A partir de données génomiques, cette étude évalue la pertinence d'un modèle de progression du cancer prenant en compte l'accumulation de mutations qualifiées de "passagères" car, par contraste avec les mutations "conductrices", elles n'ont chacune qu'un faible pouvoir délétère dans les cellules cancéreuses

Impact of deleterious passenger mutations on cancer progression

McFarland, Christopher D. ; Korolev, Kirill S. ; Kryukov, Gregory V. ; Sunyaev, Shamil R. ; Mirny, Leonid A.

Cancer progression is driven by the accumulation of a small number of genetic alterations. However, these few driver alterations reside in a cancer genome alongside tens of thousands of additional mutations termed passengers. Passengers are widely believed to have no role in cancer, yet many passengers fall within protein-coding genes and other functional elements that can have potentially deleterious effects on cancer cells. Here we investigate the potential of moderately deleterious [...]

Menée in vitro et à partir de bases de données en libre accès, cette étude met en évidence l'existence de mutations activatrices de petites GTPases de la famille RAC dans divers types de cancer

Transforming mutations of RAC guanosine triphosphatases in human cancers

Kawazu, Masahito ; Ueno, Toshihide ; Kontani, Kenji ; Ogita, Yoshitaka ; Ando, Mizuo ; Fukumura, Kazutaka ; Yamato, Azusa ; Soda, Manabu ; Takeuchi, Kengo ; Miki, Yoshio ; Yamaguchi, Hiroyuki ; Yasuda, Takahiko ; Naoe, Tomoki ; Yamashita, Yoshihiro ; Katada, Toshiaki ; Choi, Young Lim ; Mano, Hiroyuki

Members of the RAS superfamily of small guanosine triphosphatases (GTPases) transition between GDP-bound, inactive and GTP-bound, active states and thereby function as binary switches in the regulation of various cellular activities. Whereas HRAS, NRAS, and KRAS frequently acquire transforming missense mutations in human cancer, little is known of the oncogenic roles of other small GTPases, including Ras-related C3 botulinum toxin substrate (RAC) proteins. We show that the human sarcoma cell [...]

Menée sur 103 échantillons prélevés sur des patients atteints d'une leucémie lymphocytaire chronique, cette étude met en évidence le rôle joué par un ARN chimère impliquant YPEL5 et la phosphatase PP1CB dans le développement de cette forme commune de leucémie

Recurrent reciprocal RNA chimera involving YPEL5 and PPP1CB in chronic lymphocytic leukemia

Velusamy, Thirunavukkarasu ; Palanisamy, Nallasivam ; Kalyana-Sundaram, Shanker ; Sahasrabuddhe, Anagh Anant ; Maher, Christopher A. ; Robinson, Daniel R. ; Bahler, David W. ; Cornell, Timothy T. ; Wilson, Thomas E. ; Lim, Megan S. ; Chinnaiyan, Arul M. ; Elenitoba-Johnson, Kojo S. J.

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in the Western hemisphere. Tumor-specific chromosomal translocations, characteristic findings in several human malignancies that directly lead to malignant transformation, have not been identified in CLL. Using paired-end transcriptome sequencing, we identified recurrent and reciprocal RNA chimeras involving yippee like 5 (YPEL5) and serine/threonine-protein phosphatase PP1-beta-catalytic subunit (PPP1CB) in CLL. [...]

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude met en évidence des mécanismes par lesquels l'enzyme APOBEC3B favorise l'apparition de mutations somatiques

APOBEC3B is an enzymatic source of mutation in breast cancer

Burns, Michael B. ; Lackey, Lela ; Carpenter, Michael A. ; Rathore, Anurag ; Land, Allison M. ; Leonard, Brandon ; Refsland, Eric W. ; Kotandeniya, Delshanee ; Tretyakova, Natalia ; Nikas, Jason B. ; Yee, Douglas ; Temiz, Nuri A. ; Donohue, Duncan E. ; McDougle, Rebecca M. ; Brown, William L. ; Law, Emily K. ; Harris, Reuben S.

Several mutations are required for cancer development, and genome sequencing has revealed that many cancers, including breast cancer, have somatic mutation spectra dominated by C-to-T transitions. Most of these mutations occur at hydrolytically disfavoured non-methylated cytosines throughout the genome, and are sometimes clustered. Here we show that the DNA cytosine deaminase APOBEC3B is a probable source of these mutations. APOBEC3B messenger RNA is upregulated in most primary breast tumours [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par le micro-ARN 21 dans la voie de signalisation du gène suppresseur de tumeurs p53

Interaction of the oncogenic miR-21 microRNA and the p53 tumor suppressor pathway

Ma, Xiaodong ; Choudhury, Saibyasachi N ; Hua, Xiang ; Dai, Zhongping ; Li, Yong

MicroRNA-21 (miR-21) is overexpressed virtually in all human cancers and displays oncogenic activity in a transgenic murine model. Similarly, the p53 tumor suppressor gene is the most frequently mutated gene in human cancer, and its loss or mutation leads to tumor formation in mice. To ascertain the role of miR-21 in the p53 pathway in vivo and to characterize their interaction in tumorigenesis, we intercrossed the miR-21-/- and Trp53-/- mice. We found that Trp53-/-miR-21-/-mice develop tumors [...]

