Menée à l'aide de modèles murins de leucémie aiguë promyélocytaire, cette étude montre que l'histone désacétylase Hdac1 joue un rôle de suppresseur de tumeurs dans les phases précoces de la maladie et un rôle oncogénique lorsque la maladie est établie

A dual role for Hdac1: oncosuppressor in tumorigenesis, oncogene in tumor maintenance

Santoro, Fabio ; Botrugno, Oronza A. ; Dal Zuffo, Roberto ; Pallavicini, Isabella ; Matthews, Geoffrey M. ; Cluse, Leonie ; Barozzi, Iros ; Senese, Silvia ; Fornasari, Lorenzo ; Moretti, Simona ; Altucci, Lucia ; Pelicci, Pier Giuseppe ; Chiocca, Susanna ; Johnstone, Ricky W. ; Minucci, Saverio

Aberrant recruitment of histone deacetylases (HDACs) by the oncogenic fusion protein PML-RAR is involved in the pathogenesis of acute promyelocytic leukemia (APL). PML-RAR, however, is not sufficient to induce disease in mice, but requires additional oncogenic lesions during the pre-leukemic phase. Here, we show that knock-down of Hdac1 and Hdac2 dramatically accelerates leukemogenesis in transgenic pre-leukemic mice. These events are not restricted to APL, since lymphomagenesis driven by [...]

A partir d'une étude d'association génétique en population, cette étude in vitro suggère que le micro-ARN 202 joue un rôle de suppresseur de tumeurs dans les lymphomes folliculaires

Targetome Profiling, Pathway Analysis and Genetic Association Study Implicate miR-202 in Lymphomagenesis

Hoffman, Aaron E. ; Liu, Ran ; Fu, Alan ; Zheng, Tongzhang ; Slack, Frank ; Zhu, Yong

Background: miRNAs have been implicated in numerous tumorigenic pathways, and previous studies have associated miR-202 dysregulation with various cancer types, including follicular lymphoma. Methods: The miR-202 targetome was identified by ribonucleoprotein immunoprecipitation-microarray (RIP-Chip), and functional interactions among identified targets were investigated using the Ingenuity Pathway Analysis tool. We also conducted a population-based genetic association study of a polymorphism [...]

Menée in vitro et à l'aide de xénogreffes, cette étude met en évidence le rôle joué par la surexpression de la protéine PARI dans la croissance d'un adénocarcinome canalaire du pancréas

PARI overexpression promotes genomic instability and pancreatic tumorigenesis

O'Connor, Kevin W ; Dejsuphong, Donniphat ; Park, Eunmi ; Nicolae, Claudia M. ; Kimmelman, Alec C. ; D'Andrea, Alan D. ; Moldovan, George-Lucian

Treatment options for patients with pancreatic ductal adenocarcinoma remain limited. Therapeutic targets of interest include mutated molecules that predispose to pancreatic cancer such as KRAS and TP53. Here we show that an element of the homologous recombination pathway of DNA repair, the PARP-binding protein C12orf48/PARI (PARPBP), is overexpressed specifically in pancreatic cancer cells where it is an appealing candidate for targeted therapy. PARI upregulation in pancreatic cancer cells or [...]

Menée ex vivo et in vivo, cette étude met en évidence une plasticité des cellules basales de l'épithélium prostatique et suggère que différents types cellulaires sont à l'origine des différents sous-types moléculaires du cancer de la prostate

Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity

Wang, Zhu A. ; Mitrofanova, Antonina ; Bergren, Sarah K. ; Abate-Shen, Cory ; Cardiff, Robert D. ; Califano, Andrea ; Shen, Michael M.

A key issue in cancer biology is whether oncogenic transformation of different cell types of origin within an adult tissue gives rise to distinct tumour subtypes that differ in their prognosis and/or treatment response. We now show that initiation of prostate tumours in basal or luminal epithelial cells in mouse models results in tumours with distinct molecular signatures that are predictive of human patient outcomes. Furthermore, our analysis of untransformed basal cells reveals an unexpected [...]

