Menée sur des cultures de cellules multipotentes prélevées dans l'intestin grêle, le côlon et le foie chez des donneurs d'âge compris entre 3 et 87 ans, cette étude évalue notamment le taux annuel de nouvelles mutations s'accumulant dans les cellules souches de ces organes au cours de la vie

Tissue-specific mutation accumulation in human adult stem cells during life

Blokzijl, Francis ; de Ligt, Joep ; Jager, Myrthe ; Sasselli, Valentina ; Roerink, Sophie ; Sasaki, Nobuo ; Huch, Meritxell ; Boymans, Sander ; Kuijk, Ewart ; Prins, Pjotr ; Nijman, Isaac J. ; Martincorena, Inigo ; Mokry, Michal ; Wiegerinck, Caroline L. ; Middendorp, Sabine ; Sato, Toshiro ; Schwank, Gerald ; Nieuwenhuis, Edward E. S. ; Verstegen, Monique M. A. ; van der Laan, Luc J. W. ; de Jonge, Jeroen ; Ijzermans, Jan N. M. ; Vries, Robert G. ; van de Wetering, Marc ; Stratton, Michael R. ; Clevers, Hans ; Cuppen, Edwin ; van Boxtel, Ruben

The gradual accumulation of genetic mutations in human adult stem cells (ASCs) during life is associated with various age-related diseases, including cancer. Extreme variation in cancer risk across tissues was recently proposed to depend on the lifetime number of ASC divisions, owing to unavoidable random mutations that arise during DNA replication. However, the rates and patterns of mutations in normal ASCs remain unknown. Here we determine genome-wide mutation patterns in ASCs of the small [...]

A partir de données portant sur 5 930 exomes issus de 18 localisations cancéreuses, cette étude identifie notamment, pour 14 localisations, des marqueurs d'une instabilité microsatellitaire

Classification and characterization of microsatellite instability across 18 cancer types

Hause, Ronald J. ; Pritchard, Colin C. ; Shendure, Jay ; Salipante, Stephen J.

Microsatellite instability (MSI), the spontaneous loss or gain of nucleotides from repetitive DNA tracts, is a diagnostic phenotype for gastrointestinal, endometrial, and colorectal tumors, yet the landscape of instability events across a wider variety of cancer types remains poorly understood. To explore MSI across malignancies, we examined 5,930 cancer exomes from 18 cancer types at more than 200,000 microsatellite loci and constructed a genomic classifier for MSI. We identified MSI-positive [...]

A partir d'échantillons tumoraux prélevés sur 42 patients atteints d'un adénome de l'hypophyse, puis confirmée sur 87 patients complémentaires, cette étude dresse le catalogue des anomalies génomiques (mutations, insertions/délétions, nombre de copies) en fonction de sous-types histologiques et hormonaux

Landscape of genomic alterations in pituitary adenomas

Bi, Wenya Linda ; Horowtiz, Peleg ; Greenwald, Noah ; Abedalthagafi, Malak ; Agarwalla, Pankaj K. ; Gibson, William J. ; Mei, Yu ; Schumacher, Steven E. ; Ben-David, Uri ; Chevalier, Aaron ; Carter, Scott L. ; Tiao, Grace ; Brastianos, Priscilla K. ; Ligon, Azra H. ; Ducar, Matthew ; MacConaill, Laura E. ; Laws, Edward R. ; Santagata, Sandro ; Beroukhim, Rameen ; Dunn, Ian F.

Purpose: Pituitary adenomas are the second most common primary brain tumor, yet their genetic profiles are incompletely understood. Experimental Design: We performed whole-exome sequencing of 42 pituitary macroadenomas and matched normal DNA. These adenomas included hormonally active and inactive tumors, ones with typical or atypical histology, and ones that were primary or recurrent. Results: We identified mutations, insertions/deletions, and copy number alterations. Nearly one-third of [...]

