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Accueil Nota Bene Cancer V2 Numéro 136 du 15 May 2012 Biologie

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Nota Bene Cancer Numéro 136 du 15 May 2012 RSS

Biologie

Aberrations chromosomiques

Menée à l'aide de simulations numériques, cette étude montre que des mutations du gène EGFR, en induisant un état stable de la kinase EGFR, favorisent son activation

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    Menée à l'aide de simulations numériques, cette étude montre que des mutations du gène EGFR, en induisant un état stable de la kinase EGFR, favorisent son activation

    “Oncogenic Mutations Counteract Intrinsic Disorder in the EGFR Kinase and Promote Receptor Dimerization”

    • Shan, Yibing;Eastwood, Michael P;Zhang, Xuewu;Kim, Eric T;Arkhipov, Anton;Dror, Ron O;Jumper, John;Kuriyan, John;Shaw, David E

    The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with the development of a variety of cancers, making this prototypical dimerization-activated receptor tyrosine kinase a prominent target of cancer drugs. Using long-timescale molecular dynamics simulations, we find that the N lobe dimerization interface of the wild-type EGFR kinase domain is intrinsically disordered and that it becomes ordered only upon dimerization. Our simulations suggest, moreover, that some cancer-linked mutations distal to the dimerization interface, particularly the widespread L834R mutation (also referred to as L858R), facilitate EGFR dimerization by suppressing this local disorder. Corroborating these findings, our biophysical experiments and kinase enzymatic assays indicate that the L834R mutation causes abnormally high activity primarily by promoting EGFR dimerization rather than by allowing activation without dimerization. We also find that phosphorylation of EGFR ...


  • EGFR in Limbo
    Cell, Vol. 149 (4), pp. 735-737, 2012 (commentaire)
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    Menée à l'aide de simulations numériques, cette étude montre que des mutations du gène EGFR, en induisant un état stable de la kinase EGFR, favorisent son activation

    “EGFR in Limbo”

    • Eck, Michael J ; Hahn, William C

    The epidermal growth factor receptor (EGFR) is normally activated by ligand-induced dimerization. Oncogenic mutations in EGFR promote activation in a largely ligand-independent manner. Shan et al. uncover a partially disordered state of EGFR kinase, providing evidence that oncogenic mutations counteract this intrinsic structural instability to promote dimerization and aberrant activation.


Mots clés : Cancer (général); Biologie (Aberrations chromosomiques)

Menée in vitro, cette étude démontre la faisabilité d'une méthode permettant d'identifier des anomalies de méthylation de l'ADN associées à la survie de cellules cancéreuses

  • DNA Methylation Screening Identifies Driver Epigenetic Events of Cancer Cell Survival
    Cancer cell, Vol. 21 (5), pp. 655-667, 2012 (résumé)
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    Menée in vitro, cette étude démontre la faisabilité d'une méthode permettant d'identifier des anomalies de méthylation de l'ADN associées à la survie de cellules cancéreuses

    “DNA Methylation Screening Identifies Driver Epigenetic Events of Cancer Cell Survival”

    • De Carvalho, Daniel D;Sharma, Shikhar;You, Jueng Soo;Su, Sheng-Fang;Taberlay, Phillippa C;Kelly, Theresa K;Yang, Xiaojing;Liang, Gangning;Jones, Peter A

    Cancer cells typically exhibit aberrant DNA methylation patterns that can drive malignant transformation. Whether cancer cells are dependent on these abnormal epigenetic modifications remains elusive. We used experimental and bioinformatic approaches to unveil genomic regions that require DNA methylation for survival of cancer cells. First, we surveyed the residual DNA methylation profiles in cancer cells with highly impaired DNA methyltransferases. Then, we clustered these profiles according to their DNA methylation status in primary normal and tumor tissues. Finally, we used gene expression meta-analysis to identify regions that are dependent on DNA methylation-mediated gene silencing. We further showed experimentally that these genes must be silenced by DNA methylation for cancer cell survival, suggesting these are key epigenetic events associated with tumorigenesis. º An approach to discriminate between driver and passenger epigenetic events º Cancer cells become dependent ...