Cet article passe en revue les travaux récents suggérant que, dans la cancérogenèse, les mécanismes de reprogrammation métabolique et d'échappement immunitaire sont intimement liés

The Emerging "Hallmarks" of Metabolic Reprogramming and Immune Evasion: Distinct or Linked?

Kareva, Irina ; Hahnfeldt, Philip

The role of the immune system in tumor elimination has been shown to be increasingly ambiguous, as many tumors not only escape recognition by the adaptive immune response but sometimes even prime the immune cells to promote tumor growth. This effect is achieved through many mechanisms, which include both direct interference with the cells of the adaptive immune response and indirect immunosuppression achieved through modification of the tumor microenvironment. We propose that through [...]

Menée in vitro et in vivo, cette étude met notamment en évidence le rôle joué par le proto-oncogène c-Myc dans la formation de cellules souches de cancer du pancréas à fort pouvoir métastatique

Direct reprogramming by oncogenic Ras and Myc

Ischenko, Irene ; Zhi, Jizu ; Moll, Ute M. ; Nemajerova, Alice ; Petrenko, Oleksi

Genetically or epigenetically defined reprogramming is a hallmark of cancer cells. However, a causal association between genome reprogramming and cancer has not yet been conclusively established. In particular, little is known about the mechanisms that underlie metastasis of cancer, and even less is known about the identity of metastasizing cancer cells. In this study, we used a model of conditional expression of oncogenic KrasG12D allele in primary mouse cells to show that reprogramming and [...]

Menée à l'aide de modèles murins, cette étude met en évidence un mécanisme d'interaction entre les gènes Sprouty2, PTEN et PP2A pour réguler la progression d'un cancer de la prostate

Sprouty2, PTEN, and PP2A interact to regulate prostate cancer progression

Patel, Rachana ; Gao, Meiling ; Ahmad, Imran ; Fleming, Janis ; Singh, Lukram B. ; Rai, Taranjit Singh ; McKie, Arthur B. ; Seywright, Morag ; Barnetson, Robert J. ; Edwards, Joanne ; Sansom, Owen J. ; Leung, Hing Y.

Concurrent activation of RAS/ERK and PI3K/AKT pathways is implicated in prostate cancer progression. The negative regulators of these pathways, including sprouty2 (SPRY2), protein phosphatase 2A (PP2A), and phosphatase and tensin homolog (PTEN), are commonly inactivated in prostate cancer. The molecular basis of cooperation between these genetic alterations is unknown. Here, we show that SPRY2 deficiency alone triggers activation of AKT and ERK, but this is insufficient to drive tumorigenesis. [...]

Menée à l'aide de modèles murins, cette étude met en évidence le rôle joué par le récepteur de chimiokines CRXC4 et son ligand CXCL12 dans les tumeurs malignes des gaines des nerfs périphériques survenant chez un sous-groupe de patients atteints d'une neurofibromatose de type 1

CXCR4/CXCL12 Mediate Autocrine Cell- Cycle Progression in NF1-Associated Malignant Peripheral Nerve Sheath Tumors

Mo, Wei ; Chen, Jian ; Patel, Amish ; Zhang, Liang ; Chau, Vincent ; Li, Yanjiao ; Cho, Woosung ; Lim, Kyun ; Xu, Jing ; Lazar, Alexander J ; Creighton, Chad J ; Bolshakov, Svetlana ; McKay, Renée M ; Lev, Dina ; Le, Lu Q ; Parada, Luis F

Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with neurofibromatosis type 1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G-protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in nontransformed precursor cells. [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en activant les signalisations EGFR et CAMK, la protéine ANO1 favorise la progression d'une tumeur du sein

Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling

Britschgi, Adrian ; Bill, Anke ; Brinkhaus, Heike ; Rothwell, Christopher ; Clay, Ieuan ; Duss, Stephan ; Rebhan, Michael ; Raman, Pichai ; Guy, Chantale T. ; Wetzel, Kristie ; George, Elizabeth ; Popa, M. Oana ; Lilley, Sarah ; Choudhury, Hedaythul ; Gosling, Martin ; Wang, Louis ; Fitzgerald, Stephanie ; Borawski, Jason ; Baffoe, Jonathan ; Labow, Mark ; Gaither, L. Alex ; Bentires-Alj, Mohamed

The calcium-activated chloride channel anoctamin 1 (ANO1) is located within the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human cancer, but its functional role in tumorigenesis has remained unclear. The 11q13 region is amplified in ∼15% of breast cancers. Whether ANO1 is amplified in breast tumors, the extent to which gene amplification contributes to ANO1 overexpression, and whether overexpression of ANO1 is important for tumor maintenance have remained [...]

Cet article passe en revue les perspectives offertes par les concepts de la biologie des systèmes pour analyser les réseaux génétiques et épigénétiques à l'œuvre dans les tissus tumoraux

Complexity in cancer biology: is systems biology the answer?

Koutsogiannouli, Evangelia ; Papavassiliou, Athanasios G. ; Papanikolaou, Nikolaos A.

Complex phenotypes emerge from the interactions of thousands of macromolecules that are organized in multimolecular complexes and interacting functional modules. In turn, modules form functional networks in health and disease. Omics approaches collect data on changes for all genes and proteins and statistical analysis attempts to uncover the functional modules that perform the functions that characterize higher levels of biological organization. Systems biology attempts to transcend the study [...]

Cet article passe en revue les travaux récents sur les lignées cellulaires utilisées pour le développement préclinique de traitements des cancers

The Clinical Relevance of Cancer Cell Lines

Gillet, Jean-Pierre ; Varma, Sudhir ; Gottesman, Michael M.

Although advances in genomics during the last decade have opened new avenues for translational research and allowed the direct evaluation of clinical samples, there is still a need for reliable preclinical models to test therapeutic strategies. Human cancer-derived cell lines are the most widely used models to study the biology of cancer and to test hypotheses to improve the efficacy of cancer treatment. Since the development of the first cancer cell line, the clinical relevance of these models [...]

Menée à l'aide de nanoparticules d'oxyde de fer superparamagnétique et d'imagerie par résonance magnétique, cet article présente un modèle murin reproduisant la formation de métastases cérébrales d'un mélanome

Automated tracking of nanoparticle-labeled melanoma cells improves the predictive power of a brain metastasis model

Sundstrøm, Terje ; Daphu, Inderjit ; Wendelbo, Ingvild ; Hodneland, Erlend ; Lundervold, Arvid ; Immervoll, Heike ; Skaftnesmo, Kai Ove ; Babic, Michal ; Jendelova, Pavla ; Sykova, Eva ; Lund-Johansen, Morten ; Bjerkvig, Rolf ; Thorsen, Frits

Biological and therapeutic advances in melanoma brain metastasis are hampered by the paucity of reproducible and predictive animal models. In this work, we have developed a robust model of brain metastasis that empowers quantitative tracking of cellular dissemination and tumor progression. Human melanoma cells labeled with superparamagnetic iron oxide nanoparticles (SPIONs) were injected into the left cardiac ventricle of mice and visualized by magnetic resonance imaging (MRI). We show that [...]

Cet article passe en revue les travaux récents sur les modèles précliniques des cancers de l'ovaire, notamment les modèles murins génétiquement modifiés

Revisiting ovarian cancer preclinical models: Implications for a better management of the disease

Ricci, Francesca ; Broggini, Massimo ; Damia, Giovanna

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Despite progress in identifying “hallmark” genetic alterations associated with the main subtypes of epithelial ovarian cancer, the survival rate of women with EOC changed little since platinum-based treatment was introduced more than 30years ago. The successful identification of new, effective anticancer drugs largely depends on appropriate preclinical experimental models that should ideally mimic the complexity of [...]