Cet article passe en revue les travaux récents sur les anomalies génomiques dans les cancers associés au papillomavirus humain

Genomic Landscape of Human Papillomavirus-Associated Cancers

Rusan, Maria ; Li, Yvonne Y ; Hammerman, Peter S.

Recent next-generation sequencing studies have generated a comprehensive overview of the genomic landscape of Human Papillomavirus (HPV)-associated cancers. This review summarizes these findings to provide insight into the tumor biology of these cancers and potential therapeutic opportunities for HPV-driven malignancies. In addition to the tumorigenic properties of the HPV oncoproteins, integration of HPV DNA into the host genome is suggested to be a driver of the neoplastic process. [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, en favorisant une instabilité génomique, de petites séquences d'ADN organisées en répétitions inversées sont susceptibles d'induire la formation d'une tumeur

Short Inverted Repeats Are Hotspots for Genetic Instability: Relevance to Cancer Genomes

Lu, Steve ; Wang, Guliang ; Bacolla, Albino ; Zhao, Junhua ; Spitser, Scott ; Vasquez, Karen M

Analyses of chromosomal aberrations in human genetic disorders have revealed that inverted repeat sequences (IRs) often co-localize with endogenous chromosomal instability and breakage hotspots. Approximately 80% of all IRs in the human genome are short (<100 bp), yet the mutagenic potential of such short cruciform-forming sequences has not been characterized. Here, we find that short IRs are enriched at translocation breakpoints in human cancer and stimulate the formation of DNA double-strand [...]

A partir de 11 échantillons tumoraux prélevés sur des patients atteints d'un cancer du poumon non à petites cellules présentant des mutations du gène EGFR et ayant développé une résistance thérapeutique, cette étude montre que la perte du gène Rb est présente dans les adénocarcinomes qui se sont transformés en cancer à petites cellules

RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer

Niederst, Matthew J. ; Sequist, Lecia V. ; Poirier, John T. ; Mermel, Craig H. ; Lockerman, Elizabeth L. ; Garcia, Angel R. ; Katayama, Ryohei ; Costa, Carlotta ; Ross, Kenneth N. ; Moran, Teresa ; Howe, Emily ; Fulton, Linnea E. ; Mulvey, Hillary E. ; Bernardo, Lindsay A. ; Mohamoud, Farhiya ; Miyoshi, Norikatsu ; VanderLaan, Paul A. ; Costa, Daniel B. ; Jänne, Pasi A. ; Borger, Darrell R. ; Ramaswamy, Sridhar ; Shioda, Toshi ; Iafrate, Anthony J. ; Getz, Gad ; Rudin, Charles M. ; Mino-Kenudson, Mari ; Engelman, Jeffrey A.

Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived [...]

A partir d'un séquençage du génome entier d'échantillons tumoraux prélevés sur 44 patients atteints d'un rhabdomyosarcome, cette étude identifie un ensemble d'anomalies génomiques par sous-type de la maladie, puis suggère un ordre d'apparition de ces mutations au cours du développement tumoral

Clonality and Evolutionary History of Rhabdomyosarcoma

Chen, Li ; Shern, Jack F. ; Wei, Jun S. ; Yohe, Marielle E. ; Song, Young K. ; Hurd, Laura ; Liao, Hongling ; Catchpoole, Daniel ; Skapek, Stephen X. ; Barr, Frederic G. ; Hawkins, Douglas S. ; Khan, Javed

To infer the subclonality of rhabdomyosarcoma (RMS) and predict the temporal order of genetic events for the tumorigenic process, and to identify novel drivers, we applied a systematic method that takes into account germline and somatic alterations in 44 tumor-normal RMS pairs using deep whole-genome sequencing. Intriguingly, we find that loss of heterozygosity of 11p15.5 and mutations in RAS pathway genes occur early in the evolutionary history of the PAX-fusion-negative-RMS (PFN-RMS) subtype. [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels, en s'adaptant aux restrictions en nutriments à l'intérieur des tumeurs solides, les cellules malignes assurent leur survie

Metabolic pathways promoting cancer cell survival and growth

Boroughs, Lindsey K. ; DeBerardinis, Ralph J.

Activation of oncogenes and loss of tumour suppressors promote metabolic reprogramming in cancer, resulting in enhanced nutrient uptake to supply energetic and biosynthetic pathways. However, nutrient limitations within solid tumours may require that malignant cells exhibit metabolic flexibility to sustain growth and survival. Here, we highlight these adaptive mechanisms and also discuss emerging approaches to probe tumour metabolism in vivo and their potential to expand the metabolic [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, en accélérant la dégradation du suppresseur de tumeurs NKX3.1, la kinase DYRK1B favorise la croissance d'une tumeur de la prostate

The Tumor Suppressor NKX3.1 is Targeted for Degradation by DYRK1B Kinase

Song, Liang-Nian ; Silva, Jose ; Koller, Antonius ; Rosenthal, Andrew ; Chen, Emily I. ; Gelmann, Edward P.

