Menée notamment à partir de données génomiques portant sur 2 756 tumeurs couvrant 37 types de cancer et à partir du séquençage du génome entier de 72 neuroblastomes, cette étude met en évidence un mécanisme par lequel une chromothripsis, suivie de la formation d'ADNs circulaires extra-chromosomiques qui se recombinent, favorise l'amplification oncogène de régions génomiques

Chromothripsis followed by circular recombination drives oncogene amplification in human cancer

Rosswog, Carolina ; Bartenhagen, Christoph ; Welte, Anne ; Kahlert, Yvonne ; Hemstedt, Nadine ; Lorenz, Witali ; Cartolano, Maria ; Ackermann, Sandra ; Perner, Sven ; Vogel, Wenzel ; Altmuller, Janine ; Nurnberg, Peter ; Hertwig, Falk ; Göhring, Gudrun ; Lilienweiss, Esther ; Stutz, Adrian M. ; Korbel, Jan O. ; Thomas, Roman K. ; Peifer, Martin ; Fischer, Matthias

The mechanisms behind the evolution of complex genomic amplifications in cancer have remained largely unclear. Using whole-genome sequencing data of the pediatric tumor neuroblastoma, we here identified a type of amplification, termed ‘seismic amplification’, that is characterized by multiple rearrangements and discontinuous copy number levels. Overall, seismic amplifications occurred in 9.9% (274 of 2,756) of cases across 38 cancer types, and were associated with massively increased copy [...]

Menée à l'aide d'échantillons tumoraux d'origine humaine et d'une xénogreffe sur un modèle murin, cette étude met en évidence un mécanisme par lequel la voie de signalisation des kinases MAPK6 et AKT favorise la croissance tumorale et la résistance des cellules cancéreuses à l'inhibition des kinases mTOR

MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade

Qinbo Cai ; Wolong Zhou ; Wei Wang ; Bingning Dong ; Dong Han ; Tao Shen ; Chad J. Creighton ; David D. Moore ; Feng Yang

Mitogen-activated protein kinase 6 (MAPK6) is an atypical MAPK. Its function in regulating cancer growth remains elusive. Here, we reported that MAPK6 directly activated AKT and induced oncogenic outcomes. MAPK6 interacted with AKT through its C34 region and the C-terminal tail and phosphorylated AKT at S473 independent of mTORC2, the major S473 kinase. mTOR kinase inhibitors have not made notable progress in the clinic. Our identified MAPK6-AKT axis may provide a major resistance pathway. [...]

Cet article passe en revue les études in vitro, in vivo et précliniques concernant le rôle de la kinase CSNK2 dans la physiopathologie des cancers et identifie des applications thérapeutiques possibles

CSNK2 in cancer: pathophysiology and translational applications

Strum, Scott W. ; Gyenis, Laszlo ; Litchfield, David W.

Protein kinase CSNK2 (CK2) is a pleiotropic serine/threonine kinase frequently dysregulated in solid and hematologic malignancies. To consolidate a wide range of biological and clinically oriented data from this unique kinase in cancer, this systematic review summarises existing knowledge from in vitro, in vivo and pre-clinical studies on CSNK2 across 24 different human cancer types. CSNK2 mRNA transcripts, protein levels and activity were found to be routinely upregulated in cancer, and [...]

Menée à l'aide d'une méta-analyse de données transcriptomiques puis menée ex-vivo et in vivo, cette étude met en évidence un mécanisme par lequel la protéine transmembranaire MS4A3 favorise la différenciation des cellules souches et des cellules progénitrices en cellules de leucémie myéloïde chronique via l'augmentation de l'endocytose des récepteurs de cytokines à chaîne bêta commune

MS4A3 Promotes Differentiation in Chronic Myeloid Leukemia by Enhancing Common beta Chain Cytokine Receptor Endocytosis

