Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel l'expression de la gasdermine c induite par la protéine PD-L1 facilite la nécrose tumorale en favorisant le basculement de l'apoptose vers la pyroptose dans les cellules cancéreuses

PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis

Hou, Junwei ; Zhao, Rongce ; Xia, Weiya ; Chang, Chiung-Wen ; You, Yun ; Hsu, Jung-Mao ; Nie, Lei ; Chen, Yeh ; Wang, Yu-Chuan ; Liu, Chunxiao ; Wang, Wei-Jan ; Wu, Yun ; Ke, Baozhen ; Hsu, Jennifer L. ; Huang, Kebin ; Ye, Zu ; Yang, Yi ; Xia, Xianghou ; Li, Yintao ; Li, Chia-Wei ; Shao, Bin ; Tainer, John A. ; Hung, Mien-Chie

Although pyroptosis is critical for macrophages against pathogen infection, its role and mechanism in cancer cells remains unclear. PD-L1 has been detected in the nucleus, with unknown function. Here we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumour necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing the transcription of the gasdermin C (GSDMC) gene. GSDMC is specifically [...]

Menée in vitro et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la perte de l'expression des sous-unités ARID1A et ARID1B des complexes BAF favorise le développement rapide d'une tumeur

Dual ARID1A/ARID1B loss leads to rapid carcinogenesis and disruptive redistribution of BAF complexes

Wang, Zixi ; Chen, Kenian ; Jia, Yuemeng ; Chuang, Jen-Chieh ; Sun, Xuxu ; Lin, Yu-Hsuan ; Celen, Cemre ; Li, Lin ; Huang, Fang ; Liu, Xin ; Castrillon, Diego H. ; Wang, Tao ; Zhu, Hao

SWI/SNF chromatin remodelers play critical roles in development and cancer. The causal links between SWI/SNF complex disassembly and carcinogenesis are obscured by redundancy between paralogous components. Canonical BAF (cBAF)-specific paralogs ARID1A and ARID1B are synthetic lethal in some contexts, but simultaneous mutations in both ARID1s are prevalent in cancer. To understand if and how cBAF abrogation causes cancer, we examined the physiological and biochemical consequences of [...]

Menée sur des drosophiles, cette étude met en évidence un mécanisme par lequel le métabolisme oxydatif favorise l'immortalisation des cellules souches neurales pendant la tumorigenèse

Oxidative Metabolism Drives Immortalization of Neural Stem Cells during Tumorigenesis

Bonnay, François ; Veloso, Ana ; Steinmann, Victoria ; Kocher, Thomas ; Abdusselamoglu, Merve Deniz ; Bajaj, Sunanjay ; Rivelles, Elisa ; Landskron, Lisa ; Esterbauer, Harald ; Zinzen, Robert P. ; Knoblich, Juergen A.

Metabolic reprogramming is a key feature of many cancers, but how and when it contributes to tumorigenesis remains unclear. Here we demonstrate that metabolic reprogramming induced by mitochondrial fusion can be rate-limiting for immortalization of tumor-initiating cells (TICs) and trigger their irreversible dedication to tumorigenesis. Using single-cell transcriptomics, we find that Drosophila brain tumors contain a rapidly dividing stem cell population defined by upregulation of oxidative [...]

Menée notamment à l'aide d'un modèle murin et de la microscopie en fluorescence, cette étude met en évidence le rôle de la protéine PD-1 dans la suppression de la fonction des lymphocytes T CD8+ intratumoraux

PD-1 suppresses the maintenance of cell couples between cytotoxic T cells and target tumor cells within the tumor

Ambler, Rachel ; Edmunds, Grace L. ; Tan, Sin Lih ; Cirillo, Silvia ; Pernes, Jane I. ; Ruan, Xiongtao ; Huete-Carrasco, Jorge ; Wong, Carissa C. W. ; Lu, Jiahe ; Ward, Juma ; Toti, Giulia ; Hedges, Alan J. ; Dovedi, Simon J. ; Murphy, Robert F. ; Morgan, David J. ; Wülfing, Christoph

When cytotoxic T cells enter tumors and become tumor-infiltrating lymphocytes (TILs), they lose their ability to kill target tumor cells. TILs in this state express inhibitory receptors, including PD-1, which are engaged in the tumor environment. Ambler et al. performed imaging analysis of mouse TILs ex vivo and showed that the suppressed cells had defective Ca2+ signaling, impaired cytoskeletal rearrangements, and a decreased ability to form productive contacts with their targets. Blocking [...]

Menée à l'aide d'un modèle mathématique et de données de séquençage portant sur 879 tumeurs du côlon, de l'estomac ou de l'endomètre, cette étude analyse l'évolution des néoantigènes lors de la croissance tumorale

Evolutionary dynamics of neoantigens in growing tumors

Lakatos, Eszter ; Williams, Marc J. ; Schenck, Ryan O. ; Cross, William C. H. ; Househam, Jacob ; Zapata, Luis ; Werner, Benjamin ; Gatenbee, Chandler ; Robertson-Tessi, Mark ; Barnes, Chris P. ; Anderson, Alexander R. A. ; Sottoriva, Andrea ; Graham, Trevor A.

