Menée à l'aide de modèles murins de cancer du sein triplement négatif, cette étude suggère l'intérêt de combiner des techniques de séquençage de l'exome entier et de l'ARN pour identifier des anomalies génomiques susceptibles de faire l'objet d'une thérapie ciblée

Identifying and Targeting Sporadic Oncogenic Genetic Aberrations in Mouse Models of Triple Negative Breast Cancer

Liu, Hui ; Murphy, Charles J. ; Karreth, Florian A. ; Emdal, Kristina B. ; White, Forest M. ; Elemento, Olivier ; Toker, Alex ; Wulf, Gerburg M. ; Cantley, Lewis C.

Triple negative breast cancers (TNBC) are genetically characterized by aberrations in TP53 and a low rate of activating point mutations in common oncogenes, rendering it challenging in applying targeted therapies. We performed whole exome sequencing (WES) and RNAseq to identify somatic genetic alterations in mouse models of TNBCs driven by loss of Trp53 alone or in combination with Brca1. Amplifications or translocations that resulted in elevated oncoprotein expressions or [...]

Menée à l'aide de modèles murins de carcinome hépatocellulaire, cette étude met en évidence des mécanismes par lesquels, en induisant la dégradation de la sirtuine SIRT6, l'ubiquitine ligase UBE3A favorise la prolifération des cellules cancéreuses

SIRT6 is a target of regulation by UBE3A that contributes to liver tumorigenesis in an ANXA2-dependent manner

Kohli, Saishruti ; Bhardwaj, Abhishek ; Kumari, Richa ; Das, Sanjeev

UBE3A is an E3 ubiquitin ligase well known for its role in the proteasomal degradation of p53 in human papillomavirus (HPV)-associated cancers. Here we report that UBE3A ubiquitylates and triggers degradation of the tumor suppressive sirtuin SIRT6 in hepatocellular carcinoma. UBE3A ubiquitylated the highly conserved Lys160 residue on SIRT6. FOXO1-mediated transcriptional repression of UBE3A was sufficient to stabilize SIRT6 and epigenetically repress ANXA2, a key mediator of UBE3A oncogenic [...]

Menée in vitro et in vivo sur des modèles d'adénocarcinome canalaire du pancréas, cette étude met en évidence des mécanismes par lesquels, en régulant l'activation des cellules étoilées pancréatiques dans le stroma, la protéine p53 exerce une activité antitumorale

Reprogramming pancreatic stellate cells via p53 activation: A putative target for pancreatic cancer therapy

Saison-Ridinger, Maya ; DelGiorno, Kathleen E. ; Zhang, Tejia ; Kraus, Annabelle ; French, Randall ; Jaquish, Dawn ; Tsui, Crystal ; Erikson, Galina ; Spike, Benjamin T. ; Shokhirev, Maxim N. ; Liddle, Christopher ; Yu, Ruth T. ; Downes, Michael ; Evans, Ronald M. ; Saghatelian, Alan ; Lowy, Andrew M. ; Wahl, Geoffrey M.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extremely dense fibrotic stroma, which contributes to tumor growth, metastasis, and drug resistance. During tumorigenesis, quiescent pancreatic stellate cells (PSCs) are activated and become major contributors to fibrosis, by increasing growth factor signaling and extracellular matrix deposition. The p53 tumor suppressor is known to restrict tumor initiation and progression through cell autonomous mechanisms including apoptosis, [...]

Menée in vitro et in vivo sur des modèles de cancer colorectal, cette étude met en évidence des mécanismes par lesquels, via des voies de signalisation contrôlant les cellules souches, l'enzyme NAMPT favorise la croissance tumorale

NAMPT is a Potent Oncogene in Colon Cancer Progression that Modulates Cancer Stem Cell Properties and resistance to therapy through Sirt1 and PARP

Carnero, Amancio ; Lucena-Cacace, Antonio ; Otero-Albiol, Daniel ; Jimenez-Garcia, Manuel p ; Munoz-Galvan, Sandra

Purpose: Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men worldwide. However, despite current progress, many patients with advanced and metastatic tumors still die from the malignancy. Refractory disease often relies on nicotinamide adenine dinucleotide(NAD)-dependent mechanisms. NAD metabolism and a stable NAD regeneration circuit are required to maintain tissue homeostasis and metabolism. However, high levels of NAD confer therapy resistance [...]

Menée à l'aide de lignées cellulaires et d'échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence divers mécanismes induisant l'inactivation du gène suppresseur de tumeurs RHOA

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer

Dopeso, Higinio ; Rodrigues, Paulo ; Bilic, Josipa ; Bazzocco, Sarah ; Cartón-García, Fernando ; Macaya, Irati ; de Marcondes, Priscila Guimarães ; Anguita, Estefanía ; Masanas, Marc ; Jiménez-Flores, Lizbeth M. ; Martínez-Barriocanal, Águeda ; Nieto, Rocío ; Segura, Miguel F. ; Schwartz Jr, Simo ; Mariadason, John M. ; Arango, Diego

Background: Reduced RHOA signalling has been shown to increase the growth/metastatic potential of colorectal tumours. However, the mechanisms of inactivation of RHOA signalling in colon cancer have not been characterised. Methods: A panel of colorectal cancer cell lines and large cohorts of primary tumours were used to investigate the expression and activity of RHOA, as well as the presence of RHOA mutations/deletions and promoter methylation affecting RHOA. Changes in RHOA expression were [...]