Cet article passe en revue les travaux récents sur le rôle des intégrines dans les diverses étapes du développement tumoral et dans l'entretien des cellules souches cancéreuses

The complexity of integrins in cancer and new scopes for therapeutic targeting

Hamidi, Hellyeh ; Pietila, Mika ; Ivaska, Johanna

Cancer is a complex disease and progresses within a dynamically evolving extracellular matrix that controls virtually every aspect of the tumour and tumour-associated cells. Interactions with the extracellular microenvironment are predominately mediated by a family of cell-surface transmembrane receptors called integrins. Integrin-matrix engagement leads to the formation of adhesion plaques, consisting of signalling and adaptor proteins, at the plasma membrane that link the extracellular matrix [...]

Menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanimes par lesquels l'activation de l'expression de SAT1 contribue à la fonction de suppresseur de tumeurs exercée par p53 via une ferroptose (forme de mort cellulaire nécrotique)

Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses

Ou, Yang ; Wang, Shang-Jui ; Li, Dawei ; Chu, Bo ; Gu, Wei

Although p53-mediated cell-cycle arrest, senescence, and apoptosis remain critical barriers to cancer development, the emerging role of p53 in cell metabolism, oxidative responses, and ferroptotic cell death has been a topic of great interest. Nevertheless, it is unclear how p53 orchestrates its activities in multiple metabolic pathways into tumor suppressive effects. Here, we identified the SAT1 (spermidine/spermine N1-acetyltransferase 1) gene as a transcription target of p53. SAT1 is a [...]

Menée in vitro et à partir de bases de données portant sur des patients atteints d'un neuroblastome, cette étude met en évidence des mécanismes par lesquels une enzyme (GDE2) induit la différenciation des cellules cancéreuses

Glycerophosphodiesterase GDE2 Promotes Neuroblastoma Differentiation through Glypican Release and Is a Marker of Clinical Outcome

Matas-Rico, Elisa ; van Veen, Michiel ; Leyton-Puig, Daniela ; van den Berg, Jeroen ; Koster, Jan ; Kedziora, Katarzyna M ; Molenaar, Bas ; Weerts, Marjolein J A. ; de Rink, Iris ; Medema, René H ; Giepmans, Ben N G. ; Perrakis, Anastassis ; Jalink, Kees ; Versteeg, Rogier ; Moolenaar, Wouter H

Neuroblastoma is a pediatric embryonal malignancy characterized by impaired neuronal differentiation. A better understanding of neuroblastoma differentiation is essential for developing new therapeutic approaches. GDE2 (encoded by GDPD5) is a six-transmembrane-domain glycerophosphodiesterase that promotes embryonic neurogenesis. We find that high GDPD5 expression is strongly associated with favorable outcome in neuroblastoma. GDE2 induces differentiation of neuroblastoma cells, suppresses cell [...]

Menée à l'aide de modèles murins génétiquement modifiés, cette étude met en évidence des mécanismes par lesquels la perturbation du réseau de signalisation WWOX-p53 favorise le développement d'un ostéosarcome

WWOX and p53 Dysregulation Synergize to Drive the Development of Osteosarcoma

Del Mare, Sara ; Husanie, Hussam ; Iancu, Ortal ; Abu-Odeh, Mohammad ; Evangelou, Konstantinos ; Lovat, Francesca ; Volinia, Stefano ; Gordon, Jonathan ; Amir, Gail ; Stein, Janet ; Stein, Gary S. ; Croce, Carlo M. ; Gorgoulis, Vassilis ; Lian, Jane B. ; Aqeilan, Rami I.

Osteosarcoma is a highly metastatic form of bone cancer in adolescents and young adults that is resistant to existing treatments. Development of an effective therapy has been hindered by very limited understanding of the mechanisms of osteosarcomagenesis. Here, we used genetically engineered mice to investigate the effects of deleting the tumor suppressor Wwox selectively in either osteoblast progenitors or mature osteoblasts. Mice with conditional deletion of Wwox in preosteoblasts (WwoxΔosx1) [...]

