A partir d'un séquençage de l'ADN mitochondrial de 384 tumeurs prélevées sur des patients atteints d'un cancer localisé de la prostate, cette étude identifie un ensemble de mutations en association avec un caractère agressif de la maladie

Mitochondrial mutations drive prostate cancer aggression

Hopkins, Julia F. ; Sabelnykova, Veronica Y. ; Weischenfeldt, Joachim ; Simon, Ronald ; Aguiar, Jennifer A. ; Alkallas, Rached ; Heisler, Lawrence E. ; Zhang, Junyan ; Watson, John D. ; Chua, Melvin L. K. ; Fraser, Michael ; Favero, Francesco ; Lawerenz, Chris ; Plass, Christoph ; Sauter, Guido ; McPherson, John D. ; van der Kwast, Theodorus ; Korbel, Jan ; Schlomm, Thorsten ; Bristow, Robert G. ; Boutros, Paul C.

Nuclear mutations are well known to drive tumor incidence, aggression and response to therapy. By contrast, the frequency and roles of mutations in the maternally inherited mitochondrial genome are poorly understood. Here we sequence the mitochondrial genomes of 384 localized prostate cancer patients, and identify a median of one mitochondrial single-nucleotide variant (mtSNV) per patient. Some of these mtSNVs occur in recurrent mutational hotspots and associate with aggressive disease. Younger [...]

A partir d'échantillons tumoraux prélevés sur 13 patients atteints d'un fibrosarcome épithélioïde sclérosant et 6 patients atteints d'un sarcome fibromyxoïde de bas grade, cette étude identifie un ensemble d'anomalies génomiques, notamment des fusions de gènes, communes aux deux types de tumeurs

In-depth genetic analysis of sclerosing epithelioid fibrosarcoma reveals recurrent genomic alterations and potential treatment targets

Arbajian, Elsa ; Puls, Florian ; Antonescu, Cristina R. ; Amary, M Fernanda ; Sciot, Raf ; Debiec-Rychter, Maria ; Sumathi, Vaiyapuri ; Järås, Marcus ; Magnusson, Linda ; Nilsson, Jenny ; Hofvander, Jakob ; Mertens, Fredrik

Purpose: Sclerosing epithelioid fibrosarcoma (SEF) is a highly aggressive soft tissue sarcoma closely related to low-grade fibromyxoid sarcoma (LGFMS). Some tumors display morphological characteristics of both SEF and LGFMS, so called hybrid SEF/LGFMS. Despite the overlap of gene fusion variants between these two tumor types, SEF is much more aggressive. The present study aimed to further characterize SEF and hybrid SEF/LGFMS genetically in order to better understand the role of the [...]

Menée in vitro et in vivo sur des modèles de cancer du poumon à petites cellules, cette étude met en évidence des mécanismes par lesquels la protéine ASXL3 favorise la prolifération des cellules cancéreuses

ASXL3 is a Novel Pluripotency Factor in Human Respiratory Epithelial Cells and a Potential Therapeutic Target in Small Cell Lung Cancer

Shukla, Vivek ; Rao, Mahadev ; Zhang, Hongen ; Beers, Jeanette ; Wangsa, Darawalee ; Wangsa, Danny ; Buishand, Floryne O. ; Wang, Yonghong ; Yu, Zhiya ; Stevenson, Holly ; Reardon, Emily ; McLoughlin, Kaitlin C. ; Kaufman, Andrew ; Payabyab, Eden ; Hong, Julie A. ; Zhang, Mary ; Davis, Sean R. ; Edelman, Daniel C. ; Chen, Guokai ; Miettinen, Markku ; Restfo, Nicholas ; Ried, Thomas ; Meltzer, Paul S. ; Schrump, David S.

In this study, we generated induced pluripotent stem cells (iPSC) from normal human small airway epithelial cells (SAEC) to investigate epigenetic mechanisms of stemness and pluripotency in lung cancers. We documented key hallmarks of reprogramming in lung iPSC (Lu-iPSC) that coincided with modulation of more than 15,000 genes relative to parental SAEC. Of particular novelty, we identified the PRC2-associated protein, ASXL3 which was markedly upregulated in Lu-iPSC and small cell lung cancer [...]

