clés : Sarcome; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par le facteur de transcription GATA2 dans les cellules de cancer du poumon non à petites cellules présentant des mutations du gène RAS

The GATA2 Transcriptional Network Is Requisite for RAS Oncogene-Driven Non-Small Cell Lung Cancer
• Cell, Vol. 149 (3), pp. 642-655, 2012 (résumé)

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Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par le facteur de transcription GATA2 dans les cellules de cancer du poumon non à petites cellules présentant des mutations du gène RAS

“The GATA2 Transcriptional Network Is Requisite for RAS Oncogene-Driven Non-Small Cell Lung Cancer”

• Kumar, Madhu S;Hancock, David C;Molina-Arcas, Miriam;Steckel, Michael;East, Phillip;Diefenbacher, Markus;Armenteros-Monterroso, Elena;Lassailly, François;Matthews, Nik;Nye, Emma;Stamp, Gordon;Behrens, Axel;Downward, Julian

Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer deaths worldwide; nearly half contain mutations in the receptor tyrosine kinase/RAS pathway. Here we show that RAS-pathway mutant NSCLC cells depend on the transcription factor GATA2. Loss of GATA2 reduced the viability of NSCLC cells with RAS-pathway mutations, whereas wild-type cells were unaffected. Integrated gene expression and genome occupancy analyses revealed GATA2 regulation of the proteasome, and IL-1-signaling, and Rho-signaling pathways. These pathways were functionally significant, as reactivation rescued viability after GATA2 depletion. In a Kras-driven NSCLC mouse model, Gata2 loss dramatically reduced tumor development. Furthermore, Gata2 deletion in established Kras mutant tumors induced striking regression. Although GATA2 itself is likely undruggable, combined suppression of GATA2-regulated pathways with clinically approved inhibitors caused marked tumor clearance. Discovery of the nononcogene ...

Mots clés : Poumon; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur un modèle murin, cette étude met en évidence un mécanisme de nature métabolique par lequel l'expression du gène Kras favorise la croissance d'un adénocarcinome canalaire du pancréas

Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism
• Cell, Vol. 149 (3), pp. 656-670, 2012 (résumé)

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Menée sur un modèle murin, cette étude met en évidence un mécanisme de nature métabolique par lequel l'expression du gène Kras favorise la croissance d'un adénocarcinome canalaire du pancréas

“Oncogenic Kras Maintains Pancreatic Tumors through Regulation of Anabolic Glucose Metabolism”

• Ying, Haoqiang;Kimmelman, Alec C;Lyssiotis, Costas A;Hua, Sujun;Chu, Gerald C;Fletcher-Sananikone, Eliot;Locasale, Jason W;Son, Jaekyoung;Zhang, Hailei;Coloff, Jonathan L;Yan, Haiyan;Wang, Wei;Chen, Shujuan;Viale, Andrea;Zheng, Hongwu;Paik, Ji-hye;Lim, Carol;Guimaraes, Alexander R;Martin, Eric S;Chang, Jeffery;Hezel, Aram F;Perry, Samuel R;Hu, Jian;Gan, Boyi;Xiao, Yonghong;Asara, John M;Weissleder, Ralph;Wang, Y. Alan;Chin, Lynda;Cantley, Lewis C;DePinho, Ronald A

Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible KrasG12D-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on KrasG12D expression. Transcriptome and metabolomic analyses indicate that KrasG12D serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that KrasG12D drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how ...

