A partir de l'analyse du génome mitochondrial dans des échantillons de tissus prélevés à l'autopsie sur 152 personnes, cette étude met en évidence des mécanismes associés à une hétéroplasmie, notamment dans le foie

Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations

Li, Mingkun ; Schröder, Roland ; Ni, Shengyu ; Madea, Burkhard ; Stoneking, Mark

Heteroplasmy in human mtDNA may play a role in cancer, other diseases, and aging, but patterns of heteroplasmy variation across different tissues have not been thoroughly investigated. Here, we analyzed complete mtDNA genome sequences at ∼3,500× average coverage from each of 12 tissues obtained at autopsy from each of 152 individuals. We identified 4,577 heteroplasmies (with an alternative allele frequency of at least 0.5%) at 393 positions across the mtDNA genome. Surprisingly, different [...]

A partir d'échantillons de tissu tumoral et de tissu sain prélevés sur des patients atteints d'un adénocarcinome du poumon, cette étude identifie des populations sous-clonales présentant des mutations du gène KRAS et susceptibles de contribuer à la résistance aux thérapies ciblées anti EGFR

Low-frequency KRAS mutations are prevalent in lung adenocarcinomas

Myers, Meagan B. ; McKim, Karen L. ; Meng, Fanxue ; Parsons, Barbara L.

Aim: This study quantified low-frequency KRAS mutations in normal lung and lung adenocarcinomas, to understand their potential significance in the development of acquired resistance to EGFR-targeted therapies. Materials & methods: Allele-specific Competitive Blocker-PCR was used to quantify KRAS codon 12 GAT (G12D) and GTT (G12V) mutation in 19 normal lung and 21 lung adenocarcinoma samples. Results: Lung adenocarcinomas had KRAS codon 12 GAT and GTT geometric mean mutant fractions of 1.94 × [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression de longs ARNs non codants, le facteur de transcription MYC favorise le développement d'un cancer colorectal

Role of MYC-Regulated Long Noncoding RNAs in Cell Cycle Regulation and Tumorigenesis

Kim, Taewan ; Jeon, Young-Jun ; Cui, Ri ; Lee, Ji-Hoon ; Peng, Yong ; Kim, Sung-Hak ; Tili, Esmerina ; Alder, Hansjuerg ; Croce, Carlo M.

Background: The functions of long noncoding RNAs (lncRNAs) have been identified in several cancers, but the roles of lncRNAs in colorectal cancer (CRC) are less well understood. The transcription factor MYC is known to regulate lncRNAs and has been implicated in cancer cell proliferation and tumorigenesis. Methods: CRC cells and tissues were profiled to identify lncRNAs differentially expressed in CRC, from which we further selected MYC-regulated lncRNAs. We used luciferase promoter assay, [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, en régulant de façon négative l'expression de la kinase CHK1, le facteur de transcription ERG favorise le développement d'un cancer de la prostate

Suppression of CHK1 by ETS family members promotes DNA damage response by-pass and tumorigenesis

Lunardi, Andrea ; Varmeh, Shohreh ; Chen, Ming ; Taulli, Riccardo ; Guarnerio, Jlenia ; Ala, Ugo ; Seitzer, Nina ; Ishikawa, Tomoki ; Carver, Brett S ; Hobbs, Robin M. ; Quarantotti, Valentina ; Ng, Christopher ; Berger, Alice H ; Nardella, Caterina ; Poliseno, Laura ; Montironi, Rodolfo ; Castillo-Martin, Mireia ; Cordon-Cardo, Carlos ; Signoretti, Sabina ; Pandolfi, Pier Paolo

The ETS family of transcription factors has been repeatedly implicated in tumorigenesis. In prostate cancer, ETS family members such as ERG, ETV1, ETV4 and ETV5 are frequently overexpressed due to chromosomal translocations, but the molecular mechanisms by which they promote prostate tumorigenesis remain largely undefined. Here we show that ETS family members such as ERG and ETV1 directly repress the expression of the checkpoint kinase 1 (CHK1), a key DNA Damage Response (DDR) cell cycle [...]

