Biologie

Aberrations chromosomiques

Menée à partir de 77 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein ER+ et incluses dans deux essais de traitement néoadjuvant à l'aide d'un inhibiteur d'aromatase, cette étude de séquençage identifie des mutations de gènes associés à la réponse thérapeutique

Whole-genome analysis informs breast cancer response to aromatase inhibition
• Nature, sous presse, 2012 (article en libre accès)

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Menée à partir de 77 échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein ER+ et incluses dans deux essais de traitement néoadjuvant à l'aide d'un inhibiteur d'aromatase, cette étude de séquençage identifie des mutations de gènes associés à la réponse thérapeutique

“Whole-genome analysis informs breast cancer response to aromatase inhibition”

• Ellis, Matthew J.;Ding, Li;Shen, Dong;Luo, Jingqin;Suman, Vera J.;Wallis, John W.;Van Tine, Brian A.;Hoog, Jeremy;Goiffon, Reece J.;Goldstein, Theodore C.;Ng, Sam;Lin, Li;Crowder, Robert;Snider, Jacqueline;Ballman, Karla;Weber, Jason;Chen, Ken;Koboldt, Daniel C.;Kandoth, Cyriac;Schierding, William S.;McMichael, Joshua F.;Miller, Christopher A.;Lu, Charles;Harris, Christopher C.;McLellan, Michael D.;Wendl, Michael C.;DeSchryver, Katherine;Allred, D. Craig;Esserman, Laura;Unzeitig, Gary;Margenthaler, Julie;Babiera, G. V.;Marcom, P. Kelly;Guenther, J. M.;Leitch, Marilyn;Hunt, Kelly;Olson, John;Tao, Yu;Maher, Christopher A.;Fulton, Lucinda L.;Fulton, Robert S.;Harrison, Michelle;Oberkfell, Ben;Du, Feiyu;Demeter, Ryan;Vickery, Tammi L.;Elhammali, Adnan;Piwnica-Worms, Helen;McDonald, Sandra;Watson, Mark;Dooling, David J.;Ota, David;Chang, Li-Wei;Bose, Ron;Ley, Timothy J.;Piwnica-Worms, David;Stuart, Joshua M.;Wilson, Richard K.;Mardis, Elaine R.

To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to ...

Mots clés : Sein; Biologie (Aberrations chromosomiques)

Menée sur 91 échantillons tumoraux prélevés sur des patients atteints de trois formes rares de chondrosarcome, cette étude met en évidence des anomalies de la voie de signalisation du rétinoblastome dans les trois sous-types de la maladie

Genetic characterization of mesenchymal, clear cell, and dedifferentiated chondrosarcoma
• Genes, Chromosomes and Cancer, sous presse, 2012 (résumé)

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Menée sur 91 échantillons tumoraux prélevés sur des patients atteints de trois formes rares de chondrosarcome, cette étude met en évidence des anomalies de la voie de signalisation du rétinoblastome dans les trois sous-types de la maladie

“Genetic characterization of mesenchymal, clear cell, and dedifferentiated chondrosarcoma”

• Meijer, Danielle;de Jong, Danielle;Pansuriya, Twinkal C.;van den Akker, Brendy E.;Picci, Piero;Szuhai, Karoly;Bovée, Judith V. G. M.

Clear cell, mesenchymal, and dedifferentiated chondrosarcoma are rare, cartilaginous tumors with limited treatment options other than surgery. Conventional chondrosarcomas have been extensively studied at the genetic level, but for rare chondrosarcoma subtypes, this is merely restricted to case reports. Information on the genetics of rare chondrosarcomas may provide insight into the etiology of these specific disease subtypes and possible alternative treatment strategies. Therefore, the aim of this study was to genetically characterize this subset of rare tumors. Using array CGH, we gathered genomic information of 30 rare cartilaginous tumors. In addition, we constructed tissue microarrays with 2 mm cores of 23 clear cell, 23 mesenchymal, and 45 dedifferentiated chondrosarcomas, in triplicate. Using immunohistochemistry, we investigated expression of R132H IDH1, and p53 and retinoblastoma pathways. Results were verified and further investigated with a methylation assay and MLPA for ...