Mots clés : Cancer (général); Biologie (Aberrations chromosomiques)

Oncogènes et suppresseurs de tumeurs

Menée sur des échantillons tumoraux prélevés sur 103 patients atteints d'un médulloblastome et à l'aide de xénogreffes, cette étude met en évidence des mécanismes spatio-temporels par lesquels, en réponse à l'oncogène MYCN, des cellules souches neurales engendrent des tumeurs cérébrales diverses

  • Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC
    Cancer cell, Vol. 21 (5), pp. 601-613, 2012 (article en libre accès)
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    Menée sur des échantillons tumoraux prélevés sur 103 patients atteints d'un médulloblastome et à l'aide de xénogreffes, cette étude met en évidence des mécanismes spatio-temporels par lesquels, en réponse à l'oncogène MYCN, des cellules souches neurales engendrent des tumeurs cérébrales diverses

    “Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC”

    • Swartling, Fredrik J;Savov, Vasil;Persson, Anders I;Chen, Justin;Hackett, Christopher S;Northcott, Paul A;Grimmer, Matthew R;Lau, Jasmine;Chesler, Louis;Perry, Arie;Phillips, Joanna J;Taylor, Michael D;Weiss, William A

    The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally stabilized murine N-mycT58A into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem, and forebrain. Transplantation of N-mycWT NSCs was insufficient for tumor formation. N-mycT58A cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating Sonic Hedgehog (SHH) dependence and SHH independence, respectively. These differences were regulated in part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic ...


  • There's a Time and a Place for MYCN
    Cancer cell, Vol. 21 (5), pp. 593-595, 2012 (commentaire)
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    Menée sur des échantillons tumoraux prélevés sur 103 patients atteints d'un médulloblastome et à l'aide de xénogreffes, cette étude met en évidence des mécanismes spatio-temporels par lesquels, en réponse à l'oncogène MYCN, des cellules souches neurales engendrent des tumeurs cérébrales diverses

    “There's a Time and a Place for MYCN”

    • Phoenix, Timothy N ; Gilbertson, Richard J

    Brain tumors display extensive diversity. In this issue of Cancer Cell, Swartling et al. provide evidence that the temporal and spatial transcriptional programs in neural stem cells underlie a diverse response to the MYCN oncogene, potentially contributing to cancer diversity.


Mots clés : Système nerveux central; Biologie (Oncogènes et suppresseurs de tumeurs)

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel l'oncogène MYC inhibe le processus métastatique

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    Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel l'oncogène MYC inhibe le processus métastatique

    “MYC suppresses cancer metastasis by direct transcriptional silencing of [alpha]v and [beta]3 integrin subunits”

    • Liu, Hong;Radisky, Derek C.;Yang, Dun;Xu, Ren;Radisky, Evette S.;Bissell, Mina J.;Bishop, J. Michael

    Overexpression of MYC transforms cells in culture, elicits malignant tumours in experimental animals and is found in many human tumours. We now report the paradoxical finding that this powerful oncogene can also act as a suppressor of cell motility, invasiveness and metastasis. Overexpression of MYC stimulated proliferation of breast cancer cells both in culture and in vivo as expected, but inhibited motility and invasiveness in culture, and lung and liver metastases in xenografted tumours. We show further that MYC represses transcription of both subunits of αvβ3 integrin, and that exogenous expression of β3 integrin in human breast cancer cells that do not express this integrin rescues invasiveness and migration when MYC is downregulated. These data uncover an unexpected function of MYC, provide an explanation for the hitherto puzzling literature on the relationship between MYC and metastasis, and reveal a variable that could influence the development of therapies that target MYC.


