Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence, dans un sous-ensemble de cancers du poumon, un mécanisme par lequel la kinase ARAF supprime l'expression du récepteur ERBB3 et le processus métastatique

ARAF suppresses ERBB3 expression and metastasis in a subset of lung cancers

Juliane Mooz ; Kristina Riegel ; Hari PS ; Anguraj Sadanandam ; Federico Marini ; Matthias Klein ; Ulrike Werner ; Wilfried Roth ; Annett Wilken-Schmitz ; Irmgard Tegeder ; Krishnaraj Rajalingam

RAF kinases are highly conserved serine/threonine kinases, and among the three RAF isoforms (ARAF, BRAF, and CRAF), the pathophysiological relevance of ARAF is not well defined. Here, we show that patients with lung cancer exhibit low expression of ARAF, which is associated with lymph node metastasis and poor patient survival. We uncover that depletion of ARAF promotes anchorage-independent growth and metastasis through activation of AKT signaling in a subset of lung cancer cells. We identified [...]

Menée in vitro et à l'aide de deux modèles murins de leucémie myéloïde aiguë, cette étude met en évidence une corrélation entre la diméthylation de la lysine 9 de l'histone H3 et l'absence d'activation de la voie de signalisation de l'interféron

H3K9 dimethylation safeguards cancer cells against activation of the interferon pathway

Anne Meldgaard Hansen ; Ying Ge ; Mikkel Bruhn Schuster ; Sachin Pundhir ; Janus Schou Jakobsen ; Adrija Kalvisa ; Marta Cecylia Tapia ; Sandra Gordon ; Francesca Ambri ; Frederik Otzen Bagger ; Deo Pandey ; Kristian Helin ; Bo Torben Porse

Activation of interferon genes constitutes an important anticancer pathway able to restrict proliferation of cancer cells. Here, we demonstrate that the H3K9me3 histone methyltransferase (HMT) suppressor of variegation 3–9 homolog 1 (SUV39H1) is required for the proliferation of acute myeloid leukemia (AML) and find that its loss leads to activation of the interferon pathway. Mechanistically, we show that this occurs via destabilization of a complex composed of SUV39H1 and the two H3K9me2 HMTs, [...]

Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux issus de patientes atteintes d'un cancer de l'ovaire, cette étude met en évidence le rôle de la chimiokine CXCL9 dans l'inhibition de la croissance tumorale et la réponse aux inhibiteurs de points de contrôle immunitaire

CXCL9 inhibits tumour growth and drives anti-PD-L1 therapy in ovarian cancer

Seitz, Stefanie ; Dreyer, Tobias F. ; Stange, Christoph ; Steiger, Katja ; Bräuer, Rosalinde ; Scheutz, Leandra ; Multhoff, Gabriele ; Weichert, Wilko ; Kiechle, Marion ; Magdolen, Viktor ; Bronger, Holger

Background : Response to immune checkpoint blockade (ICB) in ovarian cancer remains disappointing. Several studies have identified the chemokine CXCL9 as a robust prognosticator of improved survival in ovarian cancer and a characteristic of the immunoreactive subtype, which predicts ICB response. However, the function of CXCL9 in ovarian cancer has been poorly studied. Methods : Impact of Cxcl9 overexpression in the murine ID8-Trp53  [...]

Menée à l'aide de lignées cellulaires de cancer du poumon, d'échantillons tumoraux et d'un modèle murin, cette étude met en évidence un mécanisme par lequel la phosphorylation, induite par la signalisation de la kinase ERK2, et le transport du complexe enzymatique PDHE1 alpha dans la mitochondrie favorisent l'échappement immunitaire de la tumeur

MAPK signalling-induced phosphorylation and subcellular translocation of PDHE1alpha promotes tumour immune evasion

Zhang, Yajuan ; Zhao, Ming ; Gao, Hong ; Yu, Guanzhen ; Zhao, Yun ; Yao, Feng ; Yang, Weiwei