Mots clés : Sarcome; Biologie (Aberrations chromosomiques)

Menée à l'aide de xénogreffes, cette étude de séquençage identifie des mutations du gène BAP1 en association avec un sous-type de carcinome à cellules rénales

BAP1 loss defines a new class of renal cell carcinoma
• Nature Genetics, sous presse, 2012 (résumé)

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Menée à l'aide de xénogreffes, cette étude de séquençage identifie des mutations du gène BAP1 en association avec un sous-type de carcinome à cellules rénales

“BAP1 loss defines a new class of renal cell carcinoma”

• Pena-Llopis, Samuel;Vega-Rubin-de-Celis, Silvia;Liao, Arnold;Leng, Nan;Pavia-Jimenez, Andrea;Wang, Shanshan;Yamasaki, Toshinari;Zhrebker, Leah;Sivanand, Sharanya;Spence, Patrick;Kinch, Lisa;Hambuch, Tina;Jain, Suneer;Lotan, Yair;Margulis, Vitaly;Sagalowsky, Arthur I.;Summerour, Pia Banerji;Kabbani, Wareef;Wong, S. W. Wendy;Grishin, Nick;Laurent, Marc;Xie, Xian-Jin;Haudenschild, Christian D.;Ross, Mark T.;Bentley, David R.;Kapur, Payal;Brugarolas, James

The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes, including BAP1. The BAP1 protein, a nuclear deubiquitinase, is inactivated in 15% of clear cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation but not deubiquitination of monoubiquitinated histone 2A lysine 119 (H2AK119ub1). BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Notably, mutations in BAP1 and PBRM1 anticorrelate in tumors (P = 9 × 10−6), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q = 0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q = 0.0005). Our results ...

Mots clés : Rein; Biologie (Aberrations chromosomiques)

Menée sur 689 patients atteints d'une leucémie myéloïde aiguë, cette étude analyse la diversité des mutations du gène FLT3 en association avec la survie des patients

Diversity of the juxtamembrane and TKD1 mutations (Exons 13–15) in the FLT3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data
• Genes, Chromosomes and Cancer, sous presse, 2012 (résumé)

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Menée sur 689 patients atteints d'une leucémie myéloïde aiguë, cette étude analyse la diversité des mutations du gène FLT3 en association avec la survie des patients

“Diversity of the juxtamembrane and TKD1 mutations (Exons 13–15) in the FLT3 gene with regards to mutant load, sequence, length, localization, and correlation with biological data”

• Schnittger, Susanne;Bacher, Ulrike;Haferlach, Claudia;Alpermann, Tamara;Kern, Wolfgang;Haferlach, Torsten

In acute myeloid leukemia (AML) mutations in the juxtamembrane and tyrosine kinase 1 domain (exons 13–15) of the FLT3 gene (FLT3-ITD/LM) are heterogeneous with respect to mutation load, size, and localization. We characterized length and structure of these mutations by fragment analysis and sequencing in 689 AML which were identified among 3,365 (20.5%) newly diagnosed AML (1,803 males, 1,562 females; 15.8–91.8 years). Mutations were heterogeneous in length (median: 63, range: 3–1,236 nucleotides; nt). Most frequent were sizes of 21 (8.4%) or 24 nt (6.0%). Ninety-one different insertion sites were observed (between nt 1,788 and 1,934, according to accession “FLT3 [Ensembl/Havana merge: ENSG00000122025]” with nt 1,856 (n = 41) and 1,863 (n = 35) being most frequent. In addition, 89 different insertion end points were observed between nt 1,790 and 1,994. FLT3-mutation/wild-type ratio was available in 615 patients (median, 0.80; range 0.03–181.73). 128 Patients (20.8%) had ...

Mots clés : Leucémie; Biologie (Aberrations chromosomiques)

Menée à partir de 736 échantillons de tumeurs primitives et de métastases prélevés sur 613 patients atteints d'un carcinome colorectal, cette étude met en évidence les similarités et les différences dans les mutations de divers gènes (KRAS, NRAS, BRAF, PIK3CA et TP53) entre les tumeurs primitives et les métastases

Comparative Genomic Analysis of Primary Versus Metastatic Colorectal Carcinomas
• Journal of Clinical Oncology, sous presse, 2012 (résumé)

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Menée à partir de 736 échantillons de tumeurs primitives et de métastases prélevés sur 613 patients atteints d'un carcinome colorectal, cette étude met en évidence les similarités et les différences dans les mutations de divers gènes (KRAS, NRAS, BRAF, PIK3CA et TP53) entre les tumeurs primitives et les métastases

“Comparative Genomic Analysis of Primary Versus Metastatic Colorectal Carcinomas”

• Vakiani, Efsevia;Janakiraman, Manickam;Shen, Ronglai;Sinha, Rileen;Zeng, Zhaoshi;Shia, Jinru;Cercek, Andrea;Kemeny, Nancy;D'Angelica, Michael;Viale, Agnes;Heguy, Adriana;Paty, Philip;Chan, Timothy A.;Saltz, Leonard B.;Weiser, Martin;Solit, David B.