Menée à l'aide de modèles murins, cette étude montre que l'inactivation de p53 suffit pour déclencher la transformation maligne de lymphocytes B matures et favoriser le développement d'un lymphome

Conditional inactivation of p53 in mature B cells promotes generation of nongerminal center-derived B-cell lymphomas

Gostissa, Monica ; Bianco, Julia M. ; Malkin, Daniel J. ; Kutok, Jeffery L. ; Rodig, Scott J. ; Morse, Herbert C. ; Bassing, Craig H. ; Alt, Frederick W.

The p53 tumor suppressor exerts a central role in protecting cells from oncogenic transformation. Accordingly, the p53 gene is mutated in a large number of human cancers. In mice, germ-line inactivation of p53 confers strong predisposition to development of different types of malignancies, but the early onset of thymic lymphomas in the majority of the animals prevents detailed studies of tumorigenesis in other tissues. Here, we use the Cre/Lox approach to inactivate p53 in mature B cells in [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant la signalisation TGF-β dans le micro-environnement tumoral, la protéine IQGAP1 inhibe la croissance de métastases hépatiques d'un cancer colorectal

IQGAP1 suppresses TβRII-mediated myofibroblastic activation and metastatic growth in liver

Liu, Chunsheng ; Billadeau, Daniel D. ; Abdelhakim, Haitham ; Leof, Edward ; Kaibuchi, Kozo ; Bernabeu, Carmelo ; Bloom, George S. ; Yang, Liu ; Boardman, Lisa ; Shah, Vijay H. ; Kang, Ningling

In the tumor microenvironment, TGF-β induces transdifferentiation of quiescent pericytes and related stromal cells into myofibroblasts that promote tumor growth and metastasis. The mechanisms governing myofibroblastic activation remain poorly understood, and its role in the tumor microenvironment has not been explored. Here, we demonstrate that IQ motif containing GTPase activating protein 1 (IQGAP1) binds to TGF-β receptor II (TβRII) and suppresses TβRII-mediated signaling in pericytes to [...]

Menée sur des lignées cellulaires et des échantillons tumoraux prélevés sur des patients atteints d'un carcinome épidermoïde de l'œsophage, cette étude identifie des cellules initiatrices de tumeurs caractérisées par la surexpression de CD90 et dotées d'un fort pouvoir métastatique

A CD90+ tumor-initiating cell population with an aggressive signature and metastatic capacity in esophageal cancer

Tang, Kwan Ho ; Dai, Yongdong ; Tong, Man ; Chan, Yuen-Piu ; Kwan, Pak Shing ; Fu, Li ; Qin, Yan-Ru ; Tsao, Sai Wah ; Lung, Hong Lok ; Lung, Maria Li ; Tong, Daniel K ; Law, Simon ; Chan, Kwok Wah ; Ma, Stephanie ; Guan, Xin-Yuan

Tumor-initiating cells (TICs), also known as cancer stem cells, are regarded widely as a specific subpopulation of cells needed for cancer initiation and progression. TICs have yet to be identified in esophageal tumors that have a rising incidence in developed countries. Here we report a CD90+ cell population found in esophageal squamous cell carcinoma (ESCC) which is endowed with stem cell-like properties and high tumorigenic and metastatic potential. mRNA profiling of these cells suggested [...]

Menée à l'aide de xénogreffes, cette étude met en évidence le rôle joué par la paire de micro-ARNs 126/126* dans la répression du processus métastatique d'un cancer du sein

miR-126 and miR-126* repress recruitment of mesenchymal stem cells and inflammatory monocytes to inhibit breast cancer metastasis

Zhang, Yun ; Yang, Pengyuan ; Sun, Tao ; Li, Dong ; Xu, Xin ; Rui, Yaocheng ; Li, Chaoran ; Chong, Mengyang ; Ibrahim, Toni ; Mercatali, Laura ; Amadori, Dino ; Lu, Xincheng ; Xie, Dong ; Li, Qi-Jing ; Wang, Xiao-Fan

The tumour stroma is an active participant during cancer progression. Stromal cells promote tumour progression and metastasis through multiple mechanisms including enhancing tumour invasiveness and angiogenesis, and suppressing immune surveillance. We report here that miR-126/miR-126*, a microRNA pair derived from a single precursor, independently suppress the sequential recruitment of mesenchymal stem cells and inflammatory monocytes into the tumour stroma to inhibit lung metastasis by breast [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel, en régulant l'expression du gène KLF4 dans les cellules souches cancéreuses, le micro-ARN 7 inhibe la formation de métastases cérébrales d'un cancer du sein

miR-7 Suppresses Brain Metastasis of Breast Cancer Stem-Like Cells By Modulating KLF4

