Menée sur 131 échantillons tumoraux prélevés sur des patients chinois atteints d'un cancer de l'estomac, cette étude à l'échelle du génome entier identifie notamment une amplification des gènes PAK1 et KRAS et suggère l'intérêt de développer des thérapies ciblées sur ces anomalies

Whole genome gene copy number profiling of gastric cancer identifies PAK1 and KRAS gene amplification as therapy targets

Qian, Ziliang ; Zhu, Guanshan ; Tang, Lili ; Wang, Mei ; Zhang, Lianhai ; Fu, Jiangang ; Huang, Chunlei ; Fan, Shuqiong ; Sun, Yun ; Lv, Jing ; Dong, Hua ; Gao, Beirong ; Su, Xinying ; Yu, Dehua ; Zang, Jie ; Zhang, Xiaolin ; Ji, Jiafu ; Ji, Qunsheng

Gastric cancer is the second leading cause of death from cancer worldwide, with an approximately 20% 5-year survival rate. To identify molecular subtypes associated with the clinical prognosis, in addition to genetic aberrations for potential targeted therapeutics, we conducted a comprehensive whole-genome analysis of 131 Chinese gastric cancer tissue specimens using whole-genome array comparative genomic hybridization. The analyses revealed gene focal amplifications, including CTSB, PRKCI, [...]

Menée sur 168 patients atteints d'une leucémie lymphocytaire chronique, cette étude identifie, dans les progéniteurs hématopoïétiques multipotents, des mutations acquises de plusieurs gènes

Acquired initiating mutations in early hematopoietic cells of CLL patients

Damm, Frederik ; Mylonas, Elena ; Cosson, Adrien ; Yoshida, Kenichi ; Della Valle, Veronique ; Mouly, Enguerran ; Diop, M'boyba ; Scourzic, Laurianne ; Shiraishi, Yuichi ; Chiba, Kenichi ; Tanaka, Hiroko ; Miyano, Satoru ; Kikushige, Yoshikane ; Davi, Frederick ; Lambert, Jérôme ; Gautheret, Daniel ; Merle-Beral, Helene ; Sutton, Laurent ; Dessen, Philippe ; Solary, Eric ; Akashi, Koichi ; Vainchenker, William ; Mercher, Thomas ; Droin, Nathalie ; Ogawa, Seishi ; Nguyen-Khac, Florence ; Bernard, Olivier A

Appropriate cancer care requires thorough understanding of the natural history of the disease, including the cell of origin, the clonal organization of the proliferation and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from chronic lymphocytic leukemia (CLL) patients, we established the presence of acquired mutations in multipotent hematopoietic progenitors of CLL patients. Mutations affected known lymphoid oncogenes including BRAF, NOTCH1 [...]

Menée sur 34 patients atteints d'une leucémie myéloïde aiguë avec trisomie 13, cette étude allemande identifie la présence fréquente de mutations d'un petit groupe de gènes

Isolated trisomy 13 defines a genetically homogenous AML subgroup with high frequency of mutations in spliceosome genes and poor prognosis

Herold, Tobias ; Metzeler, Klaus H. ; Vosberg, Sebastian ; Hartmann, Luise ; Röllig, Christoph ; Stölzel, Friedrich ; Schneider, Stephanie ; Hubmann, Max ; Zellmeier, Evelyn ; Ksienzyk, Bianka ; Jurinovic, Vindi ; Pasalic, Zlatana ; Kakadia, Purvi M. ; Dufour, Annika ; Graf, Alexander ; Krebs, Stefan ; Blum, Helmut ; Sauerland, Maria Cristina ; Büchner, Thomas ; Berdel, Wolfgang E. ; Woermann, Bernhard J. ; Bornhäuser, Martin ; Ehninger, Gerhard ; Mansmann, Ulrich ; Hiddemann, Wolfgang ; Bohlander, Stefan K. ; Spiekermann, Karsten ; Greif, Philipp A.

