Cet article passe en revue les travaux récents sur les influences réciproques entre altérations du génome et de l'épigénome favorisant le développement d'un cancer

Interplay between the Cancer Genome and Epigenome

Shen, Hui ; Laird, Peter W

Cancer arises as a consequence of cumulative disruptions to cellular growth control with Darwinian selection for those heritable changes that provide the greatest clonal advantage. These traits can be acquired and stably maintained by either genetic or epigenetic means. Here, we explore the ways in which alterations in the genome and epigenome influence each other and cooperate to promote oncogenic transformation. Disruption of epigenomic control is pervasive in malignancy and can be classified [...]

Cet article passe en revue les travaux récents sur les explorations systématiques des génomes de cancer

Lessons from the Cancer Genome

Garraway, Levi A ; Lander, Eric S

Systematic studies of the cancer genome have exploded in recent years. These studies have revealed scores of new cancer genes, including many in processes not previously known to be causal targets in cancer. The genes affect cell signaling, chromatin, and epigenomic regulation; RNA splicing; protein homeostasis; metabolism; and lineage maturation. Still, cancer genomics is in its infancy. Much work remains to complete the mutational catalog in primary tumors and across the natural history of [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, via la régulation d'un coactivateur de la famille p160, des mutations du gène SPOP favorisent le développement d'un cancer de la prostate

Prostate cancer-associated mutations in speckle-type POZ protein (SPOP) regulate steroid receptor coactivator 3 protein turnover

Geng, Chuandong ; He, Bin ; Xu, Limei ; Barbieri, Christopher E. ; Eedunuri, Vijay Kumar ; Chew, Sue Anne ; Zimmermann, Martin ; Bond, Richard ; Shou, John ; Li, Chao ; Blattner, Mirjam ; Lonard, David M. ; Demichelis, Francesca ; Coarfa, Cristian ; Rubin, Mark A. ; Zhou, Pengbo ; O’Malley, Bert W. ; Mitsiades, Nicholas

The p160 steroid receptor coactivators (SRCs) SRC-1, SRC-2 [nuclear receptor coactivator (NCOA)2], and SRC-3 [amplified in breast cancer 1 (AIB1)/NCOA3] are key pleiotropic “master regulators” of transcription factor activity necessary for cancer cell proliferation, survival, metabolism, and metastasis. SRC overexpression and overactivation occur in numerous human cancers and are associated with poor clinical outcomes and resistance to therapy. In prostate cancer (PC), the p160 SRCs play [...]

Menée in vitro, cette étude met en évidence des mécanismes par lesquels, dans les sarcomes synoviaux, une translocation produit une protéine de fusion SS18-SSX favorisant la prolifération cellulaire

Reversible Disruption of mSWI/SNF (BAF) Complexes by the SS18-SSX Oncogenic Fusion in Synovial Sarcoma

Kadoch, Cigall ; Crabtree, Gerald R

Recent exon sequencing studies have revealed that over 20% of human tumors have mutations in subunits of mSWI/SNF (BAF) complexes. To investigate the underlying mechanism, we studied human synovial sarcoma (SS), in which transformation results from the translocation of exactly 78 amino acids of SSX to the SS18 subunit of BAF complexes. We demonstrate that the SS18-SSX fusion protein competes for assembly with wild-type SS18, forming an altered complex lacking the tumor suppressor BAF47 (hSNF5). [...]

Menée sur des échantillons tumoraux prélevés sur 19 patients atteints d'un carcinome hépatocellulaire et à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels des rétrotransposons activent des oncogènes dans le foie de patients infectés par un virus de l'hépatite B ou C

Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma

Shukla, Ruchi ; Upton, Kyle R ; Muñoz-Lopez, Martin ; Gerhardt, Daniel J ; Fisher, Malcolm E ; Nguyen, Thu ; Brennan, Paul M ; Baillie, J.  Kenneth ; Collino, Agnese ; Ghisletti, Serena ; Sinha, Shruti ; Iannelli, Fabio ; Radaelli, Enrico ; Dos Santos, Alexandre ; Rapoud, Delphine ; Guettier, Catherine ; Samuel, Didier ; Natoli, Gioacchino ; Carninci, Piero ; Ciccarelli, Francesca D ; Garcia-Perez, Jose Luis ; Faivre, Jamila ; Faulkner, Geoffrey J

LINE-1 (L1) retrotransposons are mobile genetic elements comprising <17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events [...]

Menée in vitro et in vivo, cette étude met en évidence un mécanisme par lequel, en régulant des voies de signalisation NF-κB, la protéine GSK-3α favorise le développement d'un cancer du pancréas lié à des mutations du gène KRAS

GSK-3α Promotes Oncogenic KRAS Function in Pancreatic Cancer via TAK1-TAB Stabilization and Regulation of Non-Canonical NF-κB

Bang, Deepali ; Wilson, Willie ; Ryan, Meagan ; Yeh, Jen Jen ; Baldwin, Albert S

Mutations in KRAS drive the oncogenic phenotype in a variety of tumors of epithelial origin. The NF-κB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK, which controls canonical NF-κB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that KRAS+ upregulates GSK-3α leading to its [...]