NKX3.1 is a prostate specific homeodomain protein and tumor suppressor whose expression is reduced in the earliest phases of prostatic neoplasia. NKX3.1 expression is not only diminished by genetic loss and methylation, but the protein itself is a target for accelerated degradation caused by inflammation that is common in the aging prostate gland. NKX3.1 degradation is activated by phosphorylation at C-terminal serine residues that mediate ubiquitination and protein turnover. Since NKX3.1 is [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels deux protéines interagissant avec la folliculine, Fnip1 et Fnip2, exercent un rôle de suppresseur de tumeur dans le rein

Folliculin-interacting proteins Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn

Hasumi, Hisashi ; Baba, Masaya ; Hasumi, Yukiko ; Lang, Martin ; Huang, Ying ; Oh, HyoungBin F. ; Matsuo, Masayuki ; Merino, Maria J. ; Yao, Masahiro ; Ito, Yusuke ; Furuya, Mitsuko ; Iribe, Yasuhiro ; Kodama, Tatsuhiko ; Southon, Eileen ; Tessarollo, Lino ; Nagashima, Kunio ; Haines, Diana C. ; Linehan, W. Marston ; Schmidt, Laura S.

Folliculin (FLCN)-interacting proteins 1 and 2 (FNIP1, FNIP2) are homologous binding partners of FLCN, a tumor suppressor for kidney cancer. Recent studies have revealed potential functions for Flcn in kidney; however, kidney-specific functions for Fnip1 and Fnip2 are unknown. Here we demonstrate that Fnip1 and Fnip2 play critical roles in kidney tumor suppression in cooperation with Flcn. We observed no detectable phenotype in Fnip2 knockout mice, whereas Fnip1 deficiency produced phenotypes [...]

Cet article suggère que la dormance des cellules souches cancéreuses est un phénomène de nature épigénétique

The epigenetic/noncoding origin of tumor dormancy

Crea, Francesco ; Nur Saidy, Nur Ridzwan ; Collins, Colin C. ; Wang, Yuzhuo

Cancer stem cells (CSCs) have been implicated as the seeds of treatment resistance and metastasis, which are the most deadly features of a neoplasm. However, an unequivocal definition of the CSC phenotype is still missing. A common feature of normal and aberrant stem cells is their ability to enter a prolonged dormant state. Cancer dormancy is a key mechanism for treatment resistance and metastasis. Here we propose a unified definition of dormancy-competent CSCs (DCCs) as the neoplastic [...]

Menée in vitro et in vivo, cette étude identifie deux peptides et leurs récepteurs cibles impliqués dans la croissance d'un cancer de la prostate résistant à la castration

Selection and identification of ligand peptides targeting a model of castrate-resistant osteogenic prostate cancer and their receptors

Mandelin, Jami ; Cardó-Vila, Marina ; Driessen, Wouter H. P. ; Mathew, Paul ; Navone, Nora M. ; Lin, Sue-Hwa ; Logothetis, Christopher J. ; Rietz, Anna Cecilia ; Dobroff, Andrey S. ; Proneth, Bettina ; Sidman, Richard L. ; Pasqualini, Renata ; Arap, Wadih

We performed combinatorial peptide library screening in vivo on a novel human prostate cancer xenograft that is androgen-independent and induces a robust osteoblastic reaction in bonelike matrix and soft tissue. We found two peptides, PKRGFQD and SNTRVAP, which were enriched in the tumors, targeted the cell surface of androgen-independent prostate cancer cells in vitro, and homed to androgen receptor-null prostate cancer in vivo. Purification of tumor homogenates by affinity chromatography on [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels l'endophiline A2 favorise les processus invasifs et métastatiques dans les cancers du sein triplement négatifs

Endophilin A2 Promotes TNBC Cell Invasion and Tumor Metastasis

Baldassarre, Tomas ; Watt, Kathleen ; Truesdell, Peter ; Meens, Jalna ; Schneider, Mark M. ; SenGupta, Sandip K. ; Craig, Andrew W.

Triple-negative breast cancers (TNBCs) are highly aggressive cancers that lack targeted therapies. However, Epidermal Growth Factor Receptor (EGFR) is frequently activated in a subset of TNBCs and represents a viable clinical target. Since the endocytic adaptor protein Endophilin A2 (SH3GL1/Endo II) has been implicated in EGFR internalization, we investigated Endo II expression and function in human TNBCs. Endo II expression was high in several TNBC cells compared to normal breast epithelial [...]

Menée in vitro, in vivo et à partir de bases de données d'expression de gènes, cette étude met en évidence le rôle joué par la protéine kinase SRPK1 dans le processus métastatique d'un cancer du sein

Tumor cell migration screen identifies SRPK1 as breast cancer metastasis determinant

van Roosmalen, Wies ; Le Dévédec, Sylvia E. ; Golani, Ofra ; Smid, Marcel ; Pulyakhina, Irina ; Timmermans, Annemieke M. ; Look, Maxime P. ; Zi, Di ; Pont, Chantal ; de Graauw, Marjo ; Naffar-Abu-Amara, Suha ; Kirsanova, Catherine ; Rustici, Gabriella ; Hoen, Peter A. C. ‘t ; Martens, John W. M. ; Foekens, John A. ; Geiger, Benjamin ; van de Water, Bob

Tumor cell migration is a key process for cancer cell dissemination and metastasis that is controlled by signal-mediated cytoskeletal and cell matrix adhesion remodeling. Using a phagokinetic track assay with migratory H1299 cells, we performed an siRNA screen of almost 1,500 genes encoding kinases/phosphatases and adhesome- and migration-related proteins to identify genes that affect tumor cell migration speed and persistence. Thirty candidate genes that altered cell migration were validated [...]