Cet article passe en revue les travaux récents sur le rôle joué par des mutations somatiques dans la transformation d'une cellule normale en cellule cancéreuse

Somatic mutation in cancer and normal cells

Martincorena, Inigo ; Campbell, Peter J.

Spontaneously occurring mutations accumulate in somatic cells throughout a person’s lifetime. The majority of these mutations do not have a noticeable effect, but some can alter key cellular functions. Early somatic mutations can cause developmental disorders, whereas the progressive accumulation of mutations throughout life can lead to cancer and contribute to aging. Genome sequencing has revolutionized our understanding of somatic mutation in cancer, providing a detailed view of the [...]

A partir de données portant sur des mutations somatiques identifiées dans 4 742 échantillons tumoraux ainsi que sur les structures tridimensionnelles connues des protéines humaines, cette étude met en évidence l'intérêt d'une méthode d'analyse de la structure des protéines pour identifier des gènes impliqués dans la cancérogenèse et comprendre le rôle fonctionnel de leurs mutations

Comprehensive assessment of cancer missense mutation clustering in protein structures

Kamburov, Atanas ; Lawrence, Michael S. ; Polak, Paz ; Leshchiner, Ignaty ; Lage, Kasper ; Golub, Todd R. ; Lander, Eric S. ; Getz, Gad

Large-scale tumor sequencing projects enabled the identification of many new cancer gene candidates through computational approaches. Here, we describe a general method to detect cancer genes based on significant 3D clustering of mutations relative to the structure of the encoded protein products. The approach can also be used to search for proteins with an enrichment of mutations at binding interfaces with a protein, nucleic acid, or small molecule partner. We applied this approach to [...]

Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels, en inhibant la voie de signalisation cGAS-STING, des oncogènes de virus tumoraux à ADN favorisent l'échappement au système immunitaire

DNA tumor virus oncogenes antagonize the cGAS-STING DNA sensing pathway

Lau, Laura ; Gray, Elizabeth E. ; Brunette, Rebecca L. ; Stetson, Daniel B.

Cyclic GMP-AMP synthase (cGAS) detects intracellular DNA and signals through the adapter protein STING to initiate the antiviral response to DNA viruses. Whether DNA viruses can prevent activation of the cGAS-STING pathway remains largely unknown. Here, we identify the viral oncogenes of the DNA tumor viruses, including E7 from human papillomavirus (HPV) and E1A from adenovirus, as potent and specific inhibitors of the cGAS-STING pathway. We show that the LXCXE motif of these oncoproteins, [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels, en régulant l'expression de certains gènes, la protéine MYC exerce une fonction oncogénique

MYC: connecting selective transcriptional control to global RNA production

Kress, Theresia R. ; Sabo, Arianna ; Amati, Bruno

Two opposing models have been proposed to describe the function of the MYC oncoprotein in shaping cellular transcriptomes: one posits that MYC amplifies transcription at all active loci; the other that MYC differentially controls discrete sets of genes, the products of which affect global transcript levels. Here, we argue that differential gene regulation by MYC is the sole unifying model that is consistent with all available data. Among other effects, MYC endows cells with physiological and [...]

Cet article passe en revue les travaux récents sur le rôle des sirtuines dans le métabolisme des cellules cancéreuses, les mécanismes de réparation de l'ADN et le micro-environnement tumoral

The multifaceted functions of sirtuins in cancer

Chalkiadaki, Angeliki ; Guarente, Leonard

The sirtuins (SIRTs; of which there are seven in mammals) are NAD+-dependent enzymes that regulate a large number of cellular pathways and forestall the progression of ageing and age-associated diseases. In recent years, the role of sirtuins in cancer biology has become increasingly apparent, and growing evidence demonstrates that sirtuins regulate many processes that go awry in cancer cells, such as cellular metabolism, the regulation of chromatin structure and the maintenance of genomic [...]

Menée à l'aide d'un modèle murin et d'échantillons prélevés sur des patients atteints d'une leucémie myéloïde aiguë présentant une délétion partielle du chromosome 9, cette étude met en évidence des mécanismes par lesquels le gène hnRNP K exerce une fonction de suppresseur de tumeurs

hnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies

Gallardo, Miguel ; Lee, Hun Ju ; Zhang, Xiaorui ; Bueso-Ramos, Carlos ; Pageon, Laura R ; McArthur, Mark ; Multani, Asha ; Nazha, Aziz ; Manshouri, Taghi ; Parker-Thornburg, Jan ; Rapado, Inmaculada ; Quintas-Cardama, Alfonso ; Kornblau, Steven M ; Martínez-López, Joaquin ; Post, Sean M

hnRNP K regulates cellular programs, and changes in its expression and mutational status have been implicated in neoplastic malignancies. To directly examine its role in tumorigenesis, we generated a mouse model harboring an Hnrnpk knockout allele (Hnrnpk+/?). Hnrnpk haploinsufficiency resulted in reduced survival, increased tumor formation, genomic instability, and the development of transplantable hematopoietic neoplasms with myeloproliferation. Reduced hnRNP K expression attenuated p21 [...]

