A partir d'échantillons tumoraux prélevés sur des patients atteints d'une neurofibromatose de type 1, cette étude identifie des mutations somatiques du gène SUZ12 chez les patients ayant développé des tumeurs malignes des gaines des nerfs périphériques

Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors

Zhang, Ming ; Wang, Yuxuan ; Jones, Sian ; Sausen, Mark ; McMahon, Kevin ; Sharma, Rajni ; Wang, Qing ; Belzberg, Allan J. ; Chaichana, Kaisorn ; Gallia, Gary L. ; Gokaslan, Ziya L. ; Riggins, Greg J. ; Wolinksy, Jean-Paul ; Wood, Laura D. ; Montgomery, Elizabeth A. ; Hruban, Ralph H. ; Kinzler, Kenneth W. ; Papadopoulos, Nickolas ; Vogelstein, Bert ; Bettegowda, Chetan

Neurofibromatosis 1 is a hereditary syndrome characterized by the development of numerous benign neurofibromas, a small subset of which progress to malignant peripheral nerve sheath tumors (MPNSTs). To better understand the genetic basis for MPNSTs, we performed genome-wide or targeted sequencing on 50 cases. Sixteen MPNSTs but none of the neurofibromas tested were found to have somatic mutations in SUZ12, implicating it as having a central role in malignant transformation.

Menée sur des échantillons tumoraux prélevés sur 39 patients atteints d'un carcinome épidermoïde cutané, cette étude identifie un ensemble de mutations dans des gènes suppresseurs de tumeurs

Mutational landscape of aggressive cutaneous squamous cell carcinoma

Pickering, Curtis R ; Zhou, Jane H ; Lee, J. Jack ; Drummond, Jennifer A. ; Peng, S Andrew ; Saade, Rami E ; Tsai, Kenneth Y ; Curry, Jonathan ; Tetzlaff, Michael T ; Lai, Stephen Y. ; Yu, Jun ; Muzny, Donna M ; Doddapaneni, Harshavardhan ; Shinbrot, Eve ; Covington, Kyle R ; Zhang, Jianhua ; Seth, Sahil ; Caulin, Carlos ; Clayman, Gary L ; El-Naggar, Adel K. ; Gibbs, Richard A ; Weber, Randal S ; Myers, Jeffrey N ; Wheeler, David A ; Frederick, Mitchell J

Purpose: Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC. Experimental Design: Whole exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their [...]

Mené sur des échantillons tumoraux prélevés sur 247 patients atteints d'un adénocarcinome du poumon, cette étude met notamment en évidence une association entre la présence d'anomalies génomiques dans la voie de signalisation RB et un pronostic défavorable pour les patients atteints d'un cancer de stade précoce

Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma

Choi, Seongmin ; Kim, Hyeong Ryul ; Sung, Chang Ohk ; Kim, Jongkyu ; Kim, Sukjun ; Ahn, Sung-Min ; Choi, Chang-Min ; Chun, Sung-Min ; Choi, Eun Kyung ; Kim, Sang-We ; Kim, Yong-Hee ; Lee, Ji-Young ; Song, Joon Seon ; Kim, Deokhoon ; Haq, Farhan ; Lee, Sun Young ; Lee, Jong-Eun ; Jung, Wang-rim ; Jang, Hye Yoon ; Yang, Eunho ; Lee, Charles ; Yu, Eunsil ; Kong, Gu ; Baek, Daehyun ; Jang, Se J

Purpose: To better understand the complete genomic architecture of lung adenocarcinoma (LA). Experimental Design: We used array experiments to determine copy number variations and sequenced the complete exomes of the 247 LA tumor samples along with matched normal cells obtained from the same patients. Fully annotated clinical data were also available, providing an unprecedented opportunity to assess the impact of genomic alterations on clinical outcomes. Results: We discovered that genomic [...]

Menée initialement sur des échantillons tumoraux prélevés sur 576 patients atteints d'un adénocarcinome du poumon, puis à l'aide de techniques de séquençage à haut débit sur 24 échantillons tumoraux, cette étude met en évidence une fusion des gènes FGFR3 et TACC3 chez un petit nombre de patients, suggérant ainsi de mener des essais cliniques à l'aide d'inhibiteurs de FGFR dans cette population

Identification of recurrent FGFR3-TACC3 fusion oncogenes from lung adenocarcinoma

Capelletti, Marzia ; Dodge, Michael E ; Ercan, Dalia ; Hammerman, Peter S. ; Park, Seung-il ; Kim, Jhingook ; Sasaki, Hidefumi ; Jablons, David M ; Lipson, Doron ; Young, Lauren ; Stephens, Philip J ; Miller, Vincent A ; Lindeman, Neal ; Munir, Kiara J ; Richards, William G. ; Jänne, Pasi A.

