Menée à l'aide de modèles murins et de données épigénétiques portant sur des échantillons de muqueuses coliques d'origine humaine, cette étude démontre que la mutation du gène BRAF peut induire une transformation néoplasique rapide au niveau des épithéliums intestinaux âgés ou présentant une méthylation aberrante de l'ADN

Braf mutation induces rapid neoplastic transformation in the aged and aberrantly methylated intestinal epithelium

Fennell, Lochlan ; Kane, Alexandra ; Liu, Cheng ; McKeone, Diane ; Hartel, Gunter ; Su, Chang ; Bond, Catherine ; Bettington, Mark ; Leggett, Barbara ; Whitehall, Vicki

Objective : Sessile serrated lesions (SSLs) are common across the age spectrum, but the BRAF mutant cancers arising occur predominantly in the elderly. Aberrant DNA methylation is uncommon in SSL from young patients. Here, we interrogate the role of ageing and DNA methylation in SSL initiation and progression. Design : We used an inducible model of Braf mutation to direct recombination of the oncogenic Braf V637E allele to the murine intestine. BRAF mutation was activated after periods of [...]

Menée à l'aide d'échantillons de tumeurs colorectales, d'échantillons de tissus adjacents et de modèles murins, cette étude met en évidence un mécanisme par lequel l'intégrine bêta 7, en maintenant l'immunité antitumorale, inhibe la tumorigenèse et la progression tumorale

Integrin beta7 Inhibits Colorectal Cancer Pathogenesis via Maintaining Antitumor Immunity

Zhang, Youhua ; Xie, Ruting ; Zhang, Hailong ; Zheng, Yajuan ; Lin, Changdong ; Yang, Lei ; Huang, Mengwen ; Li, Man ; Song, Feifei ; Lu, Ling ; Yang, Muqing ; Liu, Ying ; Wei, Qing ; Li, Jiyu ; Chen, Jianfeng

Immune cell infiltration is important for predicting the clinical outcomes of colorectal cancer. Integrin β7 (ITGB7), which is expressed on the surface of leukocytes, plays an essential role in the homing of immune cells to gut-associated lymphoid tissue and facilitating the retention of lymphocytes in gut epithelium; however, its role in colorectal cancer pathogenesis is poorly explored. Here, we found that the number of β7+ cells decreased significantly in tumor tissue compared with adjacent [...]

Menée in vitro et à l'aide de modèles murins de cancer de la prostate, cette étude met en évidence le rôle du facteur de transcription HOXB9 dans la tumorigenèse et le processus métastatique

Insights into homeobox B9: a propeller for metastasis in dormant prostate cancer progenitor cells

Sui, Yi ; Hu, Wei ; Zhang, Wei ; Li, Dejian ; Zhu, Hongbo ; You, Qinghua ; Zhu, Rujian ; Yi, Qingtong ; Tang, Tao ; Gao, Lili ; Zhu, Shengjuan ; Yang, Tao

Background : Metastasis is the major cause of treatment failure and cancer-related deaths in prostate cancer (PCa) patients. Our previous study demonstrated that a CD44+ subpopulation isolated from PCa cells or tumours possesses both stem cell properties and metastatic potential, serving as metastatic prostate cancer stem cells (mPCSCs) in PCa metastasis. However, the underlying mechanisms remain unknown. Methods : In this study, we established PCa models via the orthotopic and subcutaneous [...]

Menée à l'aide de données du projet "The Cancer Genome Atlas", de modèles murins ainsi que d'échantillons tumoraux et sanguins issus de patientes atteintes d'un cancer du sein triple négatif, cette étude met en évidence un mécanisme par lequel la voie de signalisation de la kinase JNK, via la formation d'un microenvironnement tumoral immunosuppresseur, favorise le développement d'une tumeur agressive

Identification of the JNK-Active Triple-Negative Breast Cancer Cluster Associated with an Immunosuppressive Tumor Microenvironment

Semba, Takashi ; Wang, Xiaoping ; Xie, Xuemei ; Cohen, Evan N. ; Reuben, James M. ; Dalby, Kevin N. ; Long, James P. ; Hanh Phi, Lan Thi ; Tripathy, Debu ; Ueno, Naoto T.