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

Progression et métastases

Cet article passe en revue les travaux récents sur les métastases cérébrales de tumeurs gastro-intestinales

  • Brain metastases from gastrointestinal tumours: Tailoring the approach to maximize the outcome
    Critical Reviews in Oncology/Hematology, sous presse, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur les métastases cérébrales de tumeurs gastro-intestinales

    “Brain metastases from gastrointestinal tumours: Tailoring the approach to maximize the outcome”

    • Menis, Jessica;Fontanella, Caterina;Follador, Alessandro;Fasola, Gianpiero;Aprile, Giuseppe

    Brain metastases from the gastrointestinal cancers (GI) are uncommon, but their incidence is constantly increasing due to several reasons, including improved systemic therapy and survival. Nevertheless, the average outcome of these patients is poor and related to patients’ or disease characteristics, and to the availability of treatment options. Because of the lack of evidence-based recommendations, no optimal treatment strategy has been defined. The approach to brain metastases remains often tailored, and the action plan is selected on the basis of their number, size and location, the presence of symptoms and the extra-cranial disease status. Clinical prognostic factors have been identified and grouped into index scores that can be helpful in the treatment decision making. At the same time, molecular factors contributing to brain metastases are being revealed, and the role of the unique brain microenvironment is beginning to be investigated. The aim of this review is to present and ...


Mots clés : Système nerveux central; Biologie (Progression et métastases)

A partir de données d'incidence du cancer du sein aux Etats-Unis, cette étude évalue la pertinence d'un modèle de croissance des tumeurs occultes et en tire des conséquences pour l'interprétation des travaux sur la prévention du cancer du sein à l'aide d'inhibiteurs d'aromatase ou d'anti-estrogènes

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    A partir de données d'incidence du cancer du sein aux Etats-Unis, cette étude évalue la pertinence d'un modèle de croissance des tumeurs occultes et en tire des conséquences pour l'interprétation des travaux sur la prévention du cancer du sein à l'aide d'inhibiteurs d'aromatase ou d'anti-estrogènes

    “Modeling of the growth kinetics of occult breast tumors: role in interpretation of studies of prevention and menopausal hormone therapy”

    • Santen, Richard J.;Yue, Wei;Heitjan, Daniel F.

    Background: Autopsy studies report a reservoir of small, occult, undiagnosed breast cancers in up to 15.6% of women dying from unrelated causes. The effective doubling times of these occult neoplasms range from 70 to 350 days and mammographic detection threshold diameters from 0.88 to 1.66 cm. Modeling of the biologic behavior of these occult tumors facilitates interpretation of tamoxifen breast cancer prevention and menopausal hormone therapy studies. Methods: We used iterative and mathematical techniques to develop a model of occult tumor growth (OTG) whose parameters included prevalence, effective doubling time and detection threshold. The model was validated by comparing predicted with observed incidence of breast cancer in several populations. Results: Iterative analysis identified a 200-day effective doubling time, 7% prevalence and 1.16 cm detection threshold as optimal parameters for an OTG model as judged by comparison with SEER population incidence rates in the United ...


Mots clés : Sein; Biologie (Progression et métastases)

Menée sur un poisson zèbre transgénique modélisant un rhabdomyosarcome embryonnaire , cette étude d'imagerie in vivo met en évidence le rôle joué par des cellules cancéreuses spécifiques dans le processus métastatique

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    Menée sur un poisson zèbre transgénique modélisant un rhabdomyosarcome embryonnaire , cette étude d'imagerie in vivo met en évidence le rôle joué par des cellules cancéreuses spécifiques dans le processus métastatique

    “In Vivo Imaging of Tumor-Propagating Cells, Regional Tumor Heterogeneity, and Dynamic Cell Movements in Embryonal Rhabdomyosarcoma”

    • Ignatius, Myron S;Chen, Eleanor;Elpek, Natalie M;Fuller, Adam Z.;Tenente, Inês M;Clagg, Ryan;Liu, Sali;Blackburn, Jessica S;Linardic, Corinne M;Rosenberg, Andrew E.;Nielsen, Petur G;Mempel, Thorsten R;Langenau, David M

    Embryonal rhabdomyosarcoma (ERMS) is an aggressive pediatric sarcoma of muscle. Here, we show that ERMS-propagating potential is confined to myf5+ cells and can be visualized in live, fluorescent transgenic zebrafish. During early tumor growth, myf5+ ERMS cells reside adjacent normal muscle fibers. By late-stage ERMS, myf5+ cells are reorganized into distinct regions separated from differentiated tumor cells. Time-lapse imaging of late-stage ERMS revealed that myf5+ cells populate newly formed tumor only after seeding by highly migratory myogenin+ ERMS cells. Moreover, myogenin+ ERMS cells can enter the vasculature, whereas myf5+ ERMS-propagating cells do not. Our data suggest that non-tumor-propagating cells likely have important supportive roles in cancer progression and facilitate metastasis. º Functional heterogeneity of ERMS cells can be visualized in live zebrafish º Tumor-propagating potential is restricted to myf5+ ERMS cells º myogenin+ ERMS cells are highly invasive and ...