Mots clés : Pancréas; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide d'un modèle murin, cette étude suggère qu'une enzyme, la déubiquitinase Usp9x, joue un rôle de suppresseur de tumeurs dans l'adénocarcinome canalaire du pancréas

The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma
• Nature, sous presse, 2012 (résumé)

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Menée à l'aide d'un modèle murin, cette étude suggère qu'une enzyme, la déubiquitinase Usp9x, joue un rôle de suppresseur de tumeurs dans l'adénocarcinome canalaire du pancréas

“The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma”

• Perez-Mancera, Pedro A.;Rust, Alistair G.;van der Weyden, Louise;Kristiansen, Glen;Li, Allen;Sarver, Aaron L.;Silverstein, Kevin A. T.;Grutzmann, Robert;Aust, Daniela;Rummele, Petra;Knosel, Thomas;Herd, Colin;Stemple, Derek L.;Kettleborough, Ross;Brosnan, Jacqueline A.;Li, Ang;Morgan, Richard;Knight, Spencer;Yu, Jun;Stegeman, Shane;Collier, Lara S.;ten Hoeve, Jelle J.;de Ridder, Jeroen;Klein, Alison P.;Goggins, Michael;Hruban, Ralph H.;Chang, David K.;Biankin, Andrew V.;Grimmond, Sean M.;Wessels, Lodewyk F. A.;Wood, Stephen A.;Iacobuzio-Donahue, Christine A.;Pilarsky, Christian;Largaespada, David A.;Adams, David J.;Tuveson, David A.

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic KrasG12D to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia9, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and ...

Mots clés : Pancréas; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée sur un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation de la protéine PI3K dans l'intestin induit des néoplasies de stade avancé

Mice Expressing Activated PI3K Develop Advanced Colon Cancer
• Cancer Research, sous presse, 2012 (résumé)

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Menée sur un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation de la protéine PI3K dans l'intestin induit des néoplasies de stade avancé

“Mice Expressing Activated PI3K Develop Advanced Colon Cancer”

• Leystra, Alyssa A;Deming, Dustin A;Zahm, Christopher D;Farhoud, Mohammed;Paul Olson, Terrah J;Hadac, Jamie N;Nettekoven, Laura A;Albrecht, Dawn M;Clipson, Linda;Sullivan, Ruth;Washington, Mary K;Torrealba, Jose R;Weichert, Jamey P;Halberg, Richard B

Aberrations in the phosphatidylinositide-3-kinase (PI3K) signaling pathway play a key role in the pathogenesis of numerous cancers by altering cellular growth, metabolism, proliferation, and apoptosis (1). Mutations in the catalytic domain of PI3K that generate a dominantly active kinase are commonly found in human colorectal cancers and have been thought to drive tumor progression, but not initiation (2). However, the effects of constitutively activated PI3K upon the intestinal mucosa have not been previously studied in animal models. Here, we demonstrate that the expression of a dominantly active form of the PI3K protein in the mouse intestine results in hyperplasia and advanced neoplasia. Mice expressing constitutively active PI3K in the epithelial cells of the distal small bowel and colon rapidly developed invasive adenocarcinomas in the colon that spread into the mesentery and adjacent organs. The histological characteristics of these tumors were strikingly similar to invasive ...

Mots clés : Colon-rectum; Biologie (Oncogènes et suppresseurs de tumeurs)

Ces deux articles passent en revue des travaux récents sur les mécanismes, oncogéniques ou suppresseurs de tumeurs, associés à l'autophagie dans le cancer

Autophagy in tumorigenesis and cancer therapy: Dr Jekyll or Mr Hyde?
• Cancer Letters, sous presse, 2012 (résumé)

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Ces deux articles passent en revue des travaux récents sur les mécanismes, oncogéniques ou suppresseurs de tumeurs, associés à l'autophagie dans le cancer

“Autophagy in tumorigenesis and cancer therapy: Dr Jekyll or Mr Hyde?”

