In vivo modeling of metastatic human high-grade serous ovarian cancer in mice

Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies

Genomic Analyses Reveal Global Functional Alterations That Promote Tumor Growth and Novel Tumor Suppressor Genes in Natural Killer-Cell Malignancies

50th Annual Meeting of the American-Society-of-Hematology, San Francisco, CA, 06-09 December 2008. In Blood, v. 112 n. 11, p. 129

Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies

Natural killer (NK)-cell malignancies are among the most aggressive lymphoid neoplasms with very poor prognosis. We performed array comparative genomic hybridization analysis on a number of NK cell lines and primary tumors to gain better understanding of the pathogenesis and tumor biology of these malignancies. We also obtained transcriptional profiles of genes residing in these regions and compared them with normal and activated NK cells. Only 30-50% of the genes residing in the gained or deleted regions showed corresponding increased or decreased expression. However, many of the upregulated genes in regions of gain are functionally important for the proliferation and growth of the neoplastic population. Genes downregulated in regions of loss included many transcription factors or repressors, tumor suppressors or negative regulators of the cell cycle. The minimal common region of deletion in 6q21 included three known genes (PRDM1, ATG5 and AIM1) showing generally low expression. Mutations resulting in truncated PRDM1 and changes in conserved amino-acid sequences of AIM1 were detected. Highly methylated CpG islands 5′ of PRDM1 and AIM1 correlated with low expression of the transcripts. Reversal of methylation by Decitabine induced expression of PRDM1 and cell death. In conclusion, we have shown a general tumor-promoting effect of genetic alterations and have identified PRDM1 as the most likely target gene in del6q21. ATG5, an essential gene for autophagy and AIM1, a gene implicated in melanoma, may also participate in the functional abnormalities.link_to_subscribed_fulltex

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits in B-cell development and can cooperate with Bcl2 overexpression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B cells, we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the proximal regulatory regions of these genes. However, B cells with Crebbp inactivation showed high expression of Myc and patterns of altered histone acetylation that were localized to intragenic regions, enriched for Myc DNA binding motifs, andshowedMycbinding. Through the analysis ofCREBBPmutations from a large cohort of primary human FL and DLBCL, we show a significant difference in the spectrum of CREBBP mutations in these 2 diseases, with higher frequencies of nonsense/ frameshift mutations in DLBCL compared with FL. Together, our data therefore provide important links between Crebbp inactivation and Bcl2 dependence and show a role for Crebbp inactivation in the induction of Myc expression. We suggest this may parallel the role of CREBBP frameshift/nonsense mutations in DLBCL that result in loss of the protein, but may contrast the role of missense mutations in the lysine acetyltransferase domain that are more frequently observed in FL and yield an inactive protein.Research in the M.R.G. group is supported by grants from the Nebraska Department of Health and Human Services (LB506 2016-16) and the National Institutes of Health, National Cancer Institute (1R01CA201380). Research in the I.S.-G. group is partially supported by Fondo Europeo de Desarrollo Regional (FEDER) and by the Ministry of Economy and Competitiveness (SAF2012-32810, SAF2015-64420-R, and Red de Excelencia Consolider OncoBIO SAF2014-57791-REDC), Instituto de Salud Carlos III (PIE14/00066), Instituto de Salud Carlos III Plan de Ayudas Institute of Biomedical Research of Salamanca 2015 Proyectos Integrados (IBY15/00003), by Junta de Castilla y Leon (BIO/SA51/15, CSI001U14, UIC-017, andCSI001U16), Fundacion Inocente Inocente, by the German Carreras Foundation (Organisation der Deutsche Jose Carreras Leukamie-Stiftung eV R13/26), and by the Advanced Research on Interaction Mechanisms of electro Magnetic Exposures with Organisms for Risk Assessment project (European Union’s Seventh Framework Programme [FP7/2007-2013] under grant agreement no. 282891). The Nebraska Lymphoma Study Group tissue bank is supported by the Fred & Pamela Buffett Cancer Center’s National Cancer Institute Cancer Center Support Grant (P30CA036727). The I.S.-G. laboratory is a member of the EuroSyStem and the Developing Evidence to Inform Decisions about Effectiveness Network funded by the European Union under the FP7 program. Research in the C.V.-D. group is partially supported by a “Miguel Servet” Grant (CP14/00082, AES 2013-2016, FEDER) from the Instituto de Salud Carlos III (Ministerio de Economia y Competitividad). I.G.-R. was supported by BES-Ministerio de Economia y Competitividad (BES-2013-063789). G.R.-H. and L.R.-R. were supported by Fondo Social Europeo-Consejeria de Educacion de la Junta de Castilla y Leon. R.D. was supported by a fellowship from Region Ile de France (Appel hors DIM 2013). Research in the F.R.-L. group was supported by grants from Universite Paris Diderot, CNRS, Institut National du Cancer (2012-1-PL-BIO), and the Plan Cancer Environnement 2013. Ultrafast liquid chromatography analyses were done on the platform “Bioprofiler” (Unite de Biologie Fonctionnelle et Adaptative).Peer Reviewe