A partir de données issues du projet “The Cancer Genome Atlas”, cette étude identifie un “chromotype”, constitué par de fréquentes duplications en tandem, dans les tumeurs du sein triplement négatif, de l’ovaire, de l’endomètre et du foie

The tandem duplicator phenotype as a distinct genomic configuration in cancer

Menghi, Francesca ; Inaki, Koichiro ; Woo, XingYi ; Kumar, Pooja A. ; Grzeda, Krzysztof R. ; Malhotra, Ankit ; Yadav, Vinod ; Kim, Hyunsoo ; Marquez, Eladio J. ; Ucar, Duygu ; Shreckengast, Phung T. ; Wagner, Joel P. ; MacIntyre, George ; Murthy Karuturi, Krishna R. ; Scully, Ralph ; Keck, James ; Chuang, Jeffrey H. ; Liu, Edison T.

Next-generation sequencing studies have revealed genome-wide structural variation patterns in cancer, such as chromothripsis and chromoplexy, that do not engage a single discernable driver mutation, and whose clinical relevance is unclear. We devised a robust genomic metric able to identify cancers with a chromotype called tandem duplicator phenotype (TDP) characterized by frequent and distributed tandem duplications (TDs). Enriched only in triple-negative breast cancer (TNBC) and in ovarian, [...]

Cet article passe en revue les travaux récents sur l’identification de mutations de gènes dans les leucémies lymphocytaires chroniques et analyse leurs implications cliniques

The clinical implications of gene mutations in chronic lymphocytic leukaemia

Rossi, Davide ; Gaidano, Gianluca

Chronic lymphocytic leukaemia (CLL) is a molecularly heterogeneous disease as revealed by recent genomic studies. Among genetic lesions that are recurrent in CLL, few clinically validated prognostic markers, such as TP53 mutations and 17p deletion, are available for the use in clinical practice to guide treatment decisions. Recently, several novel molecular markers have been identified in CLL. Though these mutations have not yet gained the qualification of predictive factors for treatment [...]

Menée in vivo, cette étude met en évidence des mécanismes par lesquels des ARNs circulaires, produits par des translocations chromosomiques associés au cancer, favorisent le développement d’une tumeur

Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations

Guarnerio, Jlenia ; Bezzi, Marco ; Jeong, Jong Cheol ; Paffenholz, Stella V ; Berry, Kelsey ; Naldini, Matteo M ; Lo-Coco, Francesco ; Tay, Yvonne ; Beck, Andrew H ; Pandolfi, Pier Paolo

Chromosomal translocations encode oncogenic fusion proteins that have been proven to be causally involved in tumorigenesis. Our understanding of whether such genomic alterations also affect non-coding RNAs is limited, and their impact on circular RNAs (circRNAs) has not been explored. Here, we show that well-established cancer-associated chromosomal translocations give rise to fusion circRNAs (f-circRNA) that are produced from transcribed exons of distinct genes affected by the translocations. [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels des protéines impliquées dans la nécrose programmée favorisent le développement d’un adénocarcinome canalaire du pancréas

The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression

Seifert, Lena ; Werba, Gregor ; Tiwari, Shaun ; Giao Ly, Nancy Ngoc ; Alothman, Sara ; Alqunaibit, Dalia ; Avanzi, Antonina ; Barilla, Rocky ; Daley, Donnele ; Greco, Stephanie H. ; Torres-Hernandez, Alejandro ; Pergamo, Matthew ; Ochi, Atsuo ; Zambirinis, Constantinos P. ; Pansari, Mridul ; Rendon, Mauricio ; Tippens, Daniel ; Hundeyin, Mautin ; Mani, Vishnu R. ; Hajdu, Cristina ; Engle, Dannielle ; Miller, George

Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, [...]

