Menée à partir d'échantillons sanguins et d'échantillons de moelle osseuse prélevés sur 34 patients pédiatriques atteints d'un cancer et sur certains de leurs parents, cette étude identifie, à l'aide d'une cartographie optique du génome, trois nouveaux variants constitutionnels susceptibles de prédisposer au cancer, deux altérations génétiques affectant BRCA2 et un nouveau gène de susceptibilité (RPA1)

Optical genome mapping identifies structural variants in potentially new cancer predisposition candidate genes in pediatric cancer patients

Wagener, Rabea ; Brandes, Danielle ; Jung, Marie ; Huetzen, Maxim A. ; Bergmann, Anke K. ; Panier, Stephanie ; Picard, Daniel ; Fischer, Ute ; Jachimowicz, Ron D. ; Borkhardt, Arndt ; Brozou, Triantafyllia

Genetic predisposition is one of the major risk factors for pediatric cancer, with ~10% of children being carriers of a predisposing germline alteration. It is likely that this is the tip of the iceberg and many children are underdiagnosed, as most of the analysis focuses on single or short nucleotide variants, not considering the full spectrum of DNA alterations. Hence, we applied optical genome mapping (OGM) to our cohort of 34 pediatric cancer patients to perform an unbiased germline [...]

Menée à l'aide de lignées cellulaires, de sphéroïdes et de modèles murins de cancer du poumon à petites cellules, cette étude met en évidence un mécanisme par lequel des interactions entre les cellules cancéreuses et les astrocytes favorisent la formation de métastases cérébrales en induisant des programmes d'expression génétique similaires à ceux impliqués dans le développement du cerveau

Crosstalk between small-cell lung cancer cells and astrocytes mimics brain development to promote brain metastasis

Qu, Fangfei ; Brough, Siqi C. ; Michno, Wojciech ; Madubata, Chioma J. ; Hartmann, Griffin G. ; Puno, Alyssa ; Drainas, Alexandros P. ; Bhattacharya, Debadrita ; Tomasich, Erwin ; Lee, Myung Chang ; Yang, Dian ; Kim, Jun ; Peiris-Pagès, Maria ; Simpson, Kathryn L. ; Dive, Caroline ; Preusser, Matthias ; Toland, Angus ; Kong, Christina ; Das, Millie ; Winslow, Monte M. ; Pasca, Anca M. ; Sage, Julien

Brain metastases represent an important clinical problem for patients with small-cell lung cancer (SCLC). However, the mechanisms underlying SCLC growth in the brain remain poorly understood. Here, using intracranial injections in mice and assembloids between SCLC aggregates and human cortical organoids in culture, we found that SCLC cells recruit reactive astrocytes to the tumour microenvironment. This crosstalk between SCLC cells and astrocytes drives the induction of gene expression [...]

Menée à l'aide de lignées cellulaires, d'organoïdes et de modèles murins de cancer colorectal, cette étude met en évidence un mécanisme par lequel la GTPase KRAS, en déclenchant la transformation des fibroblastes associés au cancer en fibroblastes riches en lipides, favorise l'angiogenèse et la progression de la tumeur

Oncogenic KRAS drives lipo-fibrogenesis to promote angiogenesis and colon cancer progression

Hsu, Wen-Hao ; LaBella, Kyle A. ; Lin, Yiyun ; Xu, Ping ; Lee, Rumi ; Hsieh, Cheng-En ; Yang, Lei ; Zhou, Ashley ; Blecher, Jonathan M. ; Wu, Chang-Jiun ; Lin, Kangyu ; Shang, Xiaoying ; Jiang, Shan ; Spring, Denise J. ; Xia, Yan ; Chen, Peiwen ; Shen, John Paul. ; Kopetz, Scott ; DePinho, Ronald A.

Oncogenic KRAS (KRAS*) contributes to many cancer hallmarks. In colorectal cancer (CRC), KRAS* suppresses anti–tumor immunity to promote tumor invasion and metastasis. Here, we uncovered that KRAS* transforms the phenotype of carcinoma-associated fibroblasts (CAFs) into lipid–laden CAFs, promoting angiogenesis and tumor progression. Mechanistically, KRAS* activates the transcription factor CP2 (TFCP2) which upregulates the expression of the pro–adipogenic factors BMP4 and WNT5B, triggering the [...]