Mots clés : Sarcome; Biologie (Progression et métastases)

Cet article passe en revue les travaux récents sur le rôle des cellules souches cancéreuses dans les cancers de la peau hors mélanome

  • Cells of origin and tumor-initiating cells for nonmelanoma skin cancers
    Cancer Letters, sous presse, 2012 (résumé)
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    Cet article passe en revue les travaux récents sur le rôle des cellules souches cancéreuses dans les cancers de la peau hors mélanome

    “Cells of origin and tumor-initiating cells for nonmelanoma skin cancers”

    • Thieu, Khanh;Ruiz, Marlon;Owens, David M.

    The epidermis of the skin is a multilayered stratified epithelium whose primary function is to provide a barrier against our external environment. As a result, cells in the epidermis are subject to constant assault from environmental pathogens, many of which can cause deleterious mutations. However, most of these mutations do not lead to skin cancer. One explanation is that most genetic hits are sustained by mature or transit cells with limited proliferative capacity and only stem cells that acquire genetic alterations have the potential to propagate a frank tumor. In this mini-review we will discuss recent studies that provide some of the first genetic evidence to support a stem cell origin for a number of skin cancer types.


Mots clés : Peau (hors mélanome); Biologie (Progression et métastases)

Menée in vitro et sur deux échantillons de mélanome humain présentant la mutation BRAFV600E, cette étude met en évidence un mécanisme par lequel, en activant l'expression du transcrit BANCR, la protéine mutée BRAFV600E favorise la migration des cellules tumorales

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    Menée in vitro et sur deux échantillons de mélanome humain présentant la mutation BRAFV600E, cette étude met en évidence un mécanisme par lequel, en activant l'expression du transcrit BANCR, la protéine mutée BRAFV600E favorise la migration des cellules tumorales

    “BRAFV600E remodels the melanocyte transcriptome and induces BANCR to regulate melanoma cell migration”

    • Flockhart, Ross J.;Webster, Dan E.;Qu, Kun;Mascarenhas, Nicholas;Kovalski, Joanna;Kretz, Markus;Khavari, Paul A.

    Aberrations of protein-coding genes are a focus of cancer genomics; however, the impact of oncogenes on expression of the ∼50% of transcripts without protein-coding potential, including long noncoding RNAs (lncRNAs), has been largely uncharacterized. Activating mutations in the BRAF oncogene are present in >70% of melanomas, 90% of which produce active mutant BRAFV600E protein. To define the impacts of oncogenic BRAF on the melanocyte transcriptome, massively parallel cDNA sequencing (RNA-seq) was performed on genetically matched normal human melanocytes with and without BRAFV600E expression. To enhance potential disease relevance by verifying expression of altered genes in BRAF-driven cancer tissue, parallel RNA-seq was also undertaken of two BRAFV600E-mutant human melanomas. BRAFV600E regulated expression of 1027 protein-coding transcripts and 39 annotated lncRNAs, as well as 70 unannotated, potentially novel, intergenic transcripts. These transcripts display both tissue-specific ...


Mots clés : Mélanome; Biologie (Progression et métastases)

Menée sur un modèle murin, cette étude met en évidence un mécanisme par lequel, après l'infiltration du tissu tumoral par les lymphocytes T régulateurs, une prolifération de quelques clones dominants de lymphocytes T a lieu dans la tumeur

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    Menée sur un modèle murin, cette étude met en évidence un mécanisme par lequel, après l'infiltration du tissu tumoral par les lymphocytes T régulateurs, une prolifération de quelques clones dominants de lymphocytes T a lieu dans la tumeur

    “The T-cell receptor repertoire of tumor-infiltrating regulatory T lymphocytes is skewed towards public sequences”