Purpose To compare the mutational and copy number profiles of primary and metastatic colorectal carcinomas (CRCs) using both unpaired and paired samples derived from primary and metastatic disease sites.Patients and Methods We performed a multiplatform genomic analysis of 736 fresh frozen CRC tumors from 613 patients. The cohort included 84 patients in whom tumor tissue from both primary and metastatic sites was available and 31 patients with pairs of metastases. Tumors were analyzed for mutations in the KRAS, NRAS, BRAF, PIK3CA, and TP53 genes, with discordant results between paired samples further investigated by analyzing formalin-fixed, paraffin-embedded tissue and/or by 454 sequencing. Copy number aberrations in primary tumors and matched metastases were analyzed by comparative genomic hybridization (CGH).Results TP53 mutations were more frequent in metastatic versus primary tumors (53.1% v 30.3%, respectively; P < .001), whereas BRAF mutations were significantly less frequent ...

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

Menée sur 21 échantillons de tumeurs et de tissus sains prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence un plus faible taux de mutations de l'ADN mitochondrial dans les cellules tumorales que dans les cellules adjacentes non tumorales

Decreased Mitochondrial DNA Mutagenesis in Human Colorectal Cancer
• PLoS Genetics, Vol. 8 (6), pp. e1002689, 2012 (article en libre accès)

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Menée sur 21 échantillons de tumeurs et de tissus sains prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence un plus faible taux de mutations de l'ADN mitochondrial dans les cellules tumorales que dans les cellules adjacentes non tumorales

“Decreased Mitochondrial DNA Mutagenesis in Human Colorectal Cancer”

• Ericson, Nolan G.;Kulawiec, Mariola;Vermulst, Marc;Sheahan, Kieran;O'Sullivan, Jacintha;Salk, Jesse J.;Bielas, Jason H.

Mitochondria are the intracellular organelles responsible for energy production in eukaryotic cells. They are unique in that they contain their own DNA (mtDNA), which encodes genes important for mitochondrial function and is the cell's only genetic material stored outside the nucleus. Mutations in both nuclear and mtDNA are believed to have a role in tumor growth and metastasis. While it is well established that nuclear DNA has an increased overall burden of mutations in human cancers, this has not been investigated in mtDNA. Here we use a highly sensitive assay to determine mutational load in mtDNA isolated from patient-matched normal and cancerous colonic tissues. Surprisingly, we discovered that the frequency of mutations in mtDNA is actually decreased in tumors relative to healthy tissues, suggesting that, unlike in nuclear DNA, accelerated mutagenesis in mtDNA does not facilitate a cancer's development and may even hinder it. These findings raise the possibility that ...

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

Oncogènes et suppresseurs de tumeurs

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel les rayons ultra-violets A induisent, dans des fibroblastes dermiques, des modifications épigénétiques favorisant la formation de tumeurs cutanées

Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSL Signaling
• Cell, Vol. 149 (6), pp. 1207-1220, 2012 (résumé)

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Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel les rayons ultra-violets A induisent, dans des fibroblastes dermiques, des modifications épigénétiques favorisant la formation de tumeurs cutanées

“Multifocal Epithelial Tumors and Field Cancerization from Loss of Mesenchymal CSL Signaling”

• Hu, Bing;Castillo, Einar;Harewood, Louise;Ostano, Paola;Reymond, Alexandre;Dummer, Reinhard;Raffoul, Wassim;Hoetzenecker, Wolfram;Hofbauer, Günther F L.;Dotto, G. Paolo