Menée in vitro et in vivo, cette étude met en évidence le rôle joué par la signalisation mTORC2 dans le développement et la progression d'une tumeur du pancréas

mTORC2 signaling drives the development and progression of pancreatic cancer

Driscoll, David R. ; Karim, Saadia A. ; Sano, Makoto ; Gay, David M. ; Jacob, Wright ; Yu, Jun ; Mizukami, Yusuke ; Gopinathan, Aarthi ; Jodrell, Duncan I. ; Evans, T. R. Jeffry ; Bardeesy, Nabeel ; Hall, Michael N. ; Quattrochi, Brian J. ; Klimstra, David S. ; Barry, Simon T. ; Sansom, Owen J. ; Lewis, Brian C. ; Morton, Jennifer P.

mTOR signaling controls several critical cellular functions and is deregulated in many cancers, including pancreatic cancer. To date, most efforts have focused on inhibiting the mTORC1 complex. However, clinical trials of mTORC1 inhibitors in pancreatic cancer have failed, raising questions about this therapeutic approach. We employed a genetic approach to delete the obligate mTORC2 subunit Rictor and identified the critical times during which tumorigenesis requires mTORC2 signaling. Rictor [...]

Menée in vitro et à l'aide de xénogreffes, cette étude française met en évidence des mécanismes par lesquels des vésicules extracellulaires surexprimant l'annexine A6 favorisent la progression et le processus métastatique d'un adénocarcinome canalaire du pancréas

Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness

Leca, Julie ; Martinez, Sébastien ; Lac, Sophie ; Nigri, Jérémy ; Secq, Véronique ; Rubis, Marion ; Bressy, Christian ; Sergé, Arnauld ; Lavaut, Marie-Noëlle ; Dusetti, Nelson ; Loncle, Celine ; Roques, Julie ; Pietrasz, Daniel ; Bousquet, Corinne ; Garcia, Stéphane ; Granjeaud, Samuel ; Ouaissi, Mehdi ; Bachet, Jean Baptiste ; Brun, Christine ; Iovanna, Juan L. ; Zimmermann, Pascale ; Vasseur, Sophie ; Tomasini, Richard

The intratumoral microenvironment, or stroma, is of major importance in the pathobiology of pancreatic ductal adenocarcinoma (PDA), and specific conditions in the stroma may promote increased cancer aggressiveness. We hypothesized that this heterogeneous and evolving compartment drastically influences tumor cell abilities, which in turn influences PDA aggressiveness through crosstalk that is mediated by extracellular vesicles (EVs). Here, we have analyzed the PDA proteomic stromal signature and [...]

A partir d'échantillons tumoraux prélevés sur 75 patients atteints d'un cancer de la prostate, puis menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en synergie avec diverses voies de signalisation (AKT, Myc, Ras/Raf/MAPK,...), l'activation de Notch1 favorise le développement d'un adénocarcinome métastatique résistant à la castration

Activation of Notch1 synergizes with multiple pathways in promoting castration-resistant prostate cancer

Stoyanova, Tanya ; Riedinger, Mireille ; Lin, Shu ; Faltermeier, Claire M. ; Smith, Bryan A. ; Zhang, Kelvin X. ; Going, Catherine C. ; Goldstein, Andrew S. ; Lee, John K. ; Drake, Justin M. ; Rice, Meghan A. ; Hsu, En-Chi ; Nowroozizadeh, Behdokht ; Castor, Brandon ; Orellana, Sandra Y. ; Blum, Steven M. ; Cheng, Donghui ; Pienta, Kenneth J. ; Reiter, Robert E. ; Pitteri, Sharon J. ; Huang, Jiaoti ; Witte, Owen N.

Metastatic castration-resistant prostate cancer (CRPC) is the primary cause of prostate cancer-specific mortality. Defining new mechanisms that can predict recurrence and drive lethal CRPC is critical. Here, we demonstrate that localized high-risk prostate cancer and metastatic CRPC, but not benign prostate tissues or low/intermediate-risk prostate cancer, express high levels of nuclear Notch homolog 1, translocation-associated (Notch1) receptor intracellular domain. Chronic activation of [...]