Tumour cells utilize multiple strategies to evade the immune system, but the underlying metabolic mechanisms remain poorly understood. The pyruvate dehydrogenase (PDH) complex converts pyruvate to acetyl-coenzyme A in mitochondria, thereby linking glycolysis to the ricarboxylic acid cycle. Here we show that the PDH complex E1 subunit α (PDHE1α) is also located in the cytosol. Cytosolic PDHE1α interacts with IKKβ and protein phosphatase 1B, thereby facilitating the inhibition of the NF-κB [...]

Menée à l'aide de lignées cellulaires et de modèles murins, cette étude met en évidence le rôle du facteur de transcription BHLHE40 dans l'efficacité antitumorale des inhibiteurs de points de contrôle immunitaire

BHLHE40 Regulates the T-Cell Effector Function Required for Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy

Salmon, Avery J. ; Shavkunov, Alexander S. ; Miao, Qi ; Jarjour, Nicholas N. ; Keshari, Sunita ; Esaulova, Ekaterina ; Williams, Charmelle D. ; Ward, Jeffrey P. ; Highsmith, Anna M. ; Pineda, Josué E. ; Taneja, Reshma ; Chen, Ken ; Edelson, Brian T. ; Gubin, Matthew M.

Immune checkpoint therapy (ICT) using antibody blockade of programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can provoke T cell–dependent antitumor activity that generates durable clinical responses in some patients. The epigenetic and transcriptional features that T cells require for efficacious ICT remain to be fully elucidated. Herein, we report that anti–PD-1 and anti–CTLA-4 ICT induce upregulation of the transcription factor BHLHE40 in tumor [...]

Cette étude analyse, en fonction de l'origine ethnique des patients et pour sept types de cancer, la qualité des données de séquençage incluses dans la base du projet "The Cancer Genome Atlas"

Lower Exome Sequencing Coverage of Ancestrally African Patients in the Cancer Genome Atlas

Wickland, Daniel P. ; Sherman, Mark E. ; Radisky, Derek C. ; Mansfield, Aaron S. ; Asmann, Yan W.

Background : In the US, cancer disproportionately impacts Black and African American individuals. Identifying genetic factors underlying cancer disparities has been an important research focus and requires data that are equitable in both quantity and quality across racial groups. It is widely recognized that DNA databases quantitatively under-represent minorities. However, the differences in data quality between racial groups have not been well studied. Methods : We compared the qualities of [...]

Menée à l'aide de lignées cellulaires ainsi que d'échantillons sanguins et tumoraux issus de patientes atteintes d'un carcinome séreux ovarien de haut grade, cette étude identifie l'origine des anticorps ciblant les antigènes tumoraux

Tumor-reactive antibodies evolve from non-binding and autoreactive precursors

Mazor, Roei D. ; Nathan, Nachum ; Gilboa, Amit ; Stoler-Barak, Liat ; Moss, Lihee ; Solomonov, Inna ; Hanuna, Assaf ; Divinsky, Yalin ; Shmueli, Merav D. ; Hezroni, Hadas ; Zaretsky, Irina ; Mor, Michael ; Golani, Ofra ; Sabah, Gad ; Jakobson-Setton, Ariella ; Yanichkin, Natalia ; Feinmesser, Meora ; Tsoref, Daliah ; Salman, Lina ; Yeoshoua, Effi ; Peretz, Eyal ; Erlich, Inna ; Cohen, Netta Mendelson ; Gershoni, Jonathan M. ; Freund, Natalia ; Merbl, Yifat ; Yaari, Gur ; Eitan, Ram ; Sagi, Irit ; Shulman, Ziv

The tumor microenvironment hosts antibody-secreting cells (ASCs) associated with a favorable prognosis in several types of cancer. Patient-derived antibodies have diagnostic and therapeutic potential; yet, it remains unclear how antibodies gain autoreactivity and target tumors. Here, we found that somatic hypermutations (SHMs) promote antibody antitumor reactivity against surface autoantigens in high-grade serous ovarian carcinoma (HGSOC). Patient-derived tumor cells were frequently coated with [...]