• Zhou, Shengtao;Kuang, Manchao;Zhang, Bingjie;Zhao, Linjie;Liang, Zhu;Yi, Tao;Huang, Canhua;Wei, Yuquan;Zhao, Xia

Autophagy is an evolutionarily conserved mechanism for intracellular substance degradation, responsible for the recycling of metabolic substances and the maintenance of intracellular stability. It has early been demonstrated to play a significant role in tumorigenesis, but whether it acts as a promoter or a suppressor during tumorigenesis seems to be context-specific. Moreover, autophagy is also implicated in promoting chemoresistance of cancer cells so as to attenuate therapeutic efficacy of chemotherapy. On the contrary, other reports highlight a tumor-killing role of autophagy during cancer treatment. Herein, this review aims to revisit the key features of autophagy, summarize the seemingly contradictory roles of autophagy during both tumorigenesis and cancer chemotherapy, and evaluate the feasibility of altering the level of cellular autophagy as part of cancer adjuvant treatment.
Deconvoluting the context-dependent role for autophagy in cancer
• Nature Reviews Cancer, sous presse, 2012 (résumé)

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Ces deux articles passent en revue des travaux récents sur les mécanismes, oncogéniques ou suppresseurs de tumeurs, associés à l'autophagie dans le cancer

“Deconvoluting the context-dependent role for autophagy in cancer”

• White, Eileen

Autophagy (also known as macroautophagy) captures intracellular components in autophagosomes and delivers them to lysosomes, where they are degraded and recycled. Autophagy can have two functions in cancer. It can be tumour suppressive through the elimination of oncogenic protein substrates, toxic unfolded proteins and damaged organelles. Alternatively, it can be tumour promoting in established cancers through autophagy-mediated intracellular recycling that provides substrates for metabolism and that maintains the functional pool of mitochondria. Therefore, defining the context-specific role for autophagy in cancer and the mechanisms involved will be important to guide autophagy-based therapeutic intervention.

Mots clés : Cancer (général); Biologie (Oncogènes et suppresseurs de tumeurs)

Progression et métastases

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation de Stat3 dans les cellules souches urothéliales induit le développement d'une forme invasive de cancer de la vessie

Stat3 activation in urothelial stem cells leads to direct progression to invasive bladder cancer
• Cancer Research, sous presse, 2012 (résumé)

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Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel l'activation de Stat3 dans les cellules souches urothéliales induit le développement d'une forme invasive de cancer de la vessie

“Stat3 activation in urothelial stem cells leads to direct progression to invasive bladder cancer”

• Ho, Philip Levy;Lay, Erica J;Jian, Weiguo;Parra, Diana;Chan, Keith Syson

Two subtypes of human bladder cancer, non-invasive papillary and muscle-invasive cancer, develop through independent pathologic and molecular pathways. Human invasive bladder cancer frequently develops without prior clinical evidence of a non-invasive tumor stage. However, an animal model that recapitulates this unique clinical progression of invasive bladder cancer has not yet been developed. In this study we created a novel transgenic mouse model of invasive bladder cancer by targeting an active dimerized form of Stat3 to the basal cells of bladder epithelium. When exposed to the carcinogen nitrosamine, Stat3 transgenic mice developed invasive cancer directly from carcinoma in situ (CIS), bypassing the non-invasive papillary tumor stage. Remarkably, invasive bladder cancer driven by active Stat3 was predominantly comprised of stem cells, which were characterized by cytokeratin 14 (CK14) staining and enhanced tumor sphere-forming ability. Active Stat3 was also demonstrated to ...

Mots clés : Vessie; Biologie (Progression et métastases)

Menée sur des modèles murins, cette étude met en évidence le rôle joué par les récepteurs des androgènes du micro-environnement tumoral dans la progression d'un cancer de la prostate

Androgen hormone action in prostatic carcinogenesis: stromal androgen receptors mediate prostate cancer progression, malignant transformation, and metastasis
• Carcinogenesis, sous presse, 2012 (résumé)

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Menée sur des modèles murins, cette étude met en évidence le rôle joué par les récepteurs des androgènes du micro-environnement tumoral dans la progression d'un cancer de la prostate

“Androgen hormone action in prostatic carcinogenesis: stromal androgen receptors mediate prostate cancer progression, malignant transformation, and metastasis”

• Ricke, Emily A.;Williams, Karin;Lee, Yi-Fen;Couto, Suzana;Wang, Yuzhuo;Hayward, Simon W.;Cunha, Gerald R.;Ricke, William A.