It is currently unclear whether tissue changes surrounding multifocal epithelial tumors are a cause or consequence of cancer. Here, we provide evidence that loss of mesenchymal Notch/CSL signaling causes tissue alterations, including stromal atrophy and inflammation, which precede and are potent triggers for epithelial tumors. Mice carrying a mesenchymal-specific deletion of CSL/RBP-Jº, a key Notch effector, exhibit spontaneous multifocal keratinocyte tumors that develop after dermal atrophy and inflammation. CSL-deficient dermal fibroblasts promote increased tumor cell proliferation through upregulation of c-Jun and c-Fos expression and consequently higher levels of diffusible growth factors, inflammatory cytokines, and matrix-remodeling enzymes. In human skin samples, stromal fields adjacent to multifocal premalignant actinic keratosis lesions exhibit decreased Notch/CSL signaling and associated molecular changes. Importantly, these changes in gene expression are also induced by ...
Field Cancerization: Something New Under the Sun
• Cell, Vol. 149 (6), pp. 1179-1181, 2012 (commentaire)

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Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel les rayons ultra-violets A induisent, dans des fibroblastes dermiques, des modifications épigénétiques favorisant la formation de tumeurs cutanées

“Field Cancerization: Something New Under the Sun”

• Vanharanta, Sakari ; Massagué, Joan

Mutations in keratinocyte and melanocyte precursors that are caused by extensive sun exposure are well-established contributors to skin cancer. Now Hu et al. provide evidence that the sun's harmful rays may also cause tumor-promoting epigenetic modifications in dermal fibroblasts, highlighting further the importance of tumor-stroma interactions in cancer.

Mots clés : Peau (hors mélanome); Biologie (Oncogènes et suppresseurs de tumeurs)

Menée à l'aide d'un modèle murin de lymphome, cette étude met en évidence le rôle joué par un réseau de gènes suppresseurs de tumeurs impliqués dans le métabolisme des polyamines

A tumour suppressor network relying on the polyamine-hypusine axis
• Nature, sous presse, 2012 (résumé)

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Menée à l'aide d'un modèle murin de lymphome, cette étude met en évidence le rôle joué par un réseau de gènes suppresseurs de tumeurs impliqués dans le métabolisme des polyamines

“A tumour suppressor network relying on the polyamine-hypusine axis”

• Scuoppo, Claudio;Miething, Cornelius;Lindqvist, Lisa;Reyes, Jose;Ruse, Cristian;Appelmann, Iris;Yoon, Seungtai;Krasnitz, Alexander;Teruya-Feldstein, Julie;Pappin, Darryl;Pelletier, Jerry;Lowe, Scott W.

Tumour suppressor genes encode a broad class of molecules whose mutational attenuation contributes to malignant progression. In the canonical situation, the tumour suppressor is completely inactivated through a two-hit process involving a point mutation in one allele and chromosomal deletion of the other. Here, to identify tumour suppressor genes in lymphoma, we screen a short hairpin RNA library targeting genes deleted in human lymphomas. We functionally identify those genes whose suppression promotes tumorigenesis in a mouse lymphoma model. Of the nine tumour suppressors we identified, eight correspond to genes occurring in three physically linked ‘clusters’, suggesting that the common occurrence of large chromosomal deletions in human tumours reflects selective pressure to attenuate multiple genes. Among the new tumour suppressors are adenosylmethionine decarboxylase 1 (AMD1) and eukaryotic translation initiation factor 5A (eIF5A), two genes associated with hypusine, a unique ...

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

Menée in vitro et in vivo, cette étude met en évidence une activation autocrine du récepteur à activité tyrosine kinase MET dans les leucémies myéloïdes aiguës

Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia
• Nature Medicine, sous presse, 2012 (résumé)

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Menée in vitro et in vivo, cette étude met en évidence une activation autocrine du récepteur à activité tyrosine kinase MET dans les leucémies myéloïdes aiguës

“Autocrine activation of the MET receptor tyrosine kinase in acute myeloid leukemia”

• Kentsis, Alex;Reed, Casie;Rice, Kim L.;Sanda, Takaomi;Rodig, Scott J.;Tholouli, Eleni;Christie, Amanda;Valk, Peter J. M.;Delwel, Ruud;Ngo, Vu;Kutok, Jeffery L.;Dahlberg, Suzanne E.;Moreau, Lisa A.;Byers, Richard J.;Christensen, James G.;Woude, George Vande;Licht, Jonathan D.;Kung, Andrew L.;Staudt, Louis M.;Look, A. Thomas

Although the treatment of acute myeloid leukemia (AML) has improved substantially in the past three decades, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating the aberrant growth and survival of cancer cells. Thus, using a loss-of-function RNA interference genomic screen, we identified the aberrant expression of hepatocyte growth factor (HGF) as a crucial element in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples we studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance resulting from compensatory upregulation of HGF expression, leading to the restoration of MET signaling. In ...