Menée in vitro à l’aide d’un organoïde de prostate, cette étude montre que différents sous-types de cancer de la prostate peuvent se développer à partir de différents types de cellules épithéliales basales et luminales

N-Myc Drives Neuroendocrine Prostate Cancer Initiated from Human Prostate Epithelial Cells

Lee, John K ; Phillips, John W ; Smith, Bryan A ; Park, Jung Wook ; Stoyanova, Tanya ; McCaffrey, Erin F ; Baertsch, Robert ; Sokolov, Artem ; Meyerowitz, Justin G ; Mathis, Colleen ; Cheng, Donghui ; Stuart, Joshua M ; Shokat, Kevan M ; Gustafson, W.  Clay ; Huang, Jiaoti ; Witte, Owen N

MYCN amplification and overexpression are common in neuroendocrine prostate cancer (NEPC). However, the impact of aberrant N-Myc expression in prostate tumorigenesis and the cellular origin of NEPC have not been established. We define N-Myc and activated AKT1 as oncogenic components sufficient to transform human prostate epithelial cells to prostate adenocarcinoma and NEPC with phenotypic and molecular features of aggressive, late-stage human disease. We directly show that prostate [...]

Menée in vitro à l’aide d’un organoïde de prostate, cette étude montre que différents sous-types de cancer de la prostate peuvent se développer à partir de différents types de cellules épithéliales basales et luminales

Prostate epithelial cell of origin determines cancer differentiation state in an organoid transformation assay

Park, Jung Wook ; Lee, John K. ; Phillips, John W. ; Huang, Patrick ; Cheng, Donghui ; Huang, Jiaoti ; Witte, Owen N.

The cell of origin for prostate cancer remains a subject of debate. Genetically engineered mouse models have demonstrated that both basal and luminal cells can serve as cells of origin for prostate cancer. Using a human prostate regeneration and transformation assay, our group previously demonstrated that basal cells can serve as efficient targets for transformation. Recently, a subpopulation of multipotent human luminal cells defined by CD26 expression that retains progenitor activity in a [...]

Menée à l’aide de modèles murins, cette étude met en évidence des mécanismes par lesquels une phosphatase, la calcineurine, favorise la prolifération de cellules souches cancéreuses dans le côlon

Epithelial calcineurin controls microbiota-dependent intestinal tumor development

Peuker, Kenneth ; Muff, Stefanie ; Wang, Jun ; Kunzel, Sven ; Bosse, Esther ; Zeissig, Yvonne ; Luzzi, Giuseppina ; Basic, Marijana ; Strigli, Anne ; Ulbricht, Andrea ; Kaser, Arthur ; Arlt, Alexander ; Chavakis, Triantafyllos ; van den Brink, Gijs R. ; Schafmayer, Clemens ; Egberts, Jan-Hendrik ; Becker, Thomas ; Bianchi, Marco E. ; Bleich, Andre ; Röcken, Christoph ; Hampe, Jochen ; Schreiber, Stefan ; Baines, John F. ; Blumberg, Richard S. ; Zeissig, Sebastian

Inflammation-associated pathways are active in intestinal epithelial cells (IECs) and contribute to the pathogenesis of colorectal cancer (CRC). Calcineurin, a phosphatase required for the activation of the nuclear factor of activated T cells (NFAT) family of transcription factors, shows increased expression in CRC. We therefore investigated the role of calcineurin in intestinal tumor development. We demonstrate that calcineurin and NFAT factors are constitutively expressed by primary IECs and [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, en secrétant un antagoniste de Wnt (sFRP2), des fibroblastes du micro-environnement tumoral favorisent, chez les sujets âgés, le processus métastatique d'un mélanome et la résistance thérapeutique

sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance

Kaur, Amanpreet ; Webster, Marie R. ; Marchbank, Katie ; Behera, Reeti ; Ndoye, Abibatou ; Kugel, Curtis H. ; Dang, Vanessa M. ; Appleton, Jessica ; O’Connell, Michael P. ; Cheng, Phil ; Valiga, Alexander A. ; Morissette, Rachel ; McDonnell, Nazli B. ; Ferrucci, Luigi ; Kossenkov, Andrew V. ; Meeth, Katrina ; Tang, Hsin-Yao ; Yin, Xiangfan ; Wood, William H. ; Lehrmann, Elin ; Becker, Kevin G. ; Flaherty, Keith T. ; Frederick, Dennie T. ; Wargo, Jennifer A. ; Cooper, Zachary A. ; Tetzlaff, Michael T. ; Hudgens, Courtney ; Aird, Katherine M. ; Zhang, Rugang ; Xu, Xiaowei ; Liu, Qin ; Bartlett, Edmund ; Karakousis, Giorgos ; Eroglu, Zeynep ; Lo, Roger S. ; Chan, Matthew ; Menzies, Alexander M. ; Long, Georgina V. ; Johnson, Douglas B. ; Sosman, Jeffrey ; Schilling, Bastian ; Schadendorf, Dirk ; Speicher, David W. ; Bosenberg, Marcus ; Ribas, Antoni ; Weeraratna, Ashani T.

Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response [...]

Menée in vitro à l'aide de matrices extracellulaires, cette étude met en évidence le rôle joué par des caractéristiques géométriques à la périphérie des tissus tumoraux pour susciter la formation de cellules cancéreuses dotées de capacités de cellules souches

Interfacial geometry dictates cancer cell tumorigenicity

Lee, Junmin ; Abdeen, Amr A. ; Wycislo, Kathryn L. ; Fan, Timothy M. ; Kilian, Kristopher A.

Within the heterogeneous architecture of tumour tissue there exists an elusive population of stem-like cells that are implicated in both recurrence and metastasis. Here, by using engineered extracellular matrices, we show that geometric features at the perimeter of tumour tissue will prime a population of cells with a stem-cell-like phenotype. These cells show characteristics of cancer stem cells in vitro, as well as enhanced tumorigenicity in murine models of primary tumour growth and [...]

Cet article passe en revue les travaux récents sur le rôle joué par un micro-environnement tumoral hypoxique dans le processus métastatique

Hypoxic control of metastasis

Rankin, Erinn B. ; Giaccia, Amato J.

Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Hypoxia is a potent microenvironmental factor promoting metastatic progression. Clinically, hypoxia and the expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 are associated with increased distant metastasis and poor survival in a variety of tumor types. Moreover, HIF signaling in malignant cells influences multiple steps within [...]

Cet article passe en revue les travaux récents sur une approche évolutionniste du processus métastatique

Metastasis as an evolutionary process

Turajlic, Samra ; Swanton, Charles

Therapeutic advances in oncology have not fully translated to the treatment of metastatic disease, which remains largely incurable. Metastatic subclones can emerge both early and late in the life of the primary tumor. A better understanding of the genetic evolution of metastatic disease has the potential to reveal differences in the therapeutic vulnerabilities of primary and metastatic tumors, shed light on the temporal patterns of and routes to metastatic colonization, and provide insight into [...]

Menée à l'aide d'un modèle murin de leucémie myéloïde aiguë, cette étude met en évidence des mécanismes par lesquels des gènes impliqués dans la régulation du rythme circadien favorisent la prolifération des cellules souches leucémiques

Core Circadian Clock Genes Regulate Leukemia Stem Cells in AML

Puram, Rishi V ; Kowalczyk, Monika S ; de Boer, Carl G ; Schneider, Rebekka K ; Miller, Peter G ; McConkey, Marie ; Tothova, Zuzana ; Tejero, Héctor ; Heckl, Dirk ; Järås, Marcus ; Chen, Michelle C ; Li, Hubo ; Tamayo, Alfred ; Cowley, Glenn S ; Rozenblatt-Rosen, Orit ; Al-Shahrour, Fátima ; Regev, Aviv ; Ebert, Benjamin L

Leukemia stem cells (LSCs) have the capacity to self-renew and propagate disease upon serial transplantation in animal models, and elimination of this cell population is required for curative therapies. Here, we describe a series of pooled, in vivo RNAi screens to identify essential transcription factors (TFs) in a murine model of acute myeloid leukemia (AML) with genetically and phenotypically defined LSCs. These screens reveal the heterodimeric, circadian rhythm TFs Clock and Bmal1 as genes [...]