Menée à l'aide d'un modèle murin de cancer de la prostate, cette étude met en évidence des mécanismes par lesquels, en induisant une sénescence cellulaire, la protéine SIN3B limite la progression d'un adénocarcinome en une forme invasive

Chromatin-Associated Protein SIN3B Prevents Prostate Cancer Progression by Inducing Senescence

Bainor, Anthony J. ; Deng, Fang-Ming ; Wang, Yu ; Lee, Peng ; Cantor, David J. ; Logan, Susan K. ; David, Gregory

Distinguishing between indolent and aggressive prostate adenocarcinoma remains a priority to accurately identify patients who need therapeutic intervention. SIN3B has been implicated in the initiation of senescence in vitro. Here we show that in a mouse model of prostate cancer, SIN3B provides a barrier to malignant progression. SIN3B was required for PTEN-induced cellular senescence and prevented progression to invasive prostate adenocarcinoma. Furthermore, SIN3B was downregulated in human [...]

Menée à l'aide de la technologie CRISPR-Cas9 et de xénogreffes de lignées cellulaires humaines de cancer colorectal présentant un gène KRAS muté, cette étude identifie notamment deux enzymes (NADK et KHK) favorisant la croissance tumorale et une protéine impliquée dans le remodelage de la chromatine (INO80C) exerçant une fonction de suppresseur de tumeurs

Genome-wide CRISPR screen for essential cell growth mediators in mutant KRAS colorectal cancers

Rana, Tariq M. ; Yau, Edwin H. ; Kummetha, Indrasena Reddy ; Lichinchi, Gianluigi ; Tang, Rachel ; Zhang, Yunlin

Targeting mutant KRAS signaling pathways continues to attract attention as a therapeutic strategy for KRAS-driven tumors. In this study, we exploited the power of the CRISPR-Cas9 system to identify genes affecting the tumor xenograft growth of human mutant KRAS colorectal cancers (KRASMUT CRC). Using pooled lentiviral single guide RNA libraries, we conducted a genome-wide loss-of-function genetic screen in an isogenic pair of human CRC cell lines harboring mutant or wild-type KRAS. The screen [...]

A l'aide d'une technique de microscopie électronique, cette étude analyse les propriétés tridimensionnelles de la protéine BRCA1 et, notamment, identifie une région hautement susceptible à l'ubiquitination dans une région de la version mutée de la protéine

Structural analysis of BRCA1 reveals modification hotspot

Liang, Yanping ; Dearnaley, William J. ; Varano, A. Cameron ; Winton, Carly E. ; Gilmore, Brian L. ; Alden, Nick A. ; Sheng, Zhi ; Kelly, Deborah F.

Cancer cells afflicted with mutations in the breast cancer susceptibility protein (BRCA1) often suffer from increased DNA damage and genomic instability. The precise manner in which physical changes to BRCA1 influence its role in DNA maintenance remains unclear. We used single-particle electron microscopy to study the three-dimensional properties of BRCA1 naturally produced in breast cancer cells. Structural studies revealed new information for full-length BRCA1, engaging its nuclear binding [...]

Menée à l'aide de xénogreffes de lignées cellulaires de cancer du sein et de glioblastome, cette étude met en évidence des mécanismes par lesquels la formation d'un complexe c-Met/intégrine bêta 1 favorise le processus métastatique d'une tumeur du sein et la résistance au bévacizumab d'un glioblastome

Cross-activating c-Met/beta1 integrin complex drives metastasis and invasive resistance in cancer

Jahangiri, Arman ; Nguyen, Alan ; Chandra, Ankush ; Sidorov, Maxim K. ; Yagnik, Garima ; Rick, Jonathan ; Han, Sung Won ; Chen, William ; Flanigan, Patrick M. ; Schneidman-Duhovny, Dina ; Mascharak, Smita ; De Lay, Michael ; Imber, Brandon ; Park, Catherine C. ; Matsumoto, Kunio ; Lu, Kan ; Bergers, Gabriele ; Sali, Andrej ; Weiss, William A. ; Aghi, Manish K.

The molecular underpinnings of invasion, a hallmark of cancer, have been defined in terms of individual mediators but crucial interactions between these mediators remain undefined. In xenograft models and patient specimens, we identified a c-Met/β1 integrin complex that formed during significant invasive oncologic processes: breast cancer metastases and glioblastoma invasive resistance to antiangiogenic VEGF neutralizing antibody, bevacizumab. Inducing c-Met/β1 complex formation through an [...]

