Cet article passe en revue les travaux récents faisant appel à une approche évolutionniste pour étudier le génome des cancers

Evolution of the cancer genome

Podlaha, Ondrej ; Riester, Markus ; De, Subhajyoti ; Michor, Franziska

Human tumors result from an evolutionary process operating on somatic cells within tissues, whereby natural selection operates on the phenotypic variability generated by the accumulation of genetic, genomic and epigenetic alterations. This somatic evolution leads to adaptations such as increased proliferative, angiogenic, and invasive phenotypes. In this review we outline how cancer genomes are beginning to be investigated from an evolutionary perspective. We describe recent progress in the [...]

Menée sur 76 patients atteints d'une leucémie lymphocytaire chronique et 35 témoins, cette étude évalue l'association entre un mécanisme épigénétique régulant l'expression d'un gène de l'horloge circadienne, CRY1, et le pronostic de la maladie

Epigenetic Silencing of the Circadian Clock Gene CRY1 is Associated with an Indolent Clinical Course in Chronic Lymphocytic Leukemia

Hanoun, Maher ; Eisele, Lewin ; Suzuki, Masako ; Greally, John M. ; Hüttmann, Andreas ; Aydin, Semra ; Scholtysik, René ; Klein-Hitpass, Ludger ; Dührsen, Ulrich ; Dürig, Jan

Disruption of circadian rhythm is believed to play a critical role in cancer development. Cryptochrome 1 (CRY1) is a core component of the mammalian circadian clock and we have previously shown its deregulated expression in a subgroup of patients with chronic lymphocytic leukemia (CLL). Using real-time RT-PCR in a cohort of 76 CLL patients and 35 normal blood donors we now demonstrate that differential CRY1 mRNA expression in high-risk (HR) CD38+/immunoglobulin variable heavy chain gene (IgVH) [...]

Menée sur 4 patients ayant subi une prostatectomie radicale, cette étude de séquençage des exons met en évidence l'hétérogénéité du profil mutationnel des divers échantillons tumoraux prélevés sur chaque patient

Exome Sequencing of Prostate Cancer Supports the Hypothesis of Independent Tumour Origins

Johan, Lindberg ; Daniel, Klevebring ; Wennuan, Liu ; Mårten, Neiman ; Jianfeng, Xu ; Peter, Wiklund ; Fredrik, Wiklund ; Ian, Mills ; Lars, Egevad ; Henrik, Grönberg

Background: Prostate cancer (PCa) is a clinically and pathologically heterogeneous disease. The rapid development of sequencing technology has the potential to deliver new biomarkers with emphasis on aggressive disease and to revolutionise personalised cancer treatment. However, a prostate harbouring cancer commonly contains multiple separate tumour foci, with the potential to aggravate tumour sampling. The level of intraprostatic tumour heterogeneity remains to be determined. Objective: To [...]

Menée à l'aide d'anticorps anti-phosho-tyrosine sur des lignées cellulaires et des échantillons tumoraux de sarcome, cette étude met en évidence divers récepteurs dont l'activité tyrosine kinase est essentielle à la survie des cellules cancéreuses

Phosphoproteomics identifies driver tyrosine kinases in sarcoma cell lines and tumors

Bai, Yun ; Li, Jiannong ; Fang, Bin ; Edwards, Arthur ; Zhang, Guolin ; Bui, Marilyn ; Eschrich, Steven ; Altiok, Soner ; Koomen, John ; Haura, Eric B

Driver tyrosine kinase mutations are rare in sarcomas and patterns of tyrosine phosphorylation are poorly understood. To better understand the signaling pathways active in sarcoma, we examined global tyrosine phosphorylation in sarcoma cell lines and human tumor samples. Anti-phospho-tyrosine antibodies were used to purify tyrosine-phosphorylated peptides, which were then identified using liquid chromatography and tandem mass spectrometry. The findings were validated using RNA interference, [...]