Cancers accumulate mutations that lead to neoantigens, novel peptides that elicit an immune response, and consequently undergo evolutionary selection. Here we establish how negative selection shapes the clonality of neoantigens in a growing cancer by constructing a mathematical model of neoantigen evolution. The model predicts that, without immune escape, tumor neoantigens are either clonal or at low frequency; hypermutated tumors can only establish after the evolution of immune escape. [...]

Menée notamment à l'aide de modèles murins de leucémie aiguë lymphoblastique à cellules B, cette étude met en évidence un mécanisme par lequel les cellules cancéreuses favorisent la destruction osseuse via la voie de signalisation du récepteur activateur du facteur nucléaire kappa B (RANK)

B cell acute lymphoblastic leukemia cells mediate RANK-RANKL–dependent bone destruction

Rajakumar, Sujeetha A. ; Papp, Eniko ; Lee, Kathy K. ; Grandal, Ildiko ; Merico, Daniele ; Liu, Careesa C. ; Allo, Bedilu ; Zhang, Lucia ; Grynpas, Marc D. ; Minden, Mark D. ; Hitzler, Johann K. ; Guidos, Cynthia J. ; Danska, Jayne S.

B cell acute lymphoblastic leukemia is the most common type of cancer in children. Although this malignancy is often curable, it can cause multiple complications affecting the bone, sometimes even before the leukemia itself is diagnosed. To figure out what mediates the bone damage, Rajakumar et al. analyzed leukemia samples derived from human patients and performed mechanistic experiments in mouse models of both genetically engineered and transplanted cancer. They identified receptor activator [...]

Menée à l'aide de lignées cellulaires humaines de cancer du sein et à l'aide de données cliniques, cette étude met en évidence un mécanisme par lequel la différenciation ostéogène des cellules cancéreuses favorise le processus métastatique

OXPHOS-dependent metabolic reprogramming prompts metastatic potential of breast cancer cells under osteogenic differentiation

Hu, Yangling ; Xu, Weimin ; Zeng, Hui ; He, Zilong ; Lu, Xiao ; Zuo, Daming ; Qin, Genggeng ; Chen, Weiguo

Background : Microcalcification is one of the most reliable clinical features of the malignancy risk of breast cancer, and it is associated with enhanced tumour aggressiveness and poor prognosis. However, its underlying molecular mechanism remains unclear. Methods : Clinical data were retrieved to analyse the association between calcification and bone metastasis in patients with breast cancer. Using multiple human breast cancer cell lines, the osteogenic cocktail model was established in vitro [...]

Menée à l'aide de modèles murins de cancer du sein ER+, cette étude met en évidence un mécanisme par lequel la voie de signalisation IL6/STAT3 favorise le processus métastatique via les mêmes régions amplificatrices que celles utilisées par la voie de signalisation ER/FOXA1

IL6/STAT3 Signaling Hijacks Estrogen Receptor alpha

Siersbæk, Rasmus ; Scabia, Valentina ; Nagarajan, Sankari ; Chernukhin, Igor ; Papachristou, Evangelia K. ; Broome, Rebecca ; Johnston, Simon J. ; Joosten, Stacey E. P. ; Green, Andrew R. ; Kumar, Sanjeev ; Jones, Julia ; Omarjee, Soleilmane ; Alvarez-Fernandez, Ruben ; Glont, Silvia ; Aitken, Sarah J. ; Kishore, Kamal ; Cheeseman, Danya ; Rakha, Emad A. ; D'Santos, Clive ; Zwart, Wilbert ; Russell, Alasdair ; Brisken, Cathrin ; Carroll, Jason S.

The cytokine interleukin-6 (IL6) and its downstream effector STAT3 constitute a key oncogenic pathway, which has been thought to be functionally connected to estrogen receptor α (ER) in breast cancer. We demonstrate that IL6/STAT3 signaling drives metastasis in ER+ breast cancer independent of ER. STAT3 hijacks a subset of ER enhancers to drive a distinct transcriptional program. Although these enhancers are shared by both STAT3 and ER, IL6/STAT3 activity is refractory to standard ER-targeted [...]

Cet article présente une méthode, utilisant un algorithme d'apprentissage automatique intégrant des données portant sur la structure de protéines, l'expression de gènes et la présence de mutations dans les tissus tumoraux, pour cartographier les interactions moléculaires d'oncoprotéines

Oncoprotein-specific molecular interaction maps (SigMaps) for cancer network analyses

Broyde, Joshua ; Simpson, David R. ; Murray, Diana ; Paull, Evan O. ; Chu, Brennan W. ; Tagore, Somnath ; Jones, Sunny J. ; Griffin, Aaron T. ; Giorgi, Federico M. ; Lachmann, Alexander ; Jackson, Peter ; Sweet-Cordero, E. Alejandro ; Honig, Barry ; Califano, Andrea

Tumor-specific elucidation of physical and functional oncoprotein interactions could improve tumorigenic mechanism characterization and therapeutic response prediction. Current interaction models and pathways, however, lack context specificity and are not oncoprotein specific. We introduce SigMaps as context-specific networks, comprising modulators, effectors and cognate binding-partners of a specific oncoprotein. SigMaps are reconstructed de novo by integrating diverse evidence [...]

