Menée initialement à partir d'échantillons tumoraux prélevés sur 8 patients ayant survécu plus de 10 ans après une résection d'un adénocarcinome canalaire du pancréas, puis sur une cohorte complémentaire de 27 patients, cette étude de séquençage de l'exome suggère que la présence de gènes fréquemment mutés (KRAS, TP53, SMAD4, CDKN2A, ...) ne permet pas d'expliquer la survie à très long terme de ces patients

Very long-term survival following resection for pancreatic cancer is not explained by commonly mutated genes: results of whole-exome sequencing analysis

Dal Molin, Marco ; Zhang, Ming ; de Wilde, Roeland F ; Ottenhof, Niki A. ; Rezaee, Neda ; Wolfgang, Christopher L ; Blackford, Amanda L. ; Vogelstein, Bert ; Kinzler, Kenneth W. ; Papadopoulos, Nickolas ; Hruban, Ralph H. ; Maitra, Anirban ; Wood, Laura D

Purpose: The median survival following surgical resection of pancreatic ductal adenocarcinoma (PDAC) is currently <20 months. However, survival ≥10 years is achieved by a small subset of patients who are defined as very long-term survivors (VLTSs). The goal of this study was to determine whether specific genetic alterations in resected PDACs determined very long-term survival. Experimental Design: We sequenced the exomes of 8 PDACs from patients who survived ≥10 years. Based on the results of [...]

Menée sur une lignée cellulaire dérivée d'un patient atteint d'un cancer du côlon, puis à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels les isoenzymes PKC exercent une fonction de suppresseur de tumeurs

Cancer-Associated Protein Kinase C Mutations Reveal Kinase’s Role as Tumor Suppressor

Antal, Corina E ; Hudson, Andrew M ; Kang, Emily ; Zanca, Ciro ; Wirth, Christopher ; Stephenson, Natalie L ; Trotter, Eleanor W ; Gallegos, Lisa L ; Miller, Crispin J ; Furnari, Frank B ; Hunter, Tony ; Brognard, John ; Newton, Alexandra C

Protein kinase C (PKC) isozymes have remained elusive cancer targets despite the unambiguous tumor promoting function of their potent ligands, phorbol esters, and the prevalence of their mutations. We analyzed 8% of PKC mutations identified in human cancers and found that, surprisingly, most were loss of function and none were activating. Loss-of-function mutations occurred in all PKC subgroups and impeded second-messenger binding, phosphorylation, or catalysis. Correction of a loss-of-function [...]

Menée à l'aide de modèles murins et à partir d'échantillons sanguins prélevés sur des patients atteints d'un cancer du poumon ou du sein, cette étude identifie, dans la circulation sanguine, trois sous-populations de neutrophiles exerçant des fonctions différentes au cours de la progression tumorale

Phenotypic Diversity and Plasticity in Circulating Neutrophil Subpopulations in Cancer

Sagiv, Jitka Y ; Michaeli, Janna ; Assi, Simaan ; Mishalian, Inbal ; Kisos, Hen ; Levy, Liran ; Damti, Pazzit ; Lumbroso, Delphine ; Polyansky, Lola ; Sionov, Ronit V ; Ariel, Amiram ; Hovav, Avi-Hai ; Henke, Erik ; Fridlender, Zvi G ; Granot, Zvi

Controversy surrounds neutrophil function in cancer because neutrophils were shown to provide both pro- and antitumor functions. We identified a heterogeneous subset of low-density neutrophils (LDNs) that appear transiently in self-resolving inflammation but accumulate continuously with cancer progression. LDNs display impaired neutrophil function and immunosuppressive properties, characteristics that are in stark contrast to those of mature, high-density neutrophils (HDNs). LDNs consist of [...]

Menée sur des lignées cellulaires et des modèles murins, cette étude met en évidence des mécanismes par lesquels, en inactivant le suppresseur de tumeurs LKB1, la kinase IP6K2 favorise le processus métastatique

Inositol pyrophosphates promote tumor growth and metastasis by antagonizing liver kinase B1

Rao, Feng ; Xu, Jing ; Fu, Chenglai ; Cha, Jiyoung Y. ; Gadalla, Moataz M. ; Xu, Risheng ; Barrow, James C. ; Snyder, Solomon H.

The inositol pyrophosphates, molecular messengers containing an energetic pyrophosphate bond, impact a wide range of biologic processes. They are generated primarily by a family of three inositol hexakisphosphate kinases (IP6Ks), the principal product of which is diphosphoinositol pentakisphosphate (IP7). We report that IP6K2, via IP7 synthesis, is a major mediator of cancer cell migration and tumor metastasis in cell culture and in intact mice. IP6K2 acts by enhancing cell-matrix adhesion and [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels deux voies de signalisation antioxydante (glutathion et thiorédoxine) favorisent la progression tumorale

Glutathione and Thioredoxin Antioxidant Pathways Synergize to Drive Cancer Initiation and Progression

Harris, Isaac S ; Treloar, Aislinn E ; Inoue, Satoshi ; Sasaki, Masato ; Gorrini, Chiara ; Lee, Kim Chung ; Yung, Ka Yi ; Brenner, Dirk ; Knobbe-Thomsen, Christiane B ; Cox, Maureen A ; Elia, Andrew ; Berger, Thorsten ; Cescon, David W ; Adeoye, Adewunmi ; Brustle, Anne ; Molyneux, Sam D ; Mason, Jacqueline M ; Li, Wanda Y ; Yamamoto, Kazuo ; Wakeham, Andrew ; Berman, Hal K ; Khokha, Rama ; Done, Susan J ; Kavanagh, Terrance J ; Lam, Ching-Wan ; Mak, Tak W

Controversy over the role of antioxidants in cancer has persisted for decades. Here, we demonstrate that synthesis of the antioxidant glutathione (GSH), driven by GCLM, is required for cancer initiation. Genetic loss of Gclm prevents a tumor’s ability to drive malignant transformation. Intriguingly, these findings can be replicated using an inhibitor of GSH synthesis, but only if delivered prior to cancer onset, suggesting that at later stages of tumor progression GSH becomes dispensable [...]