A partir de 286 échantillons tumoraux prélevés sur des patients atteints d'un carcinome épidermoïde de l'œsophage, puis menée in vitro et in vivo, cette étude met en évidence le rôle joué par l'une des deux isoformes de STAT3 (STAT3bêta) dans la fonction exercée par STAT3, suppresseur de tumeurs ou oncogène

The opposing function of STAT3 as an oncoprotein and tumor suppressor is dictated by the expression status of STAT3β in esophageal squamous cell carcinoma

Zhang, Hai-Feng ; Chen, Ye ; Wu, Chengsheng ; Wu, Zhiyong ; Tweardy, David J ; Alshareef, Abdulraheem ; Liao, Lian-Di ; Xue, Yu-Jie ; Wu, Jian-Yi ; Chen, Bo ; Xu, Xue-E ; Gopal, Keshav ; Gupta, Nidhi ; Li, En-Min ; Xu, Li-Yan ; Lai, Raymond

Purpose: STAT3 is known to have both oncogenic and tumor suppressive effects, but the regulation of these opposing effects is elusive. We hypothesized that STAT3β, one of the two STAT3 isoforms, is the key determinant in this context. Experimental Design: The prognostic significance of STAT3β and phospho-STAT3αY705 (pSTAT3αY705) was evaluated in 286 cases of esophageal squamous cell carcinoma (ESCC) patients. STAT3β-induced changes in the chemosensitivity to cisplatin and 5-flurouracil were [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression d'une protéine impliquée dans une voie de signalisation inflammatoire, l'interleukine 17 favorise l'évolution d'une pancréatite chronique en cancer du pancréas

IL-17 functions through the novel REG3β-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer

Loncle, Celine ; Bonjoch, Laia ; Folch-Puy, Emma ; Lopez-Millan, Maria Belen ; Lac, Sophie ; Molejon, Maria Inés ; Chuluyan, Eduardo ; Cordelier, Pierre ; Dubus, Pierre ; Lomberk, Gwen ; Urrutia, Raul ; Closa, Daniel ; Iovanna, Juan L

Pancreatic ductal adenocarcinoma (PDAC) offers an optimal model for discovering "druggable" molecular pathways that participate in inflammation-associated cancer development. Chronic pancreatitis, a common prolonged inflammatory disease, behaves as a well-known premalignant condition that contributes to PDAC development. Although the mechanisms underlying the pancreatitis-to-cancer transition remain to be fully elucidated, emerging evidence supports the hypothesis that the actions of [...]

Menée à l'aide de modèles murins et de données extraites d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude met en évidence le rôle joué par la signalisation Ras dans le processus métastatique d'un cancer de type luminal

Ras signaling is a key determinant of metastatic dissemination and poor survival of luminal breast cancer patients

Wright, Katherine L ; Adams, Jessica R ; Liu, Jeff C ; Loch, Amanda J ; Wong, Ruth G ; Jo, Christine E.B. ; Beck, Lauren A ; Santhanam, Divya R ; Weiss, Laura ; Mei, Xue ; Lane, Timothy F ; Koralov, Sergei B. ; Done, Susan J ; Woodgett, James R ; Zacksenhaus, Eldad ; Hu, Pingzhao ; Egan, Sean E

Breast cancer (BC) is associated with alterations in a number of growth factor and hormone-regulated signaling pathways. Mouse models of metastatic BC typically feature mutated oncoproteins that activate PI3K, Stat3, and Ras signaling, but the individual and combined roles of these pathways in BC progression are poorly understood. In this study, we examined the relationship between oncogenic pathway activation and breast cancer subtype by analyzing mouse mammary tumor formation in which each [...]

Menée à l'aide de xénogreffes de cellules de cancer du sein, cette étude met en évidence la présence, dans les cellules métastatiques précoces, d'une signature d'expression de gènes analogue à celle qu'on identifie dans les cellules souches

Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells

Lawson, Devon A. ; Bhakta, Nirav R. ; Kessenbrock, Kai ; Prummel, Karin D. ; Yu, Ying ; Takai, Ken ; Zhou, Alicia ; Eyob, Henok ; Balakrishnan, Sanjeev ; Wang, Chih-Yang ; Yaswen, Paul ; Goga, Andrei ; Werb, Zena

Despite major advances in understanding the molecular and genetic basis of cancer, metastasis remains the cause of >90% of cancer-related mortality. Understanding metastasis initiation and progression is critical to developing new therapeutic strategies to treat and prevent metastatic disease. Prevailing theories hypothesize that metastases are seeded by rare tumour cells with unique properties, which may function like stem cells in their ability to initiate and propagate metastatic tumours. [...]