Menée in vitro sur des modèles tridimensionnels de cancer du sein, cette étude met en évidence des mécanismes par lesquels, privées de nutriments, des cellules cancéreuses entrent en dormance après avoir cannibalisé des cellules souches mésenchymateuses

Cancer cells enter dormancy after cannibalizing mesenchymal stem/stromal cells (MSCs)

Bartosh, Thomas J. ; Ullah, Mujib ; Zeitouni, Suzanne ; Beaver, Joshua ; Prockop, Darwin J.

Patients with breast cancer often develop malignant regrowth of residual drug-resistant dormant tumor cells years after primary treatment, a process defined as cancer relapse. Deciphering the causal basis of tumor dormancy therefore has obvious therapeutic significance. Because cancer cell behavior is strongly influenced by stromal cells, particularly the mesenchymal stem/stromal cells (MSCs) that are actively recruited into tumor-associated stroma, we assessed the impact of MSCs on breast [...]

Menée sur des lignées cellulaires de l'épithélium mammaire, cette étude met en évidence des mécanismes par lesquels, en régulant l'expression du facteur de transcription p63, les oncogènes RAS et PIK3CA induisent une transition épithélio-mésenchymateuse

Repression of p63 and induction of EMT by mutant Ras in mammary epithelial cells

Yoh, Kathryn E. ; Regunath, Kausik ; Guzman, Asja ; Lee, Seung-Min ; Pfister, Neil T. ; Akanni, Olutosin ; Kaufman, Laura J. ; Prives, Carol ; Prywes, Ron

The p53-related transcription factor p63 is required for maintenance of epithelial cell differentiation. We found that activated forms of the Harvey Rat Sarcoma Virus GTPase (H-RAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) oncogenes strongly repress expression of ∆Np63α, the predominant p63 isoform in basal mammary epithelial cells. This regulation occurs at the transcriptional level, and a short region of the ∆Np63 promoter is sufficient for [...]

Cet article passe en revue les principaux concepts biologiques indispensables pour la production de modèles animaux pertinents dans la recherche sur les cancers

Concepts in Cancer Modeling: A Brief History

Thomas, Renee M. ; Van Dyke, Terry ; Merlino, Glenn ; Day, Chi-Ping

Modeling, an experimental approach to investigate complex biological systems, has significantly contributed to our understanding of cancer. Although extensive cancer research has been conducted utilizing animal models for elucidating mechanisms and developing therapeutics, the concepts in a good model design and its application have not been well elaborated. In this review, we discuss the theory underlying biological modeling and the process of producing a valuable and relevant animal model. [...]

A partir d'une revue des méthodes utilisées pour évaluer les lignées cellulaires depuis 2005, cet article fournit une liste de lignées cellulaires cancéreuses qualifiées d'optimales pour mener des expériences in vitro

Optimization of cell lines as tumour models by integrating multi-omics data

Zhao, Ning ; Liu, Yongjing ; Wei, Yunzhen ; Yan, Zichuang ; Zhang, Qiang ; Wu, Cheng ; Chang, Zhiqiang ; Xu, Yan

Cell lines are widely used as in vitro models of tumorigenesis. However, an increasing number of researchers have found that cell lines differ from their sourced tumour samples after long-term cell culture. The application of unsuitable cell lines in experiments will affect the experimental accuracy and the treatment of patients. Therefore, it is imperative to identify optimal cell lines for each cancer type. Here, we review the methods used to evaluate cell lines since 2005. Furthermore, gene [...]

Cette étude présente les caractéristiques d'un modèle murin conçu pour étudier spécifiquement le développement et le processus métastatique d'une tumeur du côlon

Generation of an inducible colon-specific Cre enzyme mouse line for colon cancer research

Tetteh, Paul W. ; Kretzschmar, Kai ; Begthel, Harry ; van den Born, Maaike ; Korving, Jeroen ; Morsink, Folkert ; Farin, Henner ; van Es, Johan H. ; Offerhaus, G. Johan A. ; Clevers, Hans

Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in colonic epithelial cells. We generated a colon-specific inducible Car1CreER knock-in (KI) mouse with broad Cre activity in epithelial cells of the [...]