Menée à l'aide d'un modèle murin de cancer hépatique, cette étude met en évidence un mécanisme par lequel la protéine p53, en réprimant la voie du mévalonate, favorise la suppression tumorale

p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression

Moon, Sung-Hwan ; Huang, Chun-Hao ; Houlihan, Shauna L. ; Regunath, Kausik ; Freed-Pastor, William A. ; Morris, John P. I. V. ; Tschaharganeh, Darjus F. ; Kastenhuber, Edward R. ; Barsotti, Anthony M. ; Culp-Hill, Rachel ; Xue, Wen ; Ho, Yu-Jui ; Baslan, Timour ; Li, Xiang ; Mayle, Allison ; de Stanchina, Elisa ; Zender, Lars ; Tong, David R. ; D’Alessandro, Angelo ; Lowe, Scott W. ; Prives, Carol

There are still gaps in our understanding of the complex processes by which p53 suppresses tumorigenesis. Here we describe a novel role for p53 in suppressing the mevalonate pathway, which is responsible for biosynthesis of cholesterol and nonsterol isoprenoids. p53 blocks activation of SREBP-2, the master transcriptional regulator of this pathway, by transcriptionally inducing the ABCA1 cholesterol transporter gene. A mouse model of liver cancer reveals that downregulation of mevalonate [...]

Menée in vitro, cette étude met en évidence un mécanisme par lequel la méthyltransférase SETD6 régule la progression de la mitose via la méthylation de la PLK1, une kinase impliquée dans le contrôle de la division cellulaire et hautement exprimée dans les cellules tumorales

The methyltransferase SETD6 regulates Mitotic progression through PLK1 methylation

Feldman, Michal ; Vershinin, Zlata ; Goliand, Inna ; Elia, Natalie ; Levy, Dan

The involvement of nonhistone protein methylation in cellular essential pathways is a rising field. Here we show evidence for the involvement of direct lysine methylation of the mitosis regulator PLK1 by SETD6 methyltransferase in cell cycle promotion. Our results reveal that this methylation occurs on two lysine residues and that lack of methylation leads to enhanced PLK1 catalytic activity, causing accelerated mitosis pace and thus faster proliferation rates. These findings suggest that PLK1 [...]

Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels le récepteur PPAR delta favorise le développement d'un cancer colorectal, sa progression et l'envahissement des tissus sains

Pleiotropic effects of PPARD accelerate colorectal tumorigenesis, progression, and invasion

Liu, Yi ; Deguchi, Yasunori ; Tian, Rui ; Wei, Daoyan ; Wu, Ling ; Chen, Weidong ; Xu, Weiguo ; Xu, Min ; Liu, Fuyao ; Gao, Shen ; Jaoude, Jonathan C. ; Chrieki, Sarah P. ; Moussalli, Micheline J. ; Gagea, Mihai ; Morris, Jeffrey ; Broaddus, Russell R. ; Zuo, Xiangsheng ; Shureiqi, Imad

APC mutations activate aberrant β-catenin signaling to drive initiation of colorectal cancer (CRC), however, CRC progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of β-catenin, is upregulated in CRC. However, promotion of intestinal tumorigenesis following deletion of PPARD in Apcmin mice has raised questions about the effects of PPARD on aberrant β-catenin activation and CRC. In this study, we used mouse models of PPARD overexpression or deletion [...]

Menée à l'aide d'un modèle murin transgénique de médulloblastome, cette étude met en évidence un mécanisme par lequel le répresseur de transcription REST, en induisant la compaction de la chromatine au niveau du gène Ptch1 ainsi que l'activation de la protéine AKT, favorise le développement d'une tumeur agressive

Transcriptional repressor REST drives lineage stage–specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma

Dobson, Tara H. W. ; Tao, Rong-Hua ; Swaminathan, Jyothishmathi ; Maegawa, Shinji ; Shaik, Shavali ; Bravo-Alegria, Javiera ; Sharma, Ajay ; Kennis, Bridget ; Yang, Yanwen ; Callegari, Keri ; Haltom, Amanda R. ; Taylor, Pete ; Kogiso, Mari ; Qi, Lin ; Khatua, Soumen ; Goldman, Stewart ; Lulla, Rishi R. ; Fangusaro, Jason ; MacDonald, Tobey J. ; Li, Xiao-Nan ; Hawkins, Cynthia ; Rajaram, Veena ; Gopalakrishnan, Vidya

Medulloblastoma is a brain tumor that occurs mostly in children and has few therapeutic options. Attempts to block the Sonic Hedgehog (SHH) pathway that drives various subtypes of the tumor have been unsuccessful clinically. Dobson et al. found a mechanism by which SHH signaling may be increased in some patients. In a new mouse model, the authors found that increased expression of the transcriptional repressor REST in cells that give rise to the disease supports a more aggressive disease course [...]