Background : Although an immunosuppressive tumor microenvironment (TME) is key for tumor progression, the molecular characteristics associated with the immunosuppressive TME remain unknown in triple-negative breast cancer (TNBC). Our previous functional proteomic study of TNBC tumors identified that C-JUN N-terminal kinase (JNK) pathway–related molecules were enriched in a cluster associated with the inflammatory pathway. However, the role of the JNK pathway in the TNBC TME is still unclear. [...]

Menée à l'aide de lignées cellulaires cancéreuses et de xénogreffes sur des modèles murins, cette étude met en évidence un mécanisme par lequel l'activation enzymatique de la pyruvate kinase, en augmentant la concentration cytosolique de l'oxaloacétate, inhibe l'effet de Warburg

Enzymatic activation of pyruvate kinase increases cytosolic oxaloacetate to inhibit the Warburg effect

Wiese, Elizabeth K. ; Hitosugi, Sadae ; Loa, Sharon T. ; Sreedhar, Annapoorna ; Andres-Beck, Lindsey G. ; Kurmi, Kiran ; Pang, Yuan-Ping ; Karnitz, Larry M. ; Gonsalves, Wilson I. ; Hitosugi, Taro

Pharmacological activation of the glycolytic enzyme PKM2 or expression of the constitutively active PKM1 isoform in cancer cells results in decreased lactate production, a phenomenon known as the PKM2 paradox in the Warburg effect. Here we show that oxaloacetate (OAA) is a competitive inhibitor of human lactate dehydrogenase A (LDHA) and that elevated PKM2 activity increases de novo synthesis of OAA through glutaminolysis, thereby inhibiting LDHA in cancer cells. We also show that replacement [...]

Menée à partir de données multi-omiques portant sur 217 patients atteints d'une leucémie lymphoïde chronique et validée sur une cohorte de 547 patients complémentaires, cette étude identifie un axe biologique associé à l'activation de l'axe mTOR-MYC-OXPHOS et aux résultats cliniques

Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia

Lu, Junyan ; Cannizzaro, Ester ; Meier-Abt, Fabienne ; Scheinost, Sebastian ; Bruch, Peter-Martin ; Giles, Holly A. R. ; Lütge, Almut ; Hüllein, Jennifer ; Wagner, Lena ; Giacopelli, Brian ; Nadeu, Ferran ; Delgado, Julio ; Campo, Elias ; Mangolini, Maurizio ; Ringshausen, Ingo ; Böttcher, Martin ; Mougiakakos, Dimitrios ; Jacobs, Andrea ; Bodenmiller, Bernd ; Dietrich, Sascha ; Oakes, Christopher C. ; Zenz, Thorsten ; Huber, Wolfgang

Chronic lymphocytic leukemia (CLL) has a complex pattern of driver mutations and much of its clinical diversity remains unexplained. We devised a method for simultaneous subgroup discovery across multiple data types and applied it to genomic, transcriptomic, DNA methylation and ex vivo drug response data from 217 patients with CLL. We uncovered a biological axis of heterogeneity strongly associated with clinical behavior and orthogonal to known biomarkers. We validated its presence and clinical [...]