Menée in vitro et in vivo sur des modèles de mélanome, cette étude met en évidence des mécanismes par lesquels, en transférant du cytoplasme dans les cellules tumorales, des macrophages favorisent les processus invasif et métastatique

Macrophage-Dependent Cytoplasmic Transfer during Melanoma Invasion In Vivo

Roh-Johnson, Minna ; Shah, Arish N. ; Stonick, Jason A. ; Poudel, Kumud R. ; Kargl, Julia ; Yang, Grace H. ; Di Martino, Julie ; Hernandez, Rafael E. ; Gast, Charles E. ; Zarour, Luai R. ; Antoku, Susumu ; Houghton, A. McGarry ; Bravo-Cordero, Jose Javier ; Wong, Melissa H. ; Condeelis, John ; Moens, Cecilia B.

Interactions between tumor cells and tumor-associated macrophages play critical roles in the initiation of tumor cell motility. To capture the cellular interactions of the tumor microenvironment with high-resolution imaging, we directly visualized tumor cells and their interactions with macrophages in zebrafish. Live imaging in zebrafish revealed that macrophages are dynamic, yet maintain sustained contact with tumor cells. In addition, the recruitment of macrophages to tumor cells promotes [...]

A partir d'échantillons de métastases prélevés sur une patiente atteinte d'un cancer séreux ovarien de haut grade, cette étude identifie notamment un ensemble de 22 gènes impliqués dans le remodelage de la matrice du microenvironnement des métastases

Deconstruction of a metastatic tumor microenvironment reveals a common matrix response in human cancers

Pearce, Oliver M. T. ; Delaine-Smith, Robin ; Maniati, Eleni ; Nichols, Sam ; Wang, Jun ; Böhm, Steffen ; Rajeeve, Vinothini ; Ullah, Dayem ; Chakravarty, Probir ; Jones, Roanne R. ; Montfort, Anne ; Dowe, Tom ; Gribben, John ; Jones, J. Louise ; Kocher, Hemant M. ; Serody, Jonathan S. ; Vincent, Benjamin G. ; Connelly, John ; Brenton, James D. ; Chelala, Claude ; Cutillas, Pedro R. ; Lockley, Michelle ; Bessant, Conrad ; Knight, Martin ; Balkwill, Frances R.

We have profiled, for the first time, an evolving human metastatic microenvironment, measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, ECM organization and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer (HGSOC) metastases that ranged from minimal to extensive disease, we show how non-malignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the [...]

A partir de 33 échantillons de tumeur primitive et de ganglions lymphatiques prélevés sur 7 patients atteints d'un cancer colorectal, cette étude identifie une hétérogénéité des populations clonales entre la tumeur primitive et les métastases, ainsi qu'entre les métastases

Lymph Node Metastases in Colon Cancer are Polyclonal

Ulintz, Peter J. ; Greenson, Joel K. ; Wu, Rong ; Fearon, Eric R. ; Hardiman, Karin M.

Purpose:  Recent studies have highlighted the existence of sub-clones in tumors. Lymph nodes are generally the first location of metastasis for most solid epithelial tumors including colorectal cancer (CRC). We sought to understand the genetic origin of lymph node metastasis in CRC by evaluating the relationship between CRC tumor sub-clones present in primary tumors and lymph nodes. Experimental Design:  A total of 33 samples from seven CRC's, including two or three spatially disparate [...]

Menée sur plus de 200 tumeurs issues de modèles murins génétiquement modifiés présentant un gène KRAS muté (un modèle de cancer du poumon, deux modèles de cancer du pancréas), cette étude met en évidence l'évolution, au cours de la tumorigenèse, d'une hétérogénéité génomique à l'intérieur des tumeurs et entre les tumeurs

Kras mutant genetically engineered mouse models of human cancers are genomically heterogeneous

Chung, Wei-Jen ; Daemen, Anneleen ; Cheng, Jason H. ; Long, Jason E. ; Cooper, Jonathan E. ; Wang, Bu-Er ; Tran, Christopher ; Singh, Mallika ; Gnad, Florian ; Modrusan, Zora ; Foreman, Oded ; Junttila, Melissa R.

KRAS mutant tumors are largely recalcitrant to targeted therapies. Genetically engineered mouse models (GEMMs) of Kras mutant cancer recapitulate critical aspects of this disease and are widely used for preclinical validation of targets and therapies. Through comprehensive profiling of exomes and matched transcriptomes of >200 KrasG12D-initiated GEMM tumors from one lung and two pancreatic cancer models, we discover that significant intratumoral and intertumoral genomic heterogeneity evolves [...]

A partir de données portant sur l'exome de 4 742 tumeurs, cette étude évalue l'intérêt d'une approche statistique, basée sur les réseaux d'interaction entre protéines, pour identifier de nouveaux oncogènes

NetSig: network-based discovery from cancer genomes

Horn, Heiko ; Lawrence, Michael S. ; Chouinard, Candace R. ; Shrestha, Yashaswi ; Hu, Jessica Xin ; Worstell, Elizabeth ; Shea, Emily ; Ilic, Nina ; Kim, Eejung ; Kamburov, Atanas ; Kashani, Alireza ; Hahn, William C. ; Campbell, Joshua D. ; Boehm, Jesse S. ; Getz, Gad ; Lage, Kasper

Methods that integrate molecular network information and tumor genome data could complement gene-based statistical tests to identify likely new cancer genes; but such approaches are challenging to validate at scale, and their predictive value remains unclear. We developed a robust statistic (NetSig) that integrates protein interaction networks with data from 4,742 tumor exomes. NetSig can accurately classify known driver genes in 60% of tested tumor types and predicts 62 new driver candidates. [...]