Menée sur un modèle murin, cette étude montre que l'activation de la protéine kinase mTORC1 favorise la formation d'un carcinome hépatocellulaire

Chronic Activation of mTOR Complex 1 Is Sufficient to Cause Hepatocellular Carcinoma in Mice

Menon, Suchithra ; Yecies, Jessica L. ; Zhang, Hui H. ; Howell, Jessica J. ; Nicholatos, Justin ; Harputlugil, Eylul ; Bronson, Roderick T. ; Kwiatkowski, David J. ; Manning, Brendan D.

The mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a nutrient-sensitive protein kinase that is aberrantly activated in many human cancers. Whether dysregulation of mTORC1 signaling in normal tissues increases the risk for cancer, however, is unknown. We focused on hepatocellular carcinoma, which has been linked to environmental factors that affect mTORC1 activity, including diet. Ablation of the gene encoding TSC1 (tuberous sclerosis complex 1), which as part of the TSC1-TSC2 [...]

Cet article passe en revue les travaux récents sur le rôle du gène MYC dans le développement des cancers

MYC on the Path to Cancer

Dang, Chi V

The MYC oncogene contributes to the genesis of many human cancers. Recent insights into its expression and function have led to therapeutic opportunities. MYC's activation by bromodomain proteins could be inhibited by drug-like molecules, resulting in tumor inhibition in vivo. Tumor growth can also be curbed by pharmacologically uncoupling bioenergetic pathways involving glucose or glutamine metabolism from Myc-induced cellular biomass accumulation. Other approaches to halt Myc on the path to [...]

Menée sur des modèles murins transgéniques surexprimant le gène PTEN, cette étude met en évidence un mécanisme par lequel PTEN, en régulant un processus métabolique, joue un rôle de suppresseur de tumeurs

Systemic Elevation of PTEN Induces a Tumor-Suppressive Metabolic State

Garcia-Cao, Isabel ; Song, Min Sup ; Hobbs, Robin M ; Laurent, Gaelle ; Giorgi, Carlotta ; de Boer, Vincent C J. ; Anastasiou, Dimitrios ; Ito, Keisuke ; Sasaki, Atsuo T ; Rameh, Lucia ; Carracedo, Arkaitz ; Vander Heiden, Matthew G ; Cantley, Lewis C ; Pinton, Paolo ; Haigis, Marcia C ; Pandolfi, Pier Paolo

Decremental loss of PTEN results in cancer susceptibility and tumor progression. PTEN elevation might therefore be an attractive option for cancer prevention and therapy. We have generated several transgenic mouse lines with PTEN expression elevated to varying levels by taking advantage of bacterial artificial chromosome (BAC)-mediated transgenesis. The Super-PTEN mutants are viable and show reduced body size due to decreased cell number, with no effect on cell size. Unexpectedly, PTEN [...]

Menée sur un modèle murin de leucémie avec réarrangement MLL, cette étude met en évidence le rôle joué par l'enzyme KDM1A dans la régulation des cellules souches leucémiques

The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem Cells

Harris, William J ; Huang, Xu ; Lynch, James T ; Spencer, Gary J ; Hitchin, James R ; Li, Yaoyong ; Ciceri, Filippo ; Blaser, Julian G ; Greystoke, Brigit F ; Jordan, Allan M ; Miller, Crispin J ; Ogilvie, Donald J ; Somervaille, Tim C P.

Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogs active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary [...]

Menée sur un modèle murin et 30 échantillons prélevés sur des patients atteints de lymphomes présentant des mutations du gène BCL6, cette étude met en évidence un mécanisme impliquant une coopération entre les gènes PIM1 et BCL6 dans le développement de la maladie

PIM1 gene cooperates with human BCL6 gene to promote the development of lymphomas

Baron, Beverly W. ; Anastasi, John ; Hyjek, Elizabeth M. ; Bies, Juraj ; Reddy, Poluru L. ; Dong, Jingfang ; Joseph, Loren ; Thirman, Michael J. ; Wroblewski, Kristen ; Wolff, Linda ; Baron, Joseph M.