Menée notamment à l'aide de lignées cellulaires de tumeurs germinales et d'échantillons tumoraux, cette étude analyse le rôle de groupes de microARNs (miR-371 à 373 et miR-302/267) dans la régulation du cycle des cellules cancéreuses

Targeting oncogenic microRNAs from the miR-371~373 and miR-302/267 clusters in malignant germ cell tumours causes growth inhibition through cell cycle disruption

Bailey, Shivani ; Ferraresso, Marta ; Alonso-Crisostomo, Luz ; Ward, Dawn ; Smith, Stephen ; Nicholson, James C. ; Saini, Harpreet ; Enright, Anton J. ; Scarpini, Cinzia G. ; Coleman, Nicholas ; Murray, Matthew J.

Background : MiR-371~373 and miR-302/367 cluster over-expression occurs in all malignant germ cell tumours (GCTs), regardless of age (paediatric/adult), site (gonadal/extragonadal), or subtype [seminoma, yolk sac tumour (YST), embryonal carcinoma (EC)]. Six of eight microRNAs from these clusters contain the seed sequence ‘AAGUGC’, determining mRNA targeting. Here we sought to identify the significance of these observations by targeting these microRNAs functionally. Methods : We targeted [...]

Cet article examine la régulation et les rôles biologiques de la protéine TXNIP dans le microenvironnement tumoral

The role of TXNIP in cancer: a fine balance between redox, metabolic, and immunological tumor control

Deng, Jinhai ; Pan, Teng ; Liu, Zaoqu ; McCarthy, Caitlin ; Vicencio, Jose M. ; Cao, Lulu ; Alfano, Giovanna ; Suwaidan, Ali Abdulnabi ; Yin, Mingzhu ; Beatson, Richard ; Ng, Tony

Thioredoxin-interacting protein (TXNIP) is commonly considered a master regulator of cellular oxidation, regulating the expression and function of Thioredoxin (Trx). Recent work has identified that TXNIP has a far wider range of additional roles: from regulating glucose and lipid metabolism, to cell cycle arrest and inflammation. Its expression is increased by stressors commonly found in neoplastic cells and the wider tumor microenvironment (TME), and, as such, TXNIP has been extensively [...]

Cet article décrit les données génétiques et cliniques mises à disposition par le "Kids First Data Resource Centre" (DRC) et le "Kids First Portal" sur les cancers pédiatriques ainsi que les malformations congénitales

Leveraging Existing Pediatric Cancer Data through the Gabriella Miller Kids First Data Resource

Hudson, Alexandra ; Fournier, Marcia ; Coulombe, James ; Daee, Danielle

Childhood cancer and birth defects (BDs) are leading causes of childhood mortality, and studies suggest that BDs increase pediatric cancer risk. The Gabriella Miller Kids First Pediatric Research Program (Kids First) seeks to alleviate these conditions by building an expansive resource of genetic and clinical data from pediatric cancer and BD patients and families. This article describes the data and support provided by the Kids First Data Resource Center (DRC) and the Kids First Portal, which [...]

Menée à l'aide de modèles murins d'adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel le stress et les catécholamines, via le récepteur adrénergique bêta 1, favorisent l'épuisement des lymphocytes T

The beta1-adrenergic receptor links sympathetic nerves to T cell exhaustion

Globig, Anna-Maria ; Zhao, Steven ; Roginsky, Jessica ; Maltez, Vivien I. ; Guiza, Juan ; Avina-Ochoa, Natalia ; Heeg, Maximilian ; Araujo Hoffmann, Filipe ; Chaudhary, Omkar ; Wang, Jiawei ; Senturk, Gokhan ; Chen, Dan ; O’Connor, Carolyn ; Pfaff, Samuel ; Germain, Ronald N. ; Schalper, Kurt A. ; Emu, Brinda ; Kaech, Susan M.

CD8+ T cells are essential components of the immune response against viral infections and tumours, and are capable of eliminating infected and cancerous cells. However, when the antigen cannot be cleared, T cells enter a state known as exhaustion1. Although it is clear that chronic antigen contributes to CD8+ T cell exhaustion, less is known about how stress responses in tissues regulate T cell function. Here we show a new link between the stress-associated catecholamines and the progression of [...]