Okuda, Hiroshi ; Xing, Fei ; Pandey, Puspa R. ; Sharma, Sambad ; Watabe, Misako ; Pai, Sudha K. ; Mo, Yin-Yuan ; Iiizumi-Gairani, Megumi ; Hirota, Shigeru ; Liu, Yin ; Wu, Kerui ; Pochampally, Radhika ; Watabe, Kounosuke

Despite significant improvement in survival rates of patients with breast cancer, prognosis of metastatic disease is still dismal. Cancer stem-like cells (CSC) are considered to play a role in metastatic progression of breast cancer; however, the exact pathologic role of CSCs is yet to be elucidated. In this report, we found that CSCs (CD24−/CD44+/ESA+) isolated from metastatic breast cell lines are significantly more metastatic than non-CSC populations in an organ-specific manner. The results [...]

Menée sur des lignées cellulaires et à partir de bases de données d'expression de gènes, cette étude met en évidence le rôle joué par la protéine CtBP dans le métabolisme et la régulation épigénétique de l'instabilité génomique et de la transition épithélio-mésenchymateuse de cellules de cancer du sein

Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer

Di, Li-Jun ; Byun, Jung S. ; Wong, Madeline M. ; Wakano, Clay ; Taylor, Tara ; Bilke, Sven ; Baek, Songjoon ; Hunter, Kent ; Yang, Howard ; Lee, Maxwell ; Zvosec, Cecilia ; Khramtsova, Galina ; Cheng, Fan ; Perou, Charles M. ; Ryan Miller, C. ; Raab, Rachel ; Olopade, Olufunmilayo I. ; Gardner, Kevin

The C-terminal binding protein (CtBP) is a NADH-dependent transcriptional repressor that links carbohydrate metabolism to epigenetic regulation by recruiting diverse histone-modifying complexes to chromatin. Here global profiling of CtBP in breast cancer cells reveals that it drives epithelial-to-mesenchymal transition, stem cell pathways and genome instability. CtBP expression induces mesenchymal and stem cell-like features, whereas CtBP depletion or caloric restriction reverses gene [...]

Cet article passe en revue les travaux récents ayant fait appel à la drosophile pour l'étude des mécanismes du cancer et le développement de nouveaux traitements

Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics

Gonzalez, Cayetano

For decades, lower-model organisms such as Drosophila melanogaster have often provided the first glimpse into the mechanism of action of human cancer-related proteins, thus making a substantial contribution to elucidating the molecular basis of the disease. More recently, D. melanogaster strains that are engineered to recapitulate key aspects of specific types of human cancer have been paving the way for the future role of this 'workhorse' of biomedical research, helping to further investigate [...]

Cet article passe en revue les travaux sur les modèles numériques de croissance tumorale

The model muddle: in search of tumour growth laws

Gerlee, Philip

In this article we shall trace the historical development of tumour growth laws, which in a quantitative fashion describe the increase in tumour mass/volume over time. These models are usually formulated in terms of differential equations that relate the growth rate of the tumour to its current state, and range from the simple one-parameter exponential growth model, to more advanced models that contain a large number of parameters. Understanding the assumptions and consequences of such models [...]

Cette étude présente et évalue les performances d'une méthode, appelée MuTect, de détection de mutations somatiques ponctuelles dans des échantillons tumoraux hétérogènes et impurs

Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples

Cibulskis, Kristian ; Lawrence, Michael S. ; Carter, Scott L. ; Sivachenko, Andrey ; Jaffe, David ; Sougnez, Carrie ; Gabriel, Stacey ; Meyerson, Matthew ; Lander, Eric S. ; Getz, Gad

Detection of somatic point substitutions is a key step in characterizing the cancer genome. However, existing methods typically miss low-allelic-fraction mutations that occur in only a subset of the sequenced cells owing to either tumor heterogeneity or contamination by normal cells. Here we present MuTect, a method that applies a Bayesian classifier to detect somatic mutations with very low allele fractions, requiring only a few supporting reads, followed by carefully tuned filters that ensure [...]

Cet article passe en revue les travaux récents sur le comportement des cellules tumorales, prénéoplasiques et normales dans l'épithélium de souris transgéniques

Tracking cells in their native habitat: lineage tracing in epithelial neoplasia

Alcolea, Maria P. ; Jones, Philip H.

For tumours to develop, mutations must disrupt tissue homeostasis in favour of deregulated proliferation. Genetic lineage tracing has uncovered the behaviour of proliferating cells that underpins the maintenance of epithelial tissues and the barriers that are broken in neoplastic transformation. In this Review, we focus on new insights revealed by quantifying the behaviour of normal, preneoplastic and tumour cells in epithelia in transgenic mice and consider their potential importance in [...]