Menée sur des lignées cellulaires de cancer du sein et à l'aide de xénogreffes, cette étude met en évidence des mécanismes par lesquels, en fonction de conditions restant à élucider, une signalisation paracrine Wnt est susceptible de favoriser ou réprimer la croissance tumorale

Paracrine Wnt signaling both promotes and inhibits human breast tumor growth

Green, Jennifer L. ; La, Justin ; Yum, Kyu W. ; Desai, Payal ; Rodewald, Luo-Wei ; Zhang, Xiaomei ; Leblanc, Mathias ; Nusse, Roeland ; Lewis, Michael T. ; Wahl, Geoffrey M.

Wnt signaling in mouse mammary development and tumorigenesis has been heavily studied and characterized, but its role in human breast cancer remains elusive. Although Wnt inhibitors are in early clinical development, it is unclear whether they will be of therapeutic benefit to breast cancer patients, and subsequently, to which ones. To address this, we generated a panel of Wnt reporting human breast cancer cell lines and identified a previously unrecognized enrichment for the ability to respond [...]

Menée à l'aide d'un modèle murin de tumeur neuroendocrine du pancréas, cette étude met en évidence un mécanisme par lequel l'activation du récepteur NMDAR favorise la croissance tumorale et le processus invasif

Hijacking the Neuronal NMDAR Signaling Circuit to Promote Tumor Growth and Invasion

Li, Leanne ; Hanahan, Douglas

Glutamate and its receptor N-methyl-D-aspartate receptor (NMDAR) have been associated with cancer, although their functions are not fully understood. Herein, we implicate glutamate-driven NMDAR signaling in a mouse model of pancreatic neuroendocrine tumorigenesis (PNET) and in selected human cancers. NMDAR was upregulated at the periphery of PNET tumors, particularly invasive fronts. Moreover, elevated coexpression of NMDAR and glutamate exporters correlated with poor prognosis in cancer [...]

Menée in vitro et à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels, via les molécules de signalisation TrkB et NCAM, la protéine NeuroD1 favorise la survie des cellules tumorales et le processus métastatique d'une tumeur neuroendocrine du poumon

NeuroD1 regulates survival and migration of neuroendocrine lung carcinomas via signaling molecules TrkB and NCAM

Osborne, Jihan K. ; Larsen, Jill E. ; Shields, Misty D. ; Gonzales, Joshua X. ; Shames, David S. ; Sato, Mitsuo ; Kulkarni, Ashwinikumar ; Wistuba, Ignacio I. ; Girard, Luc ; Minna, John D. ; Cobb, Melanie H.

Small-cell lung cancer and other aggressive neuroendocrine cancers are often associated with early dissemination and frequent metastases. We demonstrate that neurogenic differentiation 1 (NeuroD1) is a regulatory hub securing cross talk among survival and migratory-inducing signaling pathways in neuroendocrine lung carcinomas. We find that NeuroD1 promotes tumor cell survival and metastasis in aggressive neuroendocrine lung tumors through regulation of the receptor tyrosine kinase [...]

Menée à l'aide de xénogreffes, cette étude met en évidence un mécanisme par lequel, via la phosphrylation du gène c-Myc, PKCζ régule le processus métastatique d'un cancer de la prostate

c-Myc phosphorylation by PKCζ represses prostate tumorigenesis

Kim, Ji Young ; Valencia, Tania ; Abu-Baker, Shadi ; Linares, Juan ; Lee, Sang Jun ; Yajima, Tomoko ; Chen, Jing ; Eroshkin, Alexey ; Castilla, Elias A. ; Brill, Laurence M. ; Medvedovic, Mario ; Leitges, Michael ; Moscat, Jorge ; Diaz-Meco, Maria T.

Studies showing reduced PKCζ expression or enzymatic activity in different types of human cancers support the clinical relevance of PKCζ as a tumor suppressor. However, the in vivo role of PKCζ and its mechanisms of action in prostate cancer remain unclear. Here we demonstrate that the genetic inactivation of PKCζ in mice results in invasive prostate carcinoma in vivo in the context of phosphatase and tensin homolog deficiency. Bioinformatic analysis of human prostate cancer gene-expression [...]

Menée in vivo et sur des échantillons tumoraux prélevés sur des patients atteints d'un glioblastome, cette étude met en évidence le rôle joué par des cellules souches de glioblastome dans la formation de péricytes qui, en remodelant le réseau vasculaire, favorisent la progression tumorale

Glioblastoma Stem Cells Generate Vascular Pericytes to Support Vessel Function and Tumor Growth

Cheng, Lin ; Huang, Zhi ; Zhou, Wenchao ; Wu, Qiulian ; Donnola, Shannon ; Liu, James K ; Fang, Xiaoguang ; Sloan, Andrew E ; Mao, Yubin ; Lathia, Justin D ; Min, Wang ; McLendon, Roger E ; Rich, Jeremy N ; Bao, Shideng

Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentiation, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters [...]

Cet article plaide pour une politique de recherche favorisant les travaux d'analyse des réseaux de signalisation impliqués dans les diverses phase d'un cancer par rapport à l'extension des projets de séquençage massif des génomes tumoraux

The Scientific Drunk and the Lamppost: Massive Sequencing Efforts in Cancer Discovery and Treatment

Yaffe, Michael B.

The massive resources devoted to genome sequencing of human tumors have produced important data sets for the cancer biology community. Paradoxically, however, these studies have revealed very little new biology. Despite this, additional resources in the United States are slated to continue such work and to expand similar efforts in genome sequencing to mouse tumors. It may be that scientists are "addicted" to the large amounts of data that can be relatively easily obtained, even though these [...]