Zhao, Helong ; Pomicter, Anthony D ; Eiring, Anna M ; Franzini, Anca ; Ahmann, Jonathan ; Hwang, Jae-Yeon ; Senina, Anna V. ; Helton, Bret ; Iyer, Siddharth M ; Yan, Dongqing ; Khorashad, Jamshid S ; Zabriskie, Matthew S ; Agarwal, Anupriya ; Redwine, Hannah M ; Bowler, Amber D ; Clair, Phillip M ; McWeeney, Shannon K. ; Druker, Brian J ; Tyner, Jeffrey W ; Stirewalt, Derek L ; Oehler, Vivian G. ; Varambally, Sooryanarayana ; Berrett, Kristofer C ; Vahrenkamp, Jeffrey M ; Gertz, Jason ; Varley, Katherine E ; Radich, Jerald ; Deininger, Michael W

The chronic phase of chronic myeloid leukemia (CP-CML) is characterized by excessive production of maturating myeloid cells. As CML stem/progenitor cells (LSPCs) are poised to cycle and differentiate, LSPCs must balance conservation and differentiation to avoid exhaustion, similar to normal hematopoiesis under stress. Since BCR-ABL1 tyrosine kinase inhibitors (TKIs) eliminate differentiating cells, but spare BCR-ABL1-independent LSPCs, understanding the mechanisms that regulate LSPC [...]

Menée in vitro et à l'aide de xénogreffes de tumeur mammaire de type basal sur des modèles murins, cette étude met en évidence le rôle de la cystathionine bêta synthase dans la progression et le caractère invasif de ce type de tumeur

Reprogrammed transsulfuration promotes basal-like breast tumor progression via realigning cellular cysteine persulfidation

Erdélyi, Katalin ; Ditrói, Tamás ; Johansson, Henrik J. ; Czikora, Ágnes ; Balog, Noémi ; Silwal-Pandit, Laxmi ; Ida, Tomoaki ; Olasz, Judit ; Hajdú, Dorottya ; Matrai, Zoltan ; Csuka, Orsolya ; Uchida, Koji ; Tóvári, József ; Engebråten, Olav ; Akaike, Takaaki ; Børresen Dale, Anne-Lise ; Kasler, Miklos ; Lehtiö, Janne ; Nagy, Péter

Basal-like breast cancers (BLBC) have poor prognosis. Here, we present evidence that reprogrammed transsulfuration is a hallmark of BLBC. Human BLBC tumors exhibit elevated levels of cystathione β-synthetase (CBS) but diminished expressions of oxidative Cys-catabolizing enzymes supporting a Cys-addicted phenotype. We demonstrated that in BLBC cells, CBS plays a role in cellular proliferation and invasiveness, HIF1-α activation under hypoxia, and protection against oxidative stress and CySSCy [...]

Cet article passe en revue les mécanismes par lesquels les longs ARNs non codants régulent l'épissage alternatif et favorisent la progression tumorale

Long non-coding RNAs are involved in alternative splicing and promote cancer progression

Ouyang, Jiawei ; Zhong, Yu ; Zhang, Yijie ; Yang, Liting ; Wu, Pan ; Hou, Xiangchan ; Xiong, Fang ; Li, Xiayu ; Zhang, Shanshan ; Gong, Zhaojian ; He, Yi ; Tang, Yanyan ; Zhang, Wenling ; Xiang, Bo ; Zhou, Ming ; Ma, Jian ; Li, Yong ; Li, Guiyuan ; Zeng, Zhaoyang ; Guo, Can ; Xiong, Wei

Alternative splicing (AS) is a key process in which precursor RNAs produce different mature RNAs, and the disorder of AS is a key factor in promoting cancer development. Compared with coding RNA, studies on the functions of long non-coding RNAs (lncRNAs) are far from enough. In fact, lncRNA is an important participant and regulator in the process of AS. On the one hand, lncRNAs regulate cancer progression as AS products of precursor messenger RNA (mRNA), but on the other hand, precursor lncRNA [...]

Cet article analyse le rôle des formes linéaire et circulaire des longs ARNs non codants PVT1 dans le cancer et autres maladies

Unravelling similarities and differences in the role of circular and linear PVT1 in cancer and human disease

Traversa, Debora ; Simonetti, Giorgia ; Tolomeo, Doron ; Visci, Grazia ; Macchia, Gemma ; Ghetti, Martina ; Martinelli, Giovanni ; Kristensen, Lasse S. ; Storlazzi, Clelia Tiziana

The plasmacytoma variant translocation 1 (PVT1) is a long non-coding RNA gene involved in human disease, mainly in cancer onset/progression. Although widely analysed, its biological roles need to be further clarified. Notably, functional studies on PVT1 are complicated by the occurrence of multiple transcript variants, linear and circular, which generate technical issues in the experimental procedures used to evaluate its impact on human disease. Among the many PVT1 transcripts, the linear PVT1 [...]