Cet article passe en revue les facteurs associés au mode de vie qui contribuent à la dérégulation du métabolisme et du système immunitaire et favorisent la tumorigenèse, puis analyse la façon dont l'exercice physique peut agir sur cette dérégulation et améliorer la fonction des tissus

Exercise and immunometabolic regulation in cancer

Koelwyn, Graeme J. ; Zhuang, Xueqian ; Tammela, Tuomas ; Schietinger, Andrea ; Jones, Lee W.

Unhealthful lifestyle factors, such as obesity, disrupt organismal homeostasis and accelerate cancer pathogenesis, partly through metabolic and immunological dysregulation. Exercise is a prototypical strategy that maintains and restores homeostasis at the organismal, tissue, cellular and molecular levels and can prevent or inhibit numerous disease conditions, including cancer. Here, we review unhealthful lifestyle factors that contribute to metabolic and immunological dysregulation and drive [...]

Menée à partir de 47 échantillons tumoraux issus de patients atteints d'un cancer du côlon, d'un adénocarcinome (col utérin, poumon, sein, ovaire, pancréas et estomac) ou d'un carcinome embryonnaire, cette étude analyse l'expression de ciRS-7 (un ARN circulaire présumé oncogène) dans les cellules cancéreuses et le microenvironnement tumoral puis examine la corrélation entre l'expression de ciRS-7 et l'expression de 20 gènes ciblés par le microARN miR-7

Spatial expression analyses of the putative oncogene ciRS-7 in cancer reshape the microRNA sponge theory

Kristensen, Lasse S. ; Ebbesen, Karoline K. ; Sokol, Martin ; Jakobsen, Theresa ; Korsgaard, Ulrik ; Eriksen, Ann C. ; Hansen, Thomas B. ; Kjems, Jørgen ; Hager, Henrik

Circular RNAs (circRNAs) have recently gained substantial attention in the cancer research field where most, including the putative oncogene ciRS-7 (CDR1as), have been proposed to function as competitive endogenous RNAs (ceRNAs)Spatial expression analyses of the putative oncogene ciRS-7 in cancer reshape the microRNA sponge theory. Here, we report the first spatially resolved cellular expression patterns of ciRS-7 in colon cancer and show that ciRS-7 is completely absent in the cancer cells, [...]

Cet article passe en revue les découvertes récentes concernant les altérations de l'ADN non codant, identifie les méthodes permettant d'étudier ces altérations et analyse les perspectives thérapeutiques associées

Illuminating the noncoding genome in cancer

Zhang, Xiaoyang ; Meyerson, Matthew

Understanding the mechanisms underlying tumorigenesis requires comprehensive annotation of the cancer genome. The majority of the human genome consists of noncoding regions, harboring functional elements that regulate the expression of protein-coding genes, including proto-oncogenes or tumor-suppressor genes. Technologies such as whole-genome and long-read sequencing provide powerful means to identify alterations in the noncoding genome of cancer cells, paving the way for the study of their [...]

A partir de l'analyse génomique d'échantillons de cancers hématologiques, cette étude examine la relation entre le sous-type moléculaire de la maladie, ses caractéristiques génétiques et épigénétiques et son environnement immunologique

Immunogenomic Landscape of Hematological Malignancies

Dufva, Olli ; Pölönen, Petri ; Brück, Oscar ; Keränen, Mikko A. I. ; Klievink, Jay ; Mehtonen, Juha ; Huuhtanen, Jani ; Kumar, Ashwini ; Malani, Disha ; Siitonen, Sanna ; Kankainen, Matti ; Ghimire, Bishwa ; Lahtela, Jenni ; Mattila, Pirkko ; Vähä-Koskela, Markus ; Wennerberg, Krister ; Granberg, Kirsi ; Leivonen, Suvi-Katri ; Meriranta, Leo ; Heckman, Caroline ; Leppä, Sirpa ; Nykter, Matti ; Lohi, Olli ; Heinäniemi, Merja ; Mustjoki, Satu

Understanding factors that shape the immune landscape across hematological malignancies is essential for immunotherapy development. We integrated over 8,000 transcriptomes and 2,000 samples with multilevel genomics of hematological cancers to investigate how immunological features are linked to cancer subtypes, genetic and epigenetic alterations, and patient survival, and validated key findings experimentally. Infiltration of cytotoxic lymphocytes was associated with TP53 and [...]