    • Sainz-Perez, Alexander;Lim, Annick;Lemercier, Brigitte;Leclerc, Claude

    The accumulation of CD4+ T regulatory cells (Treg) in tumor tissue is a widely described phenomenon in mouse models and in human cancer patients. Understanding the mechanisms by which Treg migrate and accumulate in tumors is important because they strongly influence the potential efficacy of many immunotherapies. In this study, we used immunoscope technology to analyze the T-cell receptor (TCR) repertoire of tumor-infiltrating T cells in non-TCR transgenic mice. Both tumor-infiltrating Tregs and T effector cells (Teff) displayed sequence profiles in the CDR3 region which were characteristic of biased repertoires seen during clonal cell expansions, implying that strong T-cell responses have occurred within the tumor tissue. By comparing the TCR sequences of tumor-infiltrating Tregs, we obtained evidence of the presence of so-called public TCR sequences that are common to many individuals yet were tumor-specific in nature. Such comparisons also suggested that the Treg-Teff conversion ...


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

Cette étude met en évidence le rôle joué par les voies de signalisation de SIPR1 et STAT3 des cellules myéloïdes dans le processus métastatique

  • S1PR1-STAT3 Signaling Is Crucial for Myeloid Cell Colonization at Future Metastatic Sites
    Cancer cell, Vol. 21 (5), pp. 642-654, 2012 (résumé)
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    Cette étude met en évidence le rôle joué par les voies de signalisation de SIPR1 et STAT3 des cellules myéloïdes dans le processus métastatique

    “S1PR1-STAT3 Signaling Is Crucial for Myeloid Cell Colonization at Future Metastatic Sites”

    • Deng, Jiehui;Liu, Yong;Lee, Heehyoung;Herrmann, Andreas;Zhang, Wang;Zhang, Chunyan;Shen, Shudan;Priceman, Saul J;Kujawski, Maciej;Pal, Sumanta K;Raubitschek, Andrew;Hoon, Dave S B.;Forman, Stephen;Figlin, Robert A;Liu, Jie;Jove, Richard;Yu, Hua

    Recent studies underscore the importance of myeloid cells in rendering distant organs hospitable for disseminating tumor cells to colonize. However, what enables myeloid cells to have an apparently superior capacity to colonize distant organs is unclear. Here, we show that S1PR1-STAT3 upregulation in tumor cells induces factors that activate S1PR1-STAT3 in various cells in premetastatic sites, leading to premetastatic niche formation. Targeting either S1PR1 or STAT3 in myeloid cells disrupts existing premetastatic niches. S1PR1-STAT3 pathway enables myeloid cells to intravasate, prime the distant organ microenvironment and mediate sustained proliferation and survival of their own and other stromal cells at future metastatic sites. Analyzing tumor-free lymph nodes from cancer patients shows elevated myeloid infiltrates, STAT3 activity, and increased survival signal. º STAT3 is persistently activated in future metastatic sites º STAT3 facilitates myeloid cell colonization in future ...


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

Cet article propose une classification simplifiée du processus métastatique permettant de rendre compte de la différenciation cellulaires des métastases

  • To differentiate or not — routes towards metastasis
    Nature Reviews Cancer, sous presse, 2012 (résumé)
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    Cet article propose une classification simplifiée du processus métastatique permettant de rendre compte de la différenciation cellulaires des métastases

    “To differentiate or not — routes towards metastasis”

    • Brabletz, Thomas

    Why are many metastases differentiated? Invading and disseminating carcinoma cells can undergo an epithelial–mesenchymal transition (EMT), which is associated with a gain of stem cell-like behaviour. Therefore, EMT has been linked to the cancer stem cell concept. However, it is a matter of debate how subsequent mesenchymal–epithelial transition (MET) fits into the metastatic process and whether a MET is essential. In this Opinion article, I propose two principle types of metastatic progression: phenotypic plasticity involving transient EMT–MET processes and intrinsic genetic alterations keeping cells in an EMT and stemness state. This simplified classification integrates clinically relevant aspects of dormancy, metastatic tropism and therapy resistance, and implies perspectives on treatment strategies against metastasis.


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

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