Menée in vitro et à l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un mélanome, cette étude met en évidence des mécanismes par lesquels, en facilitant les interactions entre le réseau vasculaire lymphatique et les cellules tumorales, la protéine PPP2R1A favorise le processus métastatique

Ligand-directed targeting of lymphatic vessels uncovers mechanistic insights in melanoma metastasis

Christianson, Dawn R. ; Dobroff, Andrey S. ; Proneth, Bettina ; Zurita, Amado J. ; Salameh, Ahmad ; Dondossola, Eleonora ; Makino, Jun ; Bologa, Cristian G. ; Smith, Tracey L. ; Yao, Virginia J. ; Calderone, Tiffany L. ; O'Connell, David J. ; Oprea, Tudor I. ; Kataoka, Kazunori ; Cahill, Dolores J. ; Gershenwald, Jeffrey E. ; Sidman, Richard L. ; Arap, Wadih ; Pasqualini, Renata

Metastasis is the most lethal step of cancer progression in patients with invasive melanoma. In most human cancers, including melanoma, tumor dissemination through the lymphatic vasculature provides a major route for tumor metastasis. Unfortunately, molecular mechanisms that facilitate interactions between melanoma cells and lymphatic vessels are unknown. Here, we developed an unbiased approach based on molecular mimicry to identify specific receptors that mediate lymphatic endothelial–melanoma [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes de nature métabolique par lesquels la surexpression d'un coactivateur transcriptionnel, SRC-2, favorise le processus métastatique d'un cancer de la prostate

Coactivator SRC-2–dependent metabolic reprogramming mediates prostate cancer survival and metastasis

Dasgupta, Subhamoy ; Putluri, Nagireddy ; Long, Weiwen ; Zhang, Bin ; Wang, Jianghua ; Kaushik, Akash K. ; Arnold, James M. ; Bhowmik, Salil K. ; Stashi, Erin ; Brennan, Christine A. ; Rajapakshe, Kimal ; Coarfa, Cristian ; Mitsiades, Nicholas ; Ittmann, Michael M. ; Chinnaiyan, Arul M. ; Sreekumar, Arun ; O’Malley, Bert W.

Metabolic pathway reprogramming is a hallmark of cancer cell growth and survival and supports the anabolic and energetic demands of these rapidly dividing cells. The underlying regulators of the tumor metabolic program are not completely understood; however, these factors have potential as cancer therapy targets. Here, we determined that upregulation of the oncogenic transcriptional coregulator steroid receptor coactivator 2 (SRC-2), also known as NCOA2, drives glutamine-dependent de novo [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en activant la signalisation Rac1, la perte d'expression de l'enzyme HACE1 favorise l'évolution d'un carcinome canalaire in situ en cancer invasif du sein

Loss of the E3 ubiquitin ligase HACE1 results in enhanced Rac1 signaling contributing to breast cancer progression

Goka, E. T. ; Lippman, M. E.

The transition from ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC) is a crucial step in breast cancer progression. The specific alterations that govern this transition have not been elucidated. HER2/neu is frequently overexpressed in DCIS but is less common in IBC, thereby suggesting additional requirements for transformation. To identify genes capable of cooperating with HER2/neu to fully transform mammary epithelial cells, we used an insertional mutagenesis screen on cells [...]

Cette étude présente les caractéristiques d'un modèle murin qui, par l'activation combinée de la bêta-caténine et du récepteur nucléaire CAR, récapitule le développement d'un carcinome hépatocellulaire humain

Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis

Dong, Bingning ; Lee, Ju-Seog ; Park, Yun-Yong ; Yang, Feng ; Xu, Ganyu ; Huang, Wendong ; Finegold, Milton J. ; Moore, David D.

Aberrant β-catenin activation contributes to a third or more of human hepatocellular carcinoma (HCC), but β-catenin activation alone is not sufficient to induce liver cancer in mice. Differentiated hepatocytes proliferate upon acute activation of either β-catenin or the nuclear xenobiotic receptor CAR. These responses are strictly limited and are tightly linked, since β-catenin is activated in nearly all of the CAR-dependent tumours generated by the tumour promoter phenobarbital. Here, we show [...]

A partir d'échantillons tumoraux prélevés sur 15 patients atteints d'un cancer colorectal, cette étude évalue la capacité d'un modèle appelé 'Big Bang' à rendre compte des origines et de l'évolution de l'hétérogénéité intratumorale

A Big Bang model of human colorectal tumor growth

Sottoriva, Andrea ; Kang, Haeyoun ; Ma, Zhicheng ; Graham, Trevor A. ; Salomon, Matthew P. ; Zhao, Junsong ; Marjoram, Paul ; Siegmund, Kimberly ; Press, Michael F. ; Shibata, Darryl ; Curtis, Christina

What happens in early, still undetectable human malignancies is unknown because direct observations are impractical. Here we present and validate a 'Big Bang' model, whereby tumors grow predominantly as a single expansion producing numerous intermixed subclones that are not subject to stringent selection and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors showed an [...]