Purpose: Targetable oncogenic alterations are detected more commonly in patients with non-small cell lung cancer (NSCLC) who never smoked cigarettes. For such patients, specific kinase inhibitors have emerged as effective clinical treatments. However, the currently known oncogenic alterations do not account for all never smokers who develop NSCLC. We sought to identify additional oncogenic alterations from patients with NSCLC in order to define additional treatment options. Experimental Design: [...]

Cet article passe en revue les travaux récents ayant mis en évidence des anomalies dans la séquence des gènes AXIN1 et AXIN2 chez des patients atteints d'un cancer gastrointestinal

AXIN1 and AXIN2 variants in gastrointestinal cancers

Mazzoni, Serina M. ; Fearon, Eric R.

Mutations in the APC (adenomatous polyposis coli) gene, which encodes a multi-functional protein with a well-defined role in the canonical Wnt pathway, underlie familial adenomatous polypsosis, a rare, inherited form of colorectal cancer (CRC) and contribute to the majority of sporadic CRCs. However, not all sporadic and familial CRCs can be explained by mutations in APC or other genes with well-established roles in CRC. The AXIN1 and AXIN2 proteins function in the canonical Wnt pathway, and [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels une ubiquitine ligase, SCFFbw7, exerce une fonction de suppresseur de tumeurs

Tumor Suppression by the Fbw7 Ubiquitin Ligase: Mechanisms and Opportunities

Davis, Ryan J ; Welcker, Markus ; Clurman, Bruce E

Tumor suppressors with widespread impact on carcinogenesis control broad spectra of oncogenic pathways. Protein degradation is an emerging mechanism by which tumor suppressors regulate a diversity of pathways and is exemplified by the SCFFbw7 ubiquitin ligase. Rapidly accumulating data indicate that SCFFbw7 regulates a network of crucial oncoproteins. Importantly, the FBXW7 gene, which encodes Fbw7, is one of the most frequently mutated genes in human cancers. These studies are yielding [...]

Menée à l'aide d'un modèle murin transgénique, cette étude met en évidence des mécanismes par lesquels la surexpression de l'ubiquitine ligase PELI1 favorise le développement d'un lymphome diffus à grandes cellules B

Pellino 1 promotes lymphomagenesis by deregulating BCL6 polyubiquitination

Park, Hye-Young ; Go, Heounjeong ; Song, Ha Rim ; Kim, Suhyeon ; Ha, Geun-Hyoung ; Jeon, Yoon-Kyung ; Kim, Ji-Eun ; Lee, Ho ; Cho, Hyeseong ; Kang, Ho Chul ; Chung, Hee-Young ; Kim, Chul-Woo ; Chung, Doo Hyun ; Lee, Chang-Woo

The signal-responsive E3 ubiquitin ligase pellino 1 (PELI1) regulates TLR and T cell receptor (TCR) signaling and contributes to the maintenance of autoimmunity; however, little is known about the consequence of mutations that result in upregulation of PELI1. Here, we developed transgenic mice that constitutively express human PELI1 and determined that these mice have a shorter lifespan due to tumor formation. Constitutive expression of PELI1 resulted in ligand-independent hyperactivation of B [...]

Menée in vitro et in vivo, cette étude française met en évidence des mécanismes par lesquels, via l'induction d'une autophagie, le récepteur ITPR1 favorise la survie des cellules cancéreuses d'un carcinome rénal à cellules claires

ITPR1 protects renal cancer cells against natural killer cells by inducing autophagy

Messai, Yosra ; Noman, Muhammad Zaeem ; Hasmim, Meriem ; Janji, Bassam ; Tittrelli, Andres ; Boutet, Marie ; Baud, Veronique ; Viry, Elodie ; Billot, Katy ; Nanbakhsh, Arash ; Ben Safta, Thouraya ; Richon, Catherine ; Ferlicot, Sophie ; Donnadieu, Emmanuel ; Couve, Sophie ; Gardie, Betty ; Orlanducci, Florence ; Albiges, Laurence ; Thiery, Jerome ; Olive, Daniel ; Escudier, Bernard ; Chouaib, Salem

Clear cell renal cell carcinomas (RCC) frequently display inactivation of von Hippel-Lindau (VHL) gene leading to increased level of hypoxia inducible factors (HIFs). In this study, we investigated the potential role of HIF-2α in regulating RCC susceptibility to natural killer (NK) cell-mediated killing. We demonstrated that the RCC cell line 786-0 with mutated VHL was resistant to NK-mediated lysis as compared to the VHL-corrected cell line (WT7). This resistance was found to require HIF-2α [...]