Menée à l'aide d'une technique de séquençage de l'ARN sur 4 645 cellules uniques (endothéliales, stromales, immunitaires, malignes) isolées chez 19 patients atteints d'un mélanome, cette étude met notamment en évidence deux types différents d'états d'expression génétique, dont l'un est lié au développement d'une résistance thérapeutique

Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

Tirosh, Itay ; Izar, Benjamin ; Prakadan, Sanjay M. ; Wadsworth, Marc H. ; Treacy, Daniel ; Trombetta, John J. ; Rotem, Asaf ; Rodman, Christopher ; Lian, Christine ; Murphy, George ; Fallahi-Sichani, Mohammad ; Dutton-Regester, Ken ; Lin, Jia-Ren ; Cohen, Ofir ; Shah, Parin ; Lu, Diana ; Genshaft, Alex S. ; Hughes, Travis K. ; Ziegler, Carly G. K. ; Kazer, Samuel W. ; Gaillard, Aleth ; Kolb, Kellie E. ; Villani, Alexandra-Chloé ; Johannessen, Cory M. ; Andreev, Aleksandr Y. ; Van Allen, Eliezer M. ; Bertagnolli, Monica ; Sorger, Peter K. ; Sullivan, Ryan J. ; Flaherty, Keith T. ; Frederick, Dennie T. ; Jané-Valbuena, Judit ; Yoon, Charles H. ; Rozenblatt-Rosen, Orit ; Shalek, Alex K. ; Regev, Aviv ; Garraway, Levi A.

Tumors harbor multiple cell types that are thought to play a role in the development of resistance to drug treatments. Tirosh et al. used single-cell sequencing to investigate the distribution of these differing genetic profiles within melanomas. Many cells harbored heterogeneous genetic programs that reflected two different states of genetic expression, one of which was linked to resistance development. Following drug treatment, the resistance-linked expression state was found at a much higher [...]

Menée à l'aide d'échantillons tumoraux et sanguins prélevés sur des patients atteints d'un cancer de la prostate, cette étude met en évidence, dans le micro-environnement tumoral, des mécanismes de nature immunitaire qui perturbent l'activité antitumorale des cellules NK

Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity

Pasero, Christine ; Gravis, Gwenaëlle ; Guerin, Mathilde ; Granjeaud, Samuel ; Thomassin-Piana, Jeanne ; Rocchi, Palma ; Paciencia-Gros, Maria ; Poizat, Flora ; Bentobji, Mélanie ; Azario-Cheillan, Francine ; Walz, Jochen ; Salem, Naji ; Brunelle, Serge ; Moretta, Alessandro ; Olive, Daniel

The field of immunotherapy for solid tumors, such as prostate cancer, has been recently focusing on therapies that can counter tumor-mediated immunosuppression. Precise quantification and characterization of the immune infiltrates in tumors is crucial to improve treatment efficacy. Natural killer (NK) cells, major components of the antitumor immune system, have never been isolated from prostate tumors, despite their suspected role in disease progression. Here, we examined the frequency, [...]

Cet article passe en revue les travaux récents, menés notamment à l'aide de données du projet "The Cancer Genome Atlas", sur les effets des anomalies d'homéostasie du cholestérol dans la survie des patients atteints d'un cancer

The Role of Cholesterol in Cancer

Kuzu, Omer F. ; Noory, Mohammad A. ; Robertson, Gavin P.

The roles played by cholesterol in cancer development and the potential of therapeutically targeting cholesterol homeostasis is a controversial area in the cancer community. Several epidemiologic studies report an association between cancer and serum cholesterol levels or statin use, while others suggest that there is not one. Furthermore, the Cancer Genome Atlas (TCGA) project using next-generation sequencing has profiled the mutational status and expression levels of all the genes in diverse [...]