Menée in vitro et chez la drosophile, cette étude met en évidence un mécanisme par lequel la protéine activatrice 1, en activant la transcription du gène codant pour la protéine wingless, favorise l'invasion tumorale

Wingless modulates activator protein-1-mediated tumor invasion

Zhang, Shiping ; Guo, Xiaowei ; Wu, Honggui ; Sun, Ying ; Ma, Xianjue ; Li, Jikai ; Xu, Qian ; Wu, Chenxi ; Li, Qiwen ; Jiang, Cizhong ; Li, Wenzhe ; Ho, Margaret S. ; Lv, Zhongwei ; Xue, Lei

Metastasis begins with a subset of local tumor cells acquiring the potential to invade into surrounding tissues, and remains to be a major obstacle for cancer treatments. More than 90% of cancer patients died from tumor metastasis, instead of primary tumor growth. The canonical Wnt/β-catenin pathway plays essential roles in promoting tumor formation, yet its function in regulating tumor metastasis and the underlying mechanisms remain controversial. Here we employed well-established Drosophila [...]

Menée à l'aide de fibroblastes CAF (Cancer-associated fibroblasts) issus de patients atteints d'un adénocarcinome de l'œsophage, puis à l'aide d'organoïdes et de xénogreffes sur un modèle murin, cette étude met en évidence le rôle de l'interleukine IL-6 du stroma tumoral dans la transition épithélio-mésenchymateuse et la résistance thérapeutique

Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma

Ebbing, Eva A. ; van der Zalm, Amber P. ; Steins, Anne ; Creemers, Aafke ; Hermsen, Simone ; Rentenaar, Rosa ; Klein, Michelle ; Waasdorp, Cynthia ; Hooijer, Gerrit K. J. ; Meijer, Sybren L. ; Krishnadath, Kausilia K. ; Punt, Cornelis J. A. ; van Berge Henegouwen, Mark I. ; Gisbertz, Suzanne S. ; van Delden, Otto M. ; Hulshof, Maarten C. C. M. ; Medema, Jan Paul ; van Laarhoven, Hanneke W. M. ; Bijlsma, Maarten F.

We found that cancer-associated fibroblasts, the most abundant noncancer cell type in esophageal cancer tissue, contribute to the resistance of tumors against currently applicable treatments. These cancer-associated fibroblasts do so by producing and secreting IL-6. IL-6 induces a mesenchymal, resistant tumor cell state. Inhibition of IL-6 reverted the mesenchymal cell state and resensitized tumor cells to therapy. Serum-borne proxies for the presence of IL-6–producing fibroblasts were [...]

Menée à l'aide d'une modélisation, cette étude met en évidence un mécanisme par lequel une hyperplasie bénigne de la prostate empêche la croissance d'une tumeur maligne sur ce même organe

Computer simulations suggest that prostate enlargement due to benign prostatic hyperplasia mechanically impedes prostate cancer growth

Lorenzo, Guillermo ; Hughes, Thomas J. R. ; Dominguez-Frojan, Pablo ; Reali, Alessandro ; Gomez, Hector

Benign prostatic hyperplasia (BPH) is a common disease in aging men that causes the prostate to enlarge progressively. Men with larger prostates tend to harbor prostatic tumors with more favorable features. The underlying mechanisms that explain this interaction between BPH and prostate cancer (PCa) are largely unknown. Here, we propose that BPH may mechanically impede PCa growth by producing increasingly intense mechanical stresses in the prostate over time, which are known to slow down tumor [...]

Menée sur des lymphocytes CD8+ issus de mélanomes d'origine murine ou humaine, cette étude met en évidence une corrélation entre le dysfonctionnement de l'énolase 1, une enzyme impliquée dans la glycolyse, et le dysfonctionnement des lymphocytes T CD8+ ayant infiltré la tumeur

Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8+ T cells

Gemta, Lelisa F. ; Siska, Peter J. ; Nelson, Marin E. ; Gao, Xia ; Liu, Xiaojing ; Locasale, Jason W. ; Yagita, Hideo ; Slingluff, Craig L. ; Hoehn, Kyle L. ; Rathmell, Jeffrey C. ; Bullock, Timothy N. J.

One reason T cells in the tumor microenvioronment (TME) become dysfunctional is that they compete with cancer cells for nutrients, particularly glucose. By studying the glucose metabolism of CD8+ T cells in the TME of mouse B16 and human melanomas, Gemta et al. report the activity of enzyme enolase 1 to be impaired. Enolase 1 catalyzes the synthesis of phosphenolpyruvate, which is dephosphorylated to generate pyruvate, the end product of glycolysis. In vitro, provision of pyruvate considerably [...]