Diffuse large B-cell lymphomas in humans are associated with chromosomal rearrangements (∼40%) and/or mutations disrupting autoregulation (∼16%) involving the BCL6 gene. Studies of lymphoma development in humans and mouse models have indicated that lymphomagenesis evolves through the accumulation of multiple genetic alterations. Based on our prior studies, which indicated that carcinogen-induced DNA mutations enhance the incidence of lymphomas in our mouse model expressing a human BCL6 [...]

Menée sur divers modèles murins, cette étude met en évidence le rôle joué par l'interleukine 17 dans la formation et la croissance d'un adénocarcinome de la prostate

Interleulin-17 Promotes Formation and Growth of Prostate Adenocarcinoma in Mouse Models

Zhang, Qiuyang ; Liu, Sen ; Ge, Dongxia ; Zhang, Qingsong ; Xue, Yun ; Xiong, Zhenggang ; Abdel-Mageed, Asim B ; Myers, Leann ; Hill, Steven M ; Rowan, Brian G ; Sartor, Oliver ; Melamed, Jonathan ; Chen, Zhenbang ; You, Zongbing

The contributions of interleukin-17 (IL-17) to cancer remain unclear and somewhat controversial. We took a genetic approach to explore its role in prostate cancers by interbreeding IL-17 receptor C (IL-17RC) deficient mice with mice that are conditionally mutant for PTEN, one established preclinical model for prostate cancer. Mice that were IL-17RC deficient (IL-17RC-) displayed prostates that were smaller than mice that maintained IL-17RC expression (IL-17RC+). Additionally, IL-17RC- mice [...]

Menée sur un modèle murin transgénique, cette étude montre que l'ablation du gène Tpl2 favorise un mécanisme inflammatoire et la formation d'adénomes intestinaux

Tpl2 ablation promotes intestinal inflammation and tumorigenesis in Apcmin mice by inhibiting IL-10 secretion and regulatory T-cell generation

Serebrennikova, Oksana B. ; Tsatsanis, Christos ; Mao, Changchuin ; Gounaris, Elias ; Ren, Wenying ; Siracusa, Linda D. ; Eliopoulos, Aristides G. ; Khazaie, Khashayarsha ; Tsichlis, Philip N.

To address the role of Tpl2, a MAP3K8 that regulates innate/adaptive immunity and inflammation, in intestinal tumorigenesis, we crossed a Tpl2 KO allele into the Apcmin/+ genetic background. Here, we show that Apcmin/+/Tpl2−/− mice exhibit a fivefold increase in the number of intestinal adenomas. Bone marrow transplantation experiments revealed that the enhancement of polyposis was partially hematopoietic cell-driven. Consistent with this observation, Tpl2 ablation promoted intestinal [...]

Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle de suppresseur de tumeurs joué par Lrig1 dans les cellules souches de l'intestin

The Pan-ErbB Negative Regulator Lrig1 Is an Intestinal Stem Cell Marker that Functions as a Tumor Suppressor

Powell, Anne E ; Wang, Yang ; Li, Yina ; Poulin, Emily J ; Means, Anna L ; Washington, Mary K ; Higginbotham, James N ; Juchheim, Alwin ; Prasad, Nripesh ; Levy, Shawn E ; Guo, Yan ; Shyr, Yu ; Aronow, Bruce J ; Haigis, Kevin M ; Franklin, Jeffrey L ; Coffey, Robert J

Lineage mapping has identified both proliferative and quiescent intestinal stem cells, but the molecular circuitry controlling stem cell quiescence is incompletely understood. By lineage mapping, we show Lrig1, a pan-ErbB inhibitor, marks predominately noncycling, long-lived stem cells that are located at the crypt base and that, upon injury, proliferate and divide to replenish damaged crypts. Transcriptome profiling of Lrig1+ colonic stem cells differs markedly from the profiling of highly [...]