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

Cette étude passe en revue les travaux récents sur le rôle d'une enzyme, l'ubiquitine ligase E3, dans la tumorigenèse

Spotlight on the role of COP1 in tumorigenesis
• Nature Reviews Cancer, sous presse, 2012 (résumé)

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Cette étude passe en revue les travaux récents sur le rôle d'une enzyme, l'ubiquitine ligase E3, dans la tumorigenèse

“Spotlight on the role of COP1 in tumorigenesis”

• Marine, Jean-Christophe

COP1 is an E3 ubiquitin ligase that is involved in the ubiquitylation of various protein substrates to trigger their proteasomal degradation. Although originally identified in a light signalling pathway in plants, biochemical studies have identified putative targets of mammalian COP1 with relevant roles in tumorigenesis, including the oncoproteins JUN and ETV family members, as well as the p53 tumour suppressor. Recent genetic studies have shown that COP1 deficiency leads to spontaneous tumour formation in mice, and have identified mutations in COP1 and its substrates in various human cancers. These findings add to our growing appreciation of the roles for E3 ligases in cancer.

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

Menée à l'aide de modèles murins présentant des mutations de sites d'acétylation du gène p53, cette étude montre que la fonction de suppression de tumeurs demeure active en l'absence des mécanismes d'apoptose, de sénescence et d'arrêt du cycle cellulaire habituellement induits par p53

Tumor Suppression in the Absence of p53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence
• Cell, Vol. 149 (6), pp. 1269-1283, 2012 (résumé)

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Menée à l'aide de modèles murins présentant des mutations de sites d'acétylation du gène p53, cette étude montre que la fonction de suppression de tumeurs demeure active en l'absence des mécanismes d'apoptose, de sénescence et d'arrêt du cycle cellulaire habituellement induits par p53

“Tumor Suppression in the Absence of p53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence”

• Li, Tongyuan;Kon, Ning;Jiang, Le;Tan, Minjia;Ludwig, Thomas;Zhao, Yingming;Baer, Richard;Gu, Wei

Cell-cycle arrest, apoptosis, and senescence are widely accepted as the major mechanisms by which p53 inhibits tumor formation. Nevertheless, it remains unclear whether they are the rate-limiting steps in tumor suppression. Here, we have generated mice bearing lysine to arginine mutations at one (p53K117R) or three (p533KR; K117R+K161R+K162R) of p53 acetylation sites. Although p53K117R/K117R cells are competent for p53-mediated cell-cycle arrest and senescence, but not apoptosis, all three of these processes are ablated in p533KR/3KR cells. Surprisingly, unlike p53 null mice, which rapidly succumb to spontaneous thymic lymphomas, early-onset tumor formation does not occur in either p53K117R/K117R or p533KR/3KR animals. Notably, p533KR retains the ability to regulate energy metabolism and reactive oxygen species production. These findings underscore the crucial role of acetylation in differentially modulating p53 responses and suggest that unconventional activities of p53, such as ...
Tumor Suppression by p53: Fall of the Triumvirate?
• Cell, Vol. 149 (6), pp. 1183-1185, 2012 (commentaire)

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Menée à l'aide de modèles murins présentant des mutations de sites d'acétylation du gène p53, cette étude montre que la fonction de suppression de tumeurs demeure active en l'absence des mécanismes d'apoptose, de sénescence et d'arrêt du cycle cellulaire habituellement induits par p53

“Tumor Suppression by p53: Fall of the Triumvirate?”

• Hock, Andreas K ; Vousden, Karen H

p53 is a key tumor suppressor protein that has numerous functions. Its primary mode of action has generally been ascribed to the induction of cell-cycle arrest, apoptosis, or senescence upon stress. Li et al. challenge this dogma with evidence that all three of these programs are dispensable for p53's tumor suppressive role.

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

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes de réponse aux atteintes à l'ADN associés à la fonction de suppresseur de tumeur du gène p53

Cell cycle- and DNA repair pathway-specific effects of apoptosis on tumor suppression
• Proceedings of the National Academy of Sciences, sous presse, 2012 (article en libre accès)

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Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes de réponse aux atteintes à l'ADN associés à la fonction de suppresseur de tumeur du gène p53

“Cell cycle- and DNA repair pathway-specific effects of apoptosis on tumor suppression”

• Foster, Steven S.;De, Saurav;Johnson, Linda K.;Petrini, John H. J.;Stracker, Travis H.