Cet article passe en revue les travaux récents sur les mécanismes par lesquels la plasticité cellulaire favorise le développement et la progression d'une tumeur

Cell plasticity in epithelial homeostasis and tumorigenesis

Varga, Julia ; Greten, Florian R.

The adult organism is characterized by remarkable plasticity, which enables efficient regeneration and restoration of homeostasis after damage. When aberrantly activated, this plasticity contributes to tumour initiation and progression. Here we review recent advances in this field with a focus on cell fate changes and the epithelial-mesenchymal transition - two distinct, yet closely related, forms of plasticity with fundamental roles in homeostasis and cancer.

A partir d'échantillons tumoraux prélevés sur 802 patients atteints d'un adénocarcinome du poumon, puis menée in vitro, cette étude met en évidence des mécanismes par lesquels, en stabilisant l'expression de la kinase d'adhérence focale FAK, l'enzyme ADAR favorise le processus invasif

The RNA-editing enzyme ADAR promotes lung adenocarcinoma migration and invasion by stabilizing FAK

Amin, Elianna M. ; Liu, Yuan ; Deng, Su ; Tan, Kay See ; Chudgar, Neel ; Mayo, Marty W. ; Sanchez-Vega, Francisco ; Adusumilli, Prasad S. ; Schultz, Nikolaus ; Jones, David R.

Drugs that inhibit cell migration pathways, such as that mediated by the kinase FAK, may prevent metastasis and improve long-term survival in cancer patients. Amin et al. found that the RNA-editing enzyme ADAR supports the activity of FAK. In lung adenocarcinoma cells, ADAR bound to and edited FAK mRNA in a manner that improved its stability, thus increasing the abundance of FAK protein and enhancing the migration of these cells. High ADAR expression was a poor prognostic indicator in patients. [...]

Menée in vitro et in vivo sur des modèles de cancer colorectal, cette étude met en évidence des mécanismes par lesquels, en activant la signalisation TGFbêta, le récepteur LGR5 des cellules souches intestinales réprime le processus métastatique

R-Spondin1/LGR5 Activates TGFbeta Signaling and Suppresses Colon Cancer Metastasis

Zhou, Xiaolin ; Geng, Liying ; Wang, Degeng ; Yi, Haowei ; Talmon, Geoffrey ; Wang, Jing

Leucine rich repeat containing G protein-coupled receptor 5 (LGR5), an intestinal stem cell marker is known to exhibit tumor suppressor activity in colon cancer, the mechanism of which is not understood. Here we show that R-spondin 1 (RSPO1)/LGR5 directly activates TGFβ signaling cooperatively with TGFβ type II receptor in colon cancer cells, enhancing TGFβ-mediated growth inhibition and stress-induced apoptosis. Knockdown of LGR5 attenuated downstream TGFβ signaling and increased cell [...]

A partir d'échantillons de tissu tumoral et de tissu sain prélevés sur 68 patients atteints d'un cancer de la vessie, puis menée in vitro, cette étude met en évidence des mécanismes par lesquels, en sécrétant la protéine BMP4, les cellules cancéreuses favorisent la différenciation des macrophages M2 et la transition épithélio-mésenchymateuse

BMP4 induces M2 macrophage polarization and favors tumor progression in bladder cancer

Martínez, Víctor G. ; Rubio, Carolina ; Martínez-Fernández, Mónica ; Segovia, Cristina ; López-Calderón, Fernando ; Garín, Marina ; Teijeira, Alicia ; Munera-Maravilla, Ester ; Varas, Alberto ; Sacedón, Rosa ; Guerrero-Ramos, Felix ; Villacampa, Felipe ; de la Rosa, Federico ; Castellano, Daniel ; López-Collazo, Eduardo ; Paramio, Jesus M. ; Vicente, Ángeles ; Dueñas, Marta

Purpose: Bladder cancer (BC) is a current clinical and social problem. At diagnosis, most patients present non-muscle invasive tumors, characterized by a high recurrence rate, which could progress to muscle invasive disease and metastasis. Bone morphogenetic protein (BMP)-dependent signaling arising from stromal bladder tissue mediates urothelial homeostasis by promoting urothelial cell differentiation. However, the possible role of BMP ligands in BC is still unclear. Experimental Design: Tumor [...]