A partir de données portant sur des patients atteints d'un cancer du poumon non à petites cellules, puis menée sur des lignées cellulaires, cette étude met en évidence des mécanismes par lesquels, en régulant la voie de signalisation VEGF-A/AKT, la protéine EZH2 favorise la progression tumorale

EZH2 promotes tumor progression via regulating VEGF-a/AKT signaling in non-small cell lung cancer

Geng, Jian ; Li, Xiao ; Zhou, Zhanmei ; Wu, Chin-Lee ; Dai, Meng ; Bai, Xiaoyan

Enhancer of Zeste Homologue 2 (EZH2) accounts for aggressiveness and unfavorable prognosis of tumor. We investigated the mechanisms and signaling pathways of EZH2 in non-small cell lung carcinoma (NSCLC) progression. Increased expression of EZH2, vascular endothelial growth factor-A (VEGF-A) and AKT phosphorylation correlated with differentiation, lymph node metastasis, size and TNM stage in NSCLC. There was a positive correlation between EZH2 and VEGF-A expression and high EZH2 expression, as [...]

Cet article passe en revue les travaux récents sur le rôle des interactions entre micro-ARNs et ARNs messagers dans la progression d'un cancer colorectal

MicroRNA–mRNA interactions in colorectal cancer and their role in tumor progression

Amirkhah, Raheleh ; Schmitz, Ulf ; Linnebacher, Michael ; Wolkenhauer, Olaf ; Farazmand, Ali

MicroRNAs (miRNA/miR) play an important role in gene regulatory networks through targeting mRNAs. They are involved in diverse biological processes such as cell proliferation, differentiation, angiogenesis, and apoptosis. Due to their pivotal effects on multiple genes and pathways, dysregulated miRNAs have been reported to be associated with different diseases, including colorectal cancer (CRC). Recent evidence indicates that aberrant miRNA expression is tightly linked with the initiation and [...]

Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels le micro-ARN miR-122 secrété par les cellules cancéreuses favorise la formation de métastases en régulant la disponibilité du glucose dans la niche prémétastatique

Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis

Fong, Miranda Y. ; Zhou, Weiying ; Liu, Liang ; Alontaga, Aileen Y. ; Chandra, Manasa ; Ashby, Jonathan ; Chow, Amy ; O’Connor, Sean Timothy Francis ; Li, Shasha ; Chin, Andrew R. ; Somlo, George ; Palomares, Melanie ; Li, Zhuo ; Tremblay, Jacob R. ; Tsuyada, Akihiro ; Sun, Guoqiang ; Reid, Michael A. ; Wu, Xiwei ; Swiderski, Piotr ; Ren, Xiubao ; Shi, Yanhong ; Kong, Mei ; Zhong, Wenwan ; Chen, Yuan ; Wang, Shizhen Emily

Reprogrammed glucose metabolism as a result of increased glycolysis and glucose uptake is a hallmark of cancer. Here we show that cancer cells can suppress glucose uptake by non-tumour cells in the premetastatic niche, by secreting vesicles that carry high levels of the miR-122 microRNA. High miR-122 levels in the circulation have been associated with metastasis in breast cancer patients, and we show that cancer-cell-secreted miR-122 facilitates metastasis by increasing nutrient availability in [...]

Menée à l'aide d'un modèle murin de cancer du sein, cette étude met en évidence des mécanismes par lesquels, au début de la transformation maligne, des neutrophiles suppresseurs des lymphocytes T s'accumulent dans les tissus périphériques

Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils

Casbon, Amy-Jo ; Reynaud, Damien ; Park, Chanhyuk ; Khuc, Emily ; Gan, Dennis D. ; Schepers, Koen ; Passegué, Emmanuelle ; Werb, Zena

Expansion of myeloid cells associated with solid tumor development is a key contributor to neoplastic progression. Despite their clinical relevance, the mechanisms controlling myeloid cell production and activity in cancer remains poorly understood. Using a multistage mouse model of breast cancer, we show that production of atypical T cell-suppressive neutrophils occurs during early tumor progression, at the onset of malignant conversion, and that these cells preferentially accumulate in [...]

Menée sur des lignées cellulaires, cette étude évalue l'intérêt d'un modèle issu de la théorie des jeux pour rendre compte de l'hétérogénéité des cellules cancéreuses à l'intérieur des tumeurs neuroendocrines du pancréas

Heterogeneity for IGF-II production maintained by public goods dynamics in neuroendocrine pancreatic cancer

Archetti, Marco ; Ferraro, Daniela A. ; Christofori, Gerhard

The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival. Without strict [...]