It has been postulated that prostatic carcinogenesis is androgen dependent and that androgens mediate their effects primarily through epithelial cells however, definitive proof of androgen hormone action in prostate cancer progression is lacking. Here we demonstrate through genetic loss of function experiments that prostate cancer (PRCA)-progression is androgen dependent and that androgen dependency occurs via prostatic stromal AR but not epithelial AR. Utilizing tissue recombination models of prostatic carcinogenesis, loss of AR function was evaluated by surgical castration or genetic deletion. Loss of AR function prevented prostatic carcinogenesis, malignant transformation, and metastasis. Tissue specific evaluation of androgen hormone action demonstrated that epithelial AR was not necessary for PRCA-progression, whereas stromal AR was essential for PRCA-progression, malignant transformation, and metastasis. Stromal AR was not necessary for prostatic maintenance suggesting that the ...

Mots clés : Prostate; Biologie (Progression et métastases)

Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par la métalloprotéase matricielle Mmp10 dans les cellules souches de cancer du poumon

Matrix Metalloproteinase-10 Is Required for Lung Cancer Stem Cell Maintenance, Tumor Initiation and Metastatic Potential
• PLoS ONE, Vol. 7 (4), pp. e35040, 2012 (article en libre accès)

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Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par la métalloprotéase matricielle Mmp10 dans les cellules souches de cancer du poumon

“Matrix Metalloproteinase-10 Is Required for Lung Cancer Stem Cell Maintenance, Tumor Initiation and Metastatic Potential”

• Justilien, Verline;Regala, Roderick P.;Tseng, I. Chu;Walsh, Michael P.;Batra, Jyotica;Radisky, Evette S.;Murray, Nicole R.;Fields, Alan P.

Matrix metalloproteinases (Mmps) stimulate tumor invasion and metastasis by degrading the extracellular matrix. Here we reveal an unexpected role for Mmp10 (stromelysin 2) in the maintenance and tumorigenicity of mouse lung cancer stem-like cells (CSC). Mmp10 is highly expressed in oncosphere cultures enriched in CSCs and RNAi-mediated knockdown of Mmp10 leads to a loss of stem cell marker gene expression and inhibition of oncosphere growth, clonal expansion, and transformed growth in vitro. Interestingly, clonal expansion of Mmp10 deficient oncospheres can be restored by addition of exogenous Mmp10 protein to the culture medium, demonstrating a direct role for Mmp10 in the proliferation of these cells. Oncospheres exhibit enhanced tumor-initiating and metastatic activity when injected orthotopically into syngeneic mice, whereas Mmp10-deficient cultures show a severe defect in tumor initiation. Conversely, oncospheres implanted into syngeneic non-transgenic or Mmp10−/− mice show ...

Mots clés : Poumon; Biologie (Progression et métastases)

Cet article passe en revue les travaux récents sur le processus métastatique dans le myélome multiple

Myeloma as a model for the process of metastasis: implications for therapy
• Blood, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le processus métastatique dans le myélome multiple

“Myeloma as a model for the process of metastasis: implications for therapy”

• Ghobrial, Irene M.

Multiple Myeloma (MM) is a plasma cell dyscrasia characterized by the presence of multiple myelomatous "omas" throughout the skeleton indicating that there is continuous trafficking of tumor cells to multiple areas in the bone marrow niches. MM may therefore represent one of the best models to study cell trafficking or cell metastasis. The process of cell metastasis is described as a multistep process, the invasion-metastasis cascade. This involves cell invasion, intravasation into nearby blood vessels, passage into the circulation, followed by homing into predetermined distant tissues, the formation of new foci of micrometastases, and finally the growth of micrometastasis into macroscopic tumors. This review discusses the significant advances that have been discovered in the complex process of invasion-metastasis in epithelial carcinomas and cell trafficking in hematopoietic stem cells and how this process relates to progression in MM. This progression is mediated by clonal intrinsic ...