Menée à partir d'échantillons sanguins, d'échantillons tumoraux, d'échantillons de tissus adjacents, d'échantillons ganglionnaires et d'ascites provenant de 17 patients atteints d'un cancer colorectal, cette étude analyse les caractéristiques immunitaires du microenvironnement des tumeurs primitives et de leurs métastases

Immune phenotypic linkage between colorectal cancer and liver metastasis

Liu, Yedan ; Zhang, Qiming ; Xing, Baocai ; Luo, Nan ; Gao, Ranran ; Yu, Kezhuo ; Hu, Xueda ; Bu, Zhaode ; Peng, Jirun ; Ren, Xianwen ; Zhang, Zemin

The tumor microenvironment (TME) is connected to immunotherapy responses, but it remains unclear how cancer cells and host tissues differentially influence the immune composition within TME. Here, we performed single-cell analyses for autologous samples from liver metastasized colorectal cancer to disentangle factors shaping TME. By aligning CD45+ cells across different tissues, we classified exhausted CD8+ T cells (Texs) and activated regulatory T cells as M-type, whose phenotypes were [...]

Menée in vitro et à l'aide de modèles murins, cette étude évalue l'intérêt d'une nouvelle lignée cellulaire, dérivée d'une lignée de cellules de carcinome lobulaire invasif, pour étudier in vivo la croissance des tumeurs primitives et des métastases

VIVA1: a more invasive subclone of MDA-MB-134VI invasive lobular carcinoma cells with increased metastatic potential in xenograft models

Allen, Victoria ; Coulombe, Josée ; Zhao, Huijun ; Kreps, Lauren M. ; Cook, David P. ; Pryce, Benjamin ; Clemons, Mark ; Vanderhyden, Barbara C. ; Gray, Douglas A. ; Addison, Christina L.

Background : Invasive lobular carcinoma (ILC) is the second most common type of breast cancer. As few tools exist to study ILC metastasis, we isolated ILC cells with increased invasive properties to establish a spontaneously metastasising xenograft model. Methods : MDA-MB-134VI ILC cells were placed in transwells for 7 days. Migrated cells were isolated and expanded to create the VIVA1 cell line. VIVA1 cells were compared to parental MDA-MB-134VI cells in vitro for ILC marker expression and [...]

Menée à partir de l'analyse génomique et transcriptomique, à l'échelle d'une seule cellule, de 12 glioblastomes ne présentant pas de mutation de l'isocitrate déshydrogénase, d'explants et de lignées de gliomasphères provenant de tumeurs de patients, cette étude compare l'hétérogénéité intratumorale et phénotypique des tissus tumoraux et des différents modèles dérivés de ces tissus

Single-cell landscapes of primary glioblastomas and matched explants and cell lines show variable retention of inter- and intratumor heterogeneity

LeBlanc, Véronique G. ; Trinh, Diane L. ; Aslanpour, Shaghayegh ; Hughes, Martha ; Livingstone, Dorothea ; Jin, Dan ; Ahn, Bo Young ; Blough, Michael D. ; Cairncross, J. Gregory ; Chan, Jennifer A. ; Kelly, John J. P. ; Marra, Marco A.

Glioblastomas (GBMs) are aggressive brain tumors characterized by extensive inter- and intratumor heterogeneity. Patient-derived models, such as organoids and explants, have recently emerged as useful models to study such heterogeneity, although the extent to which they can recapitulate GBM genomic features remains unclear. Here, we analyze bulk exome and single-cell genome and transcriptome profiles of 12 IDH wild-type GBMs, including two recurrent tumors, and of patient-derived explants [...]