Cette étude française présente les caractéristiques d'un modèle murin transgénique qui, via l'activation conditionnelle du récepteur Notch1 et la délétion du gène p53 dans l'épithélium digestif, permet d'étudier le processus métastatique d'un cancer colorectal

Concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis in mouse gut

Chanrion, Maia ; Kuperstein, Inna ; Barrière, Cédric ; El Marjou, Fatima ; Cohen, David ; Vignjevic, Danijela ; Stimmer, Lev ; Paul-Gilloteaux, Perrine ; Bièche, Ivan ; Tavares, Silvina Dos Reis ; Boccia, Giuseppe-Fulvio ; Cacheux, Wulfran ; Meseure, Didier ; Fre, Silvia ; Martignetti, Loredana ; Legoix-Né, Patricia ; Girard, Elodie ; Fetler, Luc ; Barillot, Emmanuel ; Louvard, Daniel ; Zinovyev, Andreï ; Robine, Sylvie

Epithelial-to-mesenchymal transition-like (EMT-like) is a critical process allowing initiation of metastases during tumour progression. Here, to investigate its role in intestinal cancer, we combine computational network-based and experimental approaches to create a mouse model with high metastatic potential. Construction and analysis of this network map depicting molecular mechanisms of EMT regulation based on the literature suggests that Notch activation and p53 deletion have a synergistic [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par l'acide lysophosphatidique dans le processus migratoire des cellules de mélanome

Melanoma Cells Break Down LPA to Establish Local Gradients That Drive Chemotactic Dispersal

Muinonen-Martin, Andrew J. ; Susanto, Olivia ; Zhang, Qifeng ; Smethurst, Elizabeth ; Faller, William J. ; Veltman, Douwe M. ; Kalna, Gabriela ; Lindsay, Colin ; Bennett, Dorothy C. ; Sansom, Owen J. ; Herd, Robert ; Jones, Robert ; Machesky, Laura M. ; Wakelam, Michael J. O. ; Knecht, David A. ; Insall, Robert H.

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that [...]

Cet article passe en revue les travaux récents sur les interactions entre les cellules souches mésenchymateuses et les cellules d'une tumeur de l'ovaire

Role of mesenchymal cells in the natural history of ovarian cancer: a review

Touboul, Cyril ; Vidal, Fabien ; Pasquier, Jennifer ; Lis, Raphael ; Rafii, Arash

Background : Ovarian cancer is the deadliest gynaecologic malignancy. Despite progresses in chemotherapy and ultra-radical surgeries, this locally metastatic disease presents a high rate of local recurrence advocating for the role of a peritoneal niche. For several years, it was believed that tumor initiation, progression and metastasis were merely due to the changes in the neoplastic cell population and the adjacent non-neoplastic tissues were regarded as bystanders. The importance of the [...]

Menée à l'aide d'un modèle murin transgénique, cette étude met en évidence des mécanismes par lesquels un traitement anti-androgénique induit une surexpression de la protéine NCoA2 et, via l'activation de la signalisation PI3K, favorise le processus métastatique d'un cancer de la prostate

Androgen deprivation–induced NCoA2 promotes metastatic and castration-resistant prostate cancer

Qin, Jun ; Lee, Hui-Ju ; Wu, San-Pin ; Lin, Shih-Chieh ; Lanz, Rainer B. ; Creighton, Chad J. ; DeMayo, Francesco J. ; Tsai, Sophia Y. ; Tsai, Ming-Jer

A major clinical hurdle for the management of advanced prostate cancer (PCa) in patients is the resistance of tumors to androgen deprivation therapy (ADT) and their subsequent development into castration-resistant prostate cancer (CRPC). While recent studies have identified potential pathways involved in CRPC development, the drivers of CRPC remain largely undefined. Here we determined that nuclear receptor coactivator 2 (NCoA2, also known as SRC-2), which is frequently amplified or [...]

Menée sur des lignées cellulaires de cancer de la prostate et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par le facteur de transcription RUNX1 dans la prolifération des cellules souches mésenchymateuses et la différenciation des myofibroblastes

RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation

Kim, Woosook ; Barron, David A. ; San Martin, Rebeca ; Chan, Keith S. ; Tran, Linda L. ; Yang, Feng ; Ressler, Steven J. ; Rowley, David R.

Myofibroblasts are a key cell type in wound repair, cardiovascular disease, and fibrosis and in the tumor-promoting microenvironment. The high accumulation of myofibroblasts in reactive stroma is predictive of the rate of cancer progression in many different tumors, yet the cell types of origin and the mechanisms that regulate proliferation and differentiation are unknown. We report here, for the first time to our knowledge, the characterization of normal human prostate-derived mesenchymal stem [...]