Menée sur deux lignées cellulaires humaines d'érythroleucémie, cette étude met en évidence un mécanisme par lequel le complexe protéique formé par la méthyltransférase DOTL1 et les protéines AF10/AF17 et ENL/AF9 régule l'initiation de la transcription

DOT1L complex regulates transcriptional initiation in human erythroleukemic cells

Wu, Aiwei ; Zhi, Junhong ; Tian, Tian ; Cihan, Ali ; Cevher, Murat A. ; Liu, Ziling ; David, Yael ; Muir, Tom W. ; Roeder, Robert G. ; Yu, Ming

DOT1L, the only H3K79 methyltransferase in human cells, forms a complex with AF10/AF17 and ENL/AF9, is dysregulated in mixed-lineage leukemia (MLLr), and is believed to regulate transcriptional elongation without direct evidence. Here, functional genomic, proteomic, and biochemical studies aimed at an understanding of the role of DOT1L in erythroleukemic cells show no major role in elongation but, surprisingly, reveal that DOT1L evidently has a role in transcriptional initiation by recruiting [...]

Menée à l'aide d'un système de co-culture tridimensionnelle de lymphocytes T cytotoxiques et de lignées cellulaires de mélanome, cette étude met en évidence le rôle des canaux calciques CRAC dans la régulation de la fonction effectrice des lymphocytes T cytotoxiques

Metabolic Screening of Cytotoxic T-cell Effector Function Reveals the Role of CRAC Channels in Regulating Lethal Hit Delivery

Slaats, Jeroen ; Dieteren, Cindy E. ; Wagena, Esther ; Wolf, Louis ; Raaijmakers, Tonke K. ; van der Laak, Jeroen A. ; Figdor, Carl G. ; Weigelin, Bettina ; Friedl, Peter

Cytotoxic T lymphocytes (CTL) mediate cytotoxicity toward tumor cells by multistep cell–cell interactions. However, the tumor microenvironment can metabolically perturb local CTL effector function. CTL activity is typically studied in two-dimensional (2D) liquid coculture, which is limited in recapitulating the mechanisms and efficacy of the multistep CTL effector response. We here developed a microscopy-based, automated three-dimensional (3D) interface coculture model suitable for [...]

Menée à l'aide de lignées cellulaires de carcinome séreux ovarien de haut grade, d'échantillons tumoraux et de données du projet "The cancer Genome Atlas", cette étude met en évidence une association entre la surexpression de la kinase du lymphome anaplasique ALK et le caractère agressif de la tumeur

Anaplastic lymphoma kinase (ALK) overexpression is associated with aggressive phenotypic characteristics of ovarian high-grade serous carcinoma

Matsumoto, Toshihide ; Oda, Yusuke ; Hasegawa, Yoshinori ; Hashimura, Miki ; Oguri, Yasuko ; Inoue, Hisako ; Yokoi, Ako ; Tochimoto, Masataka ; Nakagawa, Mayu ; Jiang, Zesong ; Saegusa, Makoto

Deregulated full-length anaplastic lymphoma kinase (ALK) overexpression has been found in some primary solid tumors, but little is known about its role in ovarian high-grade serous carcinoma (HGSC). Here we focused on the functional roles of ALK in HGSC. Cytoplasmic ALK immunoreactivity without chromosomal rearrangement and gene mutations was significantly higher in HGSC as compared to non-HGSC type ovarian carcinomas, and was significantly associated with several unfavorable [...]

Cet article passe en revue les avancées en matière de connaissance des mécanismes moléculaires impliqués dans le développement de métastases cérébrales ayant pour origine un cancer du sein, présente les stratégies thérapeutiques actuelles et identifie les axes de recherche

Breast cancer brain metastasis: insight into molecular mechanisms and therapeutic strategies

Wang, Yajie ; Ye, Fangzhou ; Liang, Yiran ; Yang, Qifeng

Breast cancer is one of the most prevalent malignancies in women worldwide. Early-stage breast cancer is considered a curable disease; however, once distant metastasis occurs, the 5-year overall survival rate of patients becomes significantly reduced. There are four distinct metastatic patterns in breast cancer: bone, lung, liver and brain. Among these, breast cancer brain metastasis (BCBM) is the leading cause of death; it is highly associated with impaired quality of life and poor prognosis [...]