Mots clés : Myélome multiple et maladies immunoprolifératives; Biologie (Progression et métastases)

Cet article passe en revue les travaux récents sur le rôle joué par des facteurs de transcription associés à la transition épithélio-mésenchymateuse dans les cellules souches cancéreuses et le processus métastatique

Cancer Stem Cells and Epithelial-Mesenchymal Transition: concepts and molecular links
• Seminars in Cancer Biology, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le rôle joué par des facteurs de transcription associés à la transition épithélio-mésenchymateuse dans les cellules souches cancéreuses et le processus métastatique

“Cancer Stem Cells and Epithelial-Mesenchymal Transition: concepts and molecular links”

• Scheel, Christina;Weinberg, Robert A.

The Epithelial-Mesenchymal Transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by carcinoma cells. EMT programs are orchestrated by a set of pleiotropically acting transcription factors (TFs). The actions of these EMT-TFs enable the early steps of metastasis: local invasion and subsequent dissemination of carcinoma cells to distant sites. However, in most malignancies, the subsequent outgrowth of micrometastatic deposits into macroscopic metastases has the greatest impact on clinical progression. Such metastatic “colonization” reflects the ability of disseminated tumor cells to adapt to a foreign tissue microenvironment. The outgrowth of a metastasis is also thought to be associated with self-renewal, the defining cellular trait of cancer stem cells (CSCs), also termed tumor-initiating cells. Importantly, molecular links between EMT-TFs and self-renewal have emerged, suggesting that EMT ...

Mots clés : Cancer (général); Biologie (Progression et métastases)

Cet article passe en revue les travaux récents sur les interactions entre les cellules souches cancéreuses et le micro-environnement tumoral

The Bed and the Bugs: Interactions between the Tumor Microenvironment and Cancer Stem Cells
• Seminars in Cancer Biology, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur les interactions entre les cellules souches cancéreuses et le micro-environnement tumoral

“The Bed and the Bugs: Interactions between the Tumor Microenvironment and Cancer Stem Cells”

• Castaño, Zafira;Fillmore, Christine M.;Kim, Carla F.;McAllister, Sandra S.

Tumors have been increasingly recognized as organs with a complexity that approaches, and may even exceed, that of healthy tissues. When viewed from this perspective, the biology of a tumor can be understood only by studying tumor cell heterogeneity and the microenvironment that is constructed during the course of tumorigenesis and malignant progression. Recent work has revealed the existence of cancer stem cells, the “bugs”, with the capacity for self-renewal and tumor propagation. In addition, it is now recognized that the tumor microenvironment, the “bed”, plays a critical role in supporting cancer stem cells and also may promote neoplasia and malignant progression. The interdependence of the cell-intrinsic features of cancer, including the cancer stem cell “bugs” and the tumor microenvironment “bed”, is only beginning to be understood. In this review, we highlight the rapidly evolving concepts about the interactions between tumor stem cells and their ...

Mots clés : Cancer (général); Biologie (Progression et métastases)

Cet article passe en revue les travaux récents sur le rôle des anomalies de fonctionnement des mitochondries dans les cellules tumorales

Mitochondrial remodeling in cancer metabolism and survival: Potential for new therapies
• Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur le rôle des anomalies de fonctionnement des mitochondries dans les cellules tumorales

“Mitochondrial remodeling in cancer metabolism and survival: Potential for new therapies”

• Barbosa, Inês A.;Machado, Nuno G.;Skildum, Andrew;Scott, Patricia M.;Oliveira, Paulo J.

Mitochondria are semi-autonomous organelles that play essential roles in cellular metabolism and programmed cell death pathways. Genomic, functional and structural mitochondrial alterations have been associated with cancer. Some of those alterations may provide a selective advantage to cells, allowing them to survive and grow under stresses created by oncogenesis. Due to the specific alterations that occur in cancer cell mitochondria, these organelles may provide promising targets for cancer therapy. The development of drugs that specifically target metabolic and mitochondrial alterations in tumor cells has become a matter of interest in recent years, with several molecules undergoing clinical trials. This review focuses on the most relevant mitochondrial alterations found in tumor cells, their contribution to cancer progression and survival, and potential usefulness for stratification and therapy.