Menée sur des lignées cellulaires de cancer colorectal, cette étude met en évidence des mécanismes par lesquels une enzyme, la pyruvate kinase M2, favorise une transition épithélio-mésenchymateuse

Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial–mesenchymal transition

Hamabe, Atsushi ; Konno, Masamitsu ; Tanuma, Nobuhiro ; Shima, Hiroshi ; Tsunekuni, Kenta ; Kawamoto, Koichi ; Nishida, Naohiro ; Koseki, Jun ; Mimori, Koshi ; Gotoh, Noriko ; Yamamoto, Hirofumi ; Doki, Yuichiro ; Mori, Masaki ; Ishii, Hideshi

Pyruvate kinase M2 (PKM2) is an alternatively spliced variant of the pyruvate kinase gene that is preferentially expressed during embryonic development and in cancer cells. PKM2 alters the final rate-limiting step of glycolysis, resulting in the cancer-specific Warburg effect (also referred to as aerobic glycolysis). Although previous reports suggest that PKM2 functions in nonmetabolic transcriptional regulation, its significance in cancer biology remains elusive. Here we report that [...]

Menée in vitro et sur plusieurs cohortes de patientes atteintes d'un cancer du sein, cette étude évalue l'association entre l'expression de micro-ARNs des cellules souches et le processus métastatique

Pluripotent Stem Cell miRNAs and Metastasis in Invasive Breast Cancer

Volinia, Stefano ; Nuovo, Gerard ; Drusco, Alessandra ; Costinean, Stefan ; Abujarour, Ramzey ; Desponts, Caroline ; Garofalo, Michela ; Baffa, Raffaele ; Aeqilan, Rami ; Maharry, Kati ; Garzon, Maria Elena Sana Ramiro ; Di Leva, Gianpiero ; Gasparini, Pierluigi ; Dama, Paola ; Marchesini, Jlenia ; Galasso, Marco ; Manfrini, Marco ; Zerbinati, Carlotta ; Corrà, Fabio ; Wise, Timothy ; Wojcik, Sylwia E. ; Previati, Maurizio ; Pichiorri, Flavia ; Zanesi, Nicola ; Alder, Hansjuerg ; Palatini, Jeff ; Huebner, Kay F. ; Shapiro, Charles L. ; Negrini, Massimo ; Vecchione, Andrea ; Rosenberg, Anne L. ; Croce, Carlo M.

Background : The purpose of this study is to determine whether microRNA for pluripotent stem cells are also expressed in breast cancer and are associated with metastasis and outcome. Methods : We studied global microRNA profiles during differentiation of human embryonic stem cells (n =26) and in breast cancer patients (n = 33) and human cell lines (n = 35). Using in situ hybridization, we then investigated MIR302 expression in 318 untreated breast cancer patients (test cohort, n = 22 and [...]

Menée à l'aide de modèles murins et d'échantillons tumoraux prélevés sur des patients atteints d'un cancer de la vessie, cette étude met en évidence le rôle joué par la signalisation Hedghog dans la progression tumorale

Hedgehog Signaling Restrains Bladder Cancer Progression by Eliciting Stromal Production of Urothelial Differentiation Factors

Shin, Kunyoo ; Lim, Agnes ; Zhao, Chen ; Sahoo, Debashis ; Pan, Ying ; Spiekerkoetter, Edda ; Liao, Joseph C ; Beachy, Philip A

Hedgehog (Hh) pathway inhibitors are clinically effective in treatment of basal cell carcinoma and medulloblastoma, but fail therapeutically or accelerate progression in treatment of endodermally derived colon and pancreatic cancers. In bladder, another organ of endodermal origin, we find that despite its initial presence in the cancer cell of origin Sonic hedgehog (Shh) expression is invariably lost during progression to invasive urothelial carcinoma. Genetic blockade of stromal response to [...]

Cet article présente les caractéristiques de modèles murins, développés à l'aide de xénogreffes dérivées de patientes, pour l'étude des différents types de cancer de l'ovaire

Patient-derived ovarian tumor xenografts recapitulate human clinicopathology and genetic alterations

Ricci, Francesca ; Bizzaro, Francesca ; Cesca, Marta ; Guffanti, Federica ; Ganzinelli, Monica ; Decio, Alessandra ; Ghilardi, Carmen ; Perego, Patrizia ; Fruscio, Robert ; Buda, Alessandro ; Milani, Rodolfo ; Ostano, Paola ; Chiorino, Giovanna ; Bani, Maria Rosa ; Damia, Giovanna ; Giavazzi, Raffaella

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy. On the basis of its histopathology and molecular-genomic changes ovarian cancer has been divided into subtypes, each with distinct biology and outcome. The aim of this study was to develop a panel of patient-derived EOC-xenografts that recapitulate the molecular and biological heterogeneity of human ovarian cancer. Thirty-four EOC-xenografts were successfully established, either subcutaneously or intraperitoneally, in [...]