Menée sur un modèle murin, cette étude met en évidence le rôle joué par HER3 dans l'épithélium mammaire avant, pendant et après la formation d'une tumeur HER2+

HER3 is required for HER2-induced pre-neoplastic changes to the breast epithelium and tumor formation

Vaught, David B ; Stanford, Jamie C ; Young, Christian ; Hicks, Donna J ; Wheeler, Frank ; Rinehart, Cammie ; Sánchez, Violeta ; Koland, John ; Muller, William J. ; Arteaga, Carlos L. ; Cook, Rebecca S

Increasing evidence suggests that HER2-amplified breast cancer cells use HER3/ErbB3 to drive therapeutic resistance to HER2 inhibitors. However, the role of ErbB3 in the earliest events of breast epithelial transformation remains unknown. Using mouse mammary-specific models of Cre-mediated ErbB3 ablation, we show that ErbB3 loss prevents the progressive transformation of HER2-overexpressing mammary epithelium. Decreased proliferation and increased apoptosis were seen in MMTV-HER2 and MMTV-Neu [...]

Menée sur des modèles murins, cette étude met en évidence un mécanisme par lequel le micro-ARN 23a favorise la transformation d'un cancer colorectal d'une forme indolente en une forme invasive

miR-23a Promotes the Transition from Indolent to Invasive Colorectal Cancer

Jahid, Sohail ; Sun, Jian ; Edwards, Robert A ; Dizon, Diana ; Panarelli, Nicole C. ; Milsom, Jeffrey W. ; Sikandar, Shaheen S. ; Gümüş, Zeynep H. ; Lipkin, Steven M

Colorectal cancer (CRC) is a classic example of a tumor that progresses through multiple distinct stages in its evolution. To understand the mechanisms regulating the transition from indolent to invasive disease, we profiled somatic copy number alterations in non-invasive adenomas and invasive adenocarcinomas from Apc and DNA mismatch repair (MMR) mutant mouse models. We identified a recurrent amplicon on mouse chromosome 8 that encodes microRNAs (miRs) 23a and 27a. miRs-23a and 27a levels are [...]

Menée à partir d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, cette étude montre qu'à l'intérieur d'une même tumeur, il existe plusieurs types de cellules dotées de caractéristiques de cellules souches

Tumor initiating but differentiated luminal-like breast cancer cells are highly invasive in the absence of basal-like activity

Kim, Jiyoung ; Villadsen, René ; Sørlie, Therese ; Fogh, Louise ; Grønlund, Signe Z. ; Fridriksdottir, Agla J. ; Kuhn, Irene ; Rank, Fritz ; Wielenga, Vera Timmermans ; Solvang, Hiroko ; Edwards, Paul A. W. ; Børresen-Dale, Anne-Lise ; Rønnov-Jessen, Lone ; Bissell, Mina J. ; Petersen, Ole William

The majority of human breast cancers exhibit luminal epithelial differentiation. However, most aggressive behavior, including invasion and purported cancer stem cell activity, are considered characteristics of basal-like cells. We asked the following questions: Must luminal-like breast cancer cells become basal-like to initiate tumors or to invade? Could luminally differentiated cells within a basally initiated hierarchy also be tumorigenic? To answer these questions, we used rare and mutually [...]

Cet article passe en revue les travaux récents sur les échanges entre le système immunitaire, inné et adaptatif, et les cellules tumorales

Cancer and the Immune System

The immune system interacts with developing cancer in ways that can protect the host against hyperproliferation but that may also contribute to malignancy. Understanding the mechanisms behind the protective and harmful effects of the innate and adaptive immune systems in their exchanges with tumor cells will help to unravel how to harness our natural defenses with targeted therapeutics. This issue's Select delves into cancer immunoediting, T cell therapy, and how the goodies can become the [...]

Cet article passe en revue les travaux récents sur le génome, les modèles animaux et les cellules souches des gliomes

Malignant Glioma: Lessons from Genomics, Mouse Models, and Stem Cells

Chen, Jian ; McKay, Renée M ; Parada, Luis F

Eighty percent of malignant tumors that develop in the central nervous system are malignant gliomas, which are essentially incurable. Here, we discuss how recent sequencing studies are identifying unexpected drivers of gliomagenesis, including mutations in isocitrate dehydrogenase 1 and the NF-ºB pathway, and how genome-wide analyses are reshaping the classification schemes for tumors and enhancing prognostic value of molecular markers. We discuss the controversies surrounding glioma stem cells [...]