The DNA damage response comprises DNA repair, cell-cycle checkpoint control, and DNA damage-induced apoptosis that collectively promote genomic integrity and suppress tumorigenesis. Previously, we have shown that the Chk2 kinase functions independently of the Mre11 complex (Mre11, Rad50, and Nbs1) and ATM in apoptosis and suppresses tumorigenesis resulting from hypomorphic alleles of Mre11 or Nbs1. Based on this work, we have proposed that Chk2 limits the oncogenic potential of replication-associated DNA damage. Here we further address the role of Chk2 and damage-induced apoptosis in suppressing the oncogenic potential of chromosome breaks. We show that loss of Chk2 or a mutation in p53 (R172P), which selectively impairs its function in apoptosis, rescued the lethality of mice lacking Lig4, a ligase required for nonhomologous end-joining (NHEJ) repair of DNA double-strand breaks in G0/G1. In contrast to Lig4−/−p53−/− mice, Lig4−/−Chk2−/− and Lig4−/−p53R172P/R172P ...

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 d'épissage alternatif régulant l'expression de CD44 et la formation de métastases pulmonaires d'un cancer du sein

Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell
• Nature Communications, Vol. 3, pp. 883, 2012 (résumé)

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Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme d'épissage alternatif régulant l'expression de CD44 et la formation de métastases pulmonaires d'un cancer du sein

“Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell”

• Yae, Toshifumi;Tsuchihashi, Kenji;Ishimoto, Takatsugu;Motohara, Takeshi;Yoshikawa, Momoko;Yoshida, Go J.;Wada, Takeyuki;Masuko, Takashi;Mogushi, Kaoru;Tanaka, Hiroshi;Osawa, Tsuyoshi;Kanki, Yasuharu;Minami, Takashi;Aburatani, Hiroyuki;Ohmura, Mitsuyo;Kubo, Akiko;Suematsu, Makoto;Takahashi, Kazuhisa;Saya, Hideyuki;Nagano, Osamu

In cancer metastasis, various environmental stressors attack the disseminating cells. The successful colonization of cancer cells in secondary sites therefore requires the ability of the cells to avoid the consequences of such exposure to the stressors. Here we show that orthotopic transplantation of a CD44 variant isoform-expressing (CD44v+) subpopulation of 4T1 breast cancer cells, but not that of a CD44v− subpopulation, in mice results in efficient lung metastasis accompanied by expansion of stem-like cancer cells. Such metastasis is dependent on the activity of the cystine transporter xCT, and the stability of this protein is controlled by CD44v. We find that epithelial splicing regulatory protein 1 regulates the expression of CD44v, and knockdown of epithelial splicing regulatory protein 1 in CD44v+ cells results in an isoform switch from CD44v to CD44 standard (CD44s), leading to reduced cell surface expression of xCT and suppression of lung colonization. The epithelial ...

Mots clés : Sein; Biologie (Progression et métastases)

Cet article passe en revue les travaux récents sur les diverses voies de signalisation et molécules impliquées dans la régulation de l'angiogenèse lors du développement d'un cancer

Role of angiogenesis in the pathogenesis of cancer
• Cancer treatment reviews, sous presse, 2012 (résumé)

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Cet article passe en revue les travaux récents sur les diverses voies de signalisation et molécules impliquées dans la régulation de l'angiogenèse lors du développement d'un cancer

“Role of angiogenesis in the pathogenesis of cancer”

• Hoff, Paulo M.;Machado, Karime Kalil

It has been recognized for decades that angiogenesis is an important event in tumor growth and metastasis; the concept of the “angiogenic switch,” whereby tumors acquire the ability to grow exponentially and disseminate beyond their primary site, is one of the central components in our understanding of cancer. A vast network of signaling molecules and receptors that are involved in the regulation of angiogenesis have been identified and characterized; most notably, the vascular endothelial growth factor (VEGF) family. Indeed, the VEGF family of growth factors and receptors has become a prototype for our understanding of angiogenesis during early development and in pathological conditions such as cancer. The specific inhibition of key regulatory molecules including VEGF-A (such as with bevacizumab treatment) has been recognized as a useful strategy to reduce tumor growth and progression in several tumor types. Nevertheless, the contribution of other members of the VEGF family, ...