Menée notamment à l'aide d'un modèle murin de cancer de l'ovaire, cette étude met en évidence le rôle des cellules souches mésenchymateuses associées au cancer dans l'exclusion immunitaire et la résistance aux immunothérapies des cellules cancéreuses, puis démontre que l'inhibition de Hedgehog supprime les effets de ces cellules souches mésenchymateuses

Cancer-associated MSC drive tumor immune exclusion and resistance to immunotherapy, which can be overcome by Hedgehog inhibition

Sandra Cascio ; Chelsea Chandler ; Linan Zhang ; Sarah Sinno ; Bingsi Gao ; Sayali Onkar ; Tullia C. Bruno ; Dario A. A. Vignali ; Haider Mahdi ; Hatice U. Osmanbeyoglu ; Anda M. Vlad ; Lan G. Coffman ; Ronald J. Buckanovich

We investigated the impact of cancer-associated mesenchymal stem cells (CA-MSCs) on ovarian tumor immunity. In patient samples, CA-MSC presence inversely correlates with the presence of intratumoral CD8+ T cells. Using an immune “hot” mouse ovarian cancer model, we found that CA-MSCs drive CD8+ T cell tumor immune exclusion and reduce response to anti–PD-L1 immune checkpoint inhibitor (ICI) via secretion of numerous chemokines (Ccl2, Cx3cl1, and Tgf-

Menée à l'aide de cellules cancéreuses, de cellules mésenchymateuses et d'allogreffes d'adénocarcinome canalaire du pancréas sur des modèles murins, cette étude démontre que la pyruvate carboxylase des fibroblastes est nécessaire à la production de collagène dans le microenvironnement tumoral

Fibroblast pyruvate carboxylase is required for collagen production in the tumour microenvironment

Schwörer, Simon ; Pavlova, Natalya N. ; Cimino, Francesco V. ; King, Bryan ; Cai, Xin ; Sizemore, Gina M. ; Thompson, Craig B.

The aberrant production of collagen by fibroblasts is a hallmark of many solid tumours and can influence cancer progression. How the mesenchymal cells in the tumour microenvironment maintain their production of extracellular matrix proteins as the vascular delivery of glutamine and glucose becomes compromised remains unclear. Here we show that pyruvate carboxylase (PC)-mediated anaplerosis in tumour-associated fibroblasts contributes to tumour fibrosis and growth. Using cultured mesenchymal and [...]

Menée à l'aide de lignées cellulaires, de modèles murins et de xénogreffes dérivées de tumeurs de patients atteints d'un cancer du pancréas, cette étude met en évidence un mécanisme par lequel les macrophages sécrétant le TNF alpha déterminent l'identité cellulaire des tumeurs du pancréas, le caractère agressif de ces dernières et le pronostic

TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer

Tu, Mengyu ; Klein, Lukas ; Espinet, Elisa ; Georgomanolis, Theodoros ; Wegwitz, Florian ; Li, Xiaojuan ; Urbach, Laura ; Danieli-Mackay, Adi ; Küffer, Stefan ; Bojarczuk, Kamil ; Mizi, Athanasia ; Günesdogan, Ufuk ; Chapuy, Björn ; Gu, Zuguang ; Neesse, Albrecht ; Kishore, Uday ; Ströbel, Philipp ; Hessmann, Elisabeth ; Hahn, Stephan A. ; Trumpp, Andreas ; Papantonis, Argyris ; Ellenrieder, Volker ; Singh, Shiv K.

Large-scale genomic profiling of pancreatic cancer (PDAC) has revealed two distinct subtypes: ‘classical’ and ‘basal-like’. Their variable coexistence within the stromal immune microenvironment is linked to differential prognosis; however, the extent to which these neoplastic subtypes shape the stromal immune landscape and impact clinical outcome remains unclear. By combining preclinical models, patient-derived xenografts, as well as FACS-sorted PDAC patient biopsies, we show that the [...]