Mots clés : Cancer (général); Biologie (Progression et métastases)

Ressources et infrastructures (Biologie)

A partir de travaux portant sur des échantillons tumoraux prélevés sur 4 patients atteints d'un carcinome à cellules rénales, cette étude évalue la capacité d'une méthode de séquençage profond, appelée deepSNV, pour détecter et quantifier des variants à simple nucléotide dans des populations cellulaires tumorales

Reliable detection of subclonal single-nucleotide variants in tumour cell populations
• Nature Communications, Vol. 3, pp. 811, 2012 (résumé)

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A partir de travaux portant sur des échantillons tumoraux prélevés sur 4 patients atteints d'un carcinome à cellules rénales, cette étude évalue la capacité d'une méthode de séquençage profond, appelée deepSNV, pour détecter et quantifier des variants à simple nucléotide dans des populations cellulaires tumorales

“Reliable detection of subclonal single-nucleotide variants in tumour cell populations”

• Gerstung, Moritz;Beisel, Christian;Rechsteiner, Markus;Wild, Peter;Schraml, Peter;Moch, Holger;Beerenwinkel, Niko

According to the clonal evolution model, tumour growth is driven by competing subclones in somatically evolving cancer cell populations, which gives rise to genetically heterogeneous tumours. Here we present a comparative targeted deep-sequencing approach combined with a customised statistical algorithm, called deepSNV, for detecting and quantifying subclonal single-nucleotide variants in mixed populations. We show in a rigorous experimental assessment that our approach is capable of detecting variants with frequencies as low as 1/10,000 alleles. In selected genomic loci of the TP53 and VHL genes isolated from matched tumour and normal samples of four renal cell carcinoma patients, we detect 24 variants at allele frequencies ranging from 0.0002 to 0.34. Moreover, we demonstrate how the allele frequencies of known single-nucleotide polymorphisms can be exploited to detect loss of heterozygosity. Our findings demonstrate that genomic diversity is common in renal cell carcinomas and ...

Mots clés : Cancer (général); Biologie (Ressources et infrastructures (Biologie))

Menée initialement sur 214 échantillons tumoraux prélevés sur des patientes atteintes d'un carcinome ovarien, puis sur 3 155 échantillons tumoraux de divers types de cancer, cette étude évalue la faisabilité d'une méthode de quantification des anomalies somatiques de l'ADN

Absolute quantification of somatic DNA alterations in human cancer
• Nature Biotechnology, sous presse, 2012 (résumé)

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Menée initialement sur 214 échantillons tumoraux prélevés sur des patientes atteintes d'un carcinome ovarien, puis sur 3 155 échantillons tumoraux de divers types de cancer, cette étude évalue la faisabilité d'une méthode de quantification des anomalies somatiques de l'ADN

“Absolute quantification of somatic DNA alterations in human cancer”

• Carter, Scott L.;Cibulskis, Kristian;Helman, Elena;McKenna, Aaron;Shen, Hui;Zack, Travis;Laird, Peter W.;Onofrio, Robert C.;Winckler, Wendy;Weir, Barbara A.;Beroukhim, Rameen;Pellman, David;Levine, Douglas A.;Lander, Eric S.;Meyerson, Matthew;Getz, Gad

We describe a computational method that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. The method, named ABSOLUTE, can detect subclonal heterogeneity and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations. We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs. This analysis identified both pervasive subclonal somatic point-mutations and a small subset of predominantly clonal and homozygous mutations, which were overrepresented in the tumor suppressor genes TP53 and NF1 and in a candidate tumor suppressor gene CDK12. We also used ABSOLUTE to infer absolute allelic copy-number profiles from 3,155 diverse cancer specimens, revealing that genome-doubling events are common in human cancer, likely occur in cells that are already aneuploid, and influence pathways of tumor progression (for example, with recessive inactivation of NF1 being less ...