Isolated trisomy 13 (AML+13) is a rare chromosomal abnormality in acute myeloid leukemia (AML), and its prognostic relevance is poorly characterized. We analyzed the clinical course of 34 AML+13 patients enrolled in the German AMLCG-1999 and SAL trials and studied their biological characteristics by exome sequencing, targeted sequencing of candidate genes and gene expression profiling. Relapse-free (RFS) and overall survival (OS) of AML+13 patients were inferior compared to other ELN [...]

Menée sur 430 cellules issues d'échantillons tumoraux prélevés sur des patients atteints d'un glioblastome, cette étude de séquençage de l'ARN met en évidence une hétérogénéité intratumorale de plusieurs programmes de transcription impliqués dans la signalisation oncogénique

Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma

Patel, Anoop P. ; Tirosh, Itay ; Trombetta, John J. ; Shalek, Alex K. ; Gillespie, Shawn M. ; Wakimoto, Hiroaki ; Cahill, Daniel P. ; Nahed, Brian V. ; Curry, William T. ; Martuza, Robert L. ; Louis, David N. ; Rozenblatt-Rosen, Orit ; Suvà, Mario L. ; Regev, Aviv ; Bernstein, Bradley E.

Human cancers are complex ecosystems composed of cells with distinct phenotypes, genotypes, and epigenetic states, but current models do not adequately reflect tumor composition in patients. We used single-cell RNA sequencing (RNA-seq) to profile 430 cells from five primary glioblastomas, which we found to be inherently variable in their expression of diverse transcriptional programs related to oncogenic signaling, proliferation, complement/immune response, and hypoxia. We also observed a [...]

Cet article passe en revue les travaux récents sur les mécanismes épigénétiques à l'oeuvre dans les cellules souches cancéreuses

Epigenetic mechanisms of tumorigenicity manifesting in stem cells

Tung, P. Y. ; Knoepfler, P. S.

One of the biggest roadblocks to using stem cells as the basis for regenerative medicine therapies is the tumorigenicity of stem cells. Unfortunately, the unique abilities of stem cells to self-renew and differentiate into a variety of cell types are also mechanistically linked to their tumorigenic behaviors. Understanding the mechanisms underlying the close relationship between stem cells and cancer cells has therefore become a primary goal in the field. In addition, knowledge gained from [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, de façon précoce au cours de la formation d'une tumeur du poumon, la protéine Myc supprime la sénescence induite par l'expression du gène BRAFV600E

MYC Synergizes with Activated BRAFV600E in Mouse Lung Tumor Development by Suppressing Senescence

Tabor, Vedrana ; Bocci, Matteo ; Alikhani, Nyosha ; Kuiper, Raoul ; Larsson, Lars-Gunnar

The activated RAS/RAF cascade plays a crucial role in lung cancer, but is also known to induce cellular senescence - a major barrier imposed to tumor cells early in tumorigenesis. MYC is a key factor in suppression of RAS/BRAFV600E-induced senescence in vitro. However, it is still unclear whether Myc has the same role during tumor development in vivo. Using a conditional, compound knock-in model of Cre-activated BRAFV600E and tamoxifen (TAM)-regulatable MycER, we show that TAM-induced [...]

Menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels, en induisant l'expression de gènes codant des sous-unités d'intégrines, la protéine LMTK3 favorise le processus métastatique d'un cancer du sein

The Kinase LMTK3 Promotes Invasion in Breast Cancer Through GRB2-Mediated Induction of Integrin {beta}1

Xu, Yichen ; Zhang, Hua ; Lit, Lei C. ; Grothey, Arnhild ; Athanasiadou, Maria ; Kiritsi, Marianna ; Lombardo, Ylenia ; Frampton, Adam E. ; Green, Andrew R. ; Ellis, Ian O. ; Ali, Simak ; Lenz, Heinz-Josef ; Thanou, Maya ; Stebbing, Justin ; Giamas, Georgios

Lemur tyrosine kinase 3 (LMTK3) is associated with cell proliferation and endocrine resistance in breast cancer. We found that, in cultured breast cancer cell lines, LMTK3 promotes the development of a metastatic phenotype by inducing the expression of genes encoding integrin subunits. Invasive behavior in various breast cancer cell lines positively correlated with the abundance of LMTK3. Overexpression of LMTK3 in a breast cancer cell line with low endogenous LMTK3 abundance promoted actin [...]

Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence des mécanismes par lesquels, dans des conditions d'hypoxie, les cellules de cancer du sein déversent des microvésicules dans la circulation sanguine et, ainsi, favorisent la formation de métastases

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis

Wang, Ting ; Gilkes, Daniele M. ; Takano, Naoharu ; Xiang, Lisha ; Luo, Weibo ; Bishop, Corey J. ; Chaturvedi, Pallavi ; Green, Jordan J. ; Semenza, Gregg L.

Extracellular vesicles such as exosomes and microvesicles (MVs) are shed by cancer cells, are detected in the plasma of cancer patients, and promote cancer progression, but the molecular mechanisms regulating their production are not well understood. Intratumoral hypoxia is common in advanced breast cancers and is associated with an increased risk of metastasis and patient mortality that is mediated in part by the activation of hypoxia-inducible factors (HIFs). In this paper, we report that [...]

Menée sur 26 paires d'échantillons de tumeur primitive et de tissu ganglionnaire métastatique prélevés sur des patients atteints d'un carcinome épidermoïde de la tête et du cou, puis in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels l'expression du gène TMEM16A agit dans le processus métastatique

To "Grow" or "Go": TMEM16A Expression as a Switch between Tumor Growth and Metastasis in SCCHN

Shiwarski, Daniel J. ; Shao, Chunbo ; Bill, Anke ; Kim, Jean ; Xiao, Dong ; Bertrand, Carol ; Seethala, Raja R ; Sano, Daisuke ; Myers, Jeffrey N. ; Ha, Patrick K ; Grandis, Jennifer R ; Gaither, L. Alex ; Puthenveedu, Manojkumar A. ; Duvvuri, Umamaheswar

Purpose: Tumor metastasis is the leading cause of death in cancer patients. However, the mechanisms that underlie metastatic progression remain unclear. We examined TMEM16A (ANO1) expression as a key factor shifting tumors between growth and metastasis. Experimental Design: We evaluated 26 pairs of primary and metastatic lymph node tissue from patients with squamous cell carcinoma of the head and neck (SCCHN) for differential expression of TMEM16A. Additionally, we identified mechanisms by [...]

Cet article passe en revue les travaux récents sur le rôle des cellules souches de l'intestin dans le développement d'une tumeur colorectale

Stem cell dynamics in homeostasis and cancer of the intestine

Vermeulen, Louis ; Snippert, Hugo J.

Intestinal stem cells (ISCs) and colorectal cancer (CRC) biology are tightly linked in many aspects. It is generally thought that ISCs are the cells of origin for a large proportion of CRCs and crucial ISC-associated signalling pathways are often affected in CRCs. Moreover, CRCs are thought to retain a cellular hierarchy that is reminiscent of the intestinal epithelium. Recent studies offer quantitative insights into the dynamics of ISC behaviour that govern homeostasis and thereby provide the [...]

Menée in vitro, cette étude met en évidence le rôle joué par la raideur mécanique et la composition de la matrice extracellulaire dans l'induction d'un phénotype malin de cellules de l'épithélium mammaire

Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium

Chaudhuri, Ovijit ; Koshy, Sandeep T. ; Branco da Cunha, Cristiana ; Shin, Jae-Won ; Verbeke, Catia S. ; Allison, Kimberly H. ; Mooney, David J.

In vitro models of normal mammary epithelium have correlated increased extracellular matrix (ECM) stiffness with malignant phenotypes. However, the role of increased stiffness in this transformation remains unclear because of difficulties in controlling ECM stiffness, composition and architecture independently. Here we demonstrate that interpenetrating networks of reconstituted basement membrane matrix and alginate can be used to modulate ECM stiffness independently of composition and [...]