Purpose: Patient-derived xenograft models are considered to represent the heterogeneity of human cancers and advanced preclinical models. Our consortium joins efforts to extensively develop and characterize a new collection of patient-derived colorectal cancer (CRC) models.Experimental Design: From the 85 unsupervised surgical colorectal samples collection, 54 tumors were successfully xenografted in immunodeficient mice and rats, representing 35 primary tumors, 5 peritoneal carcinoses and 14 metastases. Histologic and molecular characterization of patient tumors, first and late passages on mice includes the sequence of key genes involved in CRC (i.e., APC, KRAS, TP53), aCGH, and transcriptomic analysis.Results: This comprehensive characterization shows that our collection recapitulates the clinical situation about the histopathology and molecular diversity of CRC. Moreover, patient tumors and corresponding models are clustering together allowing comparison studies between clinical and preclinical data. Hence, we conducted pharmacologic monotherapy studies with standard of care for CRC (5-fluorouracil, oxaliplatin, irinotecan, and cetuximab). Through this extensive in vivo analysis, we have shown the loss of human stroma cells after engraftment, observed a metastatic phenotype in some models, and finally compared the molecular profile with the drug sensitivity of each tumor model. Through an experimental cetuximab phase II trial, we confirmed the key role of KRAS mutation in cetuximab resistance.Conclusions: This new collection could bring benefit to evaluate novel targeted therapeutic strategies and to better understand the basis for sensitivity or resistance of tumors from individual patients.

No abstract

At the stage of carcinoma in situ, the basement membrane (BM) segregates tumor cells from the stroma. This barrier must be breached to allow dissemination of the tumor cells to adjacent tissues. Cancer cells can perforate the BM using proteolysis; however, whether stromal cells play a role in this process remains unknown. Here we show that an abundant stromal cell population, cancer-associated fibroblasts (CAFs), promote cancer cell invasion through the BM. CAFs facilitate the breaching of the BM in a matrix metalloproteinase-independent manner. Instead, CAFs pull, stretch, and soften the BM leading to the formation of gaps through which cancer cells can migrate. By exerting contractile forces, CAFs alter the organization and the physical properties of the BM, making it permissive for cancer cell invasion. Blocking the ability of stromal cells to exert mechanical forces on the BM could therefore represent a new therapeutic strategy against aggressive tumors.

Cancer-associated fibroblasts (CAFs) promote cancer cell invasion and dissemination by remodeling the extracellular matrix; however, the mechanism by which CAFs remodel the matrix is still unknown. Attieh et al. show that CAFs induce cancer cell invasion through fibronectin matrix assembly that is mainly mediated by integrin-αvβ3.

Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been recently investigated in several cancer types, but their respective clinical significance remains to be determined. In our prospective study, we compared the detection rate and the prognostic value of these two circulating biomarkers in patients with metastatic uveal melanoma. GNAQ=GNA11 mutations were characterized in archived tumor tissue. Using a highly sensitive and mutation-specific bidirectional pyrophosphorolysisactivated polymerization (bi-PAP) technique, GNAQ c.626A>T, GNAQ c.626A>C and GNA11 c.626A>T copy numbers were quantified in plasma from 12 mL of blood. CTCs were detected at the same time in 7.5 mL of blood by the CellSearchV R technique. Patient characteristics and outcome were prospectively collected. CTCs (1) were detected in 12 of the 40 included patients (30%, range 1-20). Among the 26 patients with known detectable mutations, ctDNA was detected and quantified in 22 (84%, range 4-11,421 copies=mL). CTC count and ctDNA levels were associated with the presence of miliary hepatic metastasis (p 5 0.004 and 0.03, respectively), with metastasis volume (p 5 0.005 and 0.004) and with each other (p < 0.0001). CTC count and ctDNA levels were both strongly associated with progression-free survival (p 5 0.003 and 0.001) and overall survival (p 5 0.0009 and <0.0001). In multivariate analyses, ctDNA appeared to be a better prognostic marker than CTC. In conclusion, ctDNA and CTC are correlated and both have poor prognostic significance. CTC detection can be performed in every patient but, in patients with detectable mutations, ctDNA was more frequently detected than CTC and has possibly more prognostic value.Uveal melanoma is a rare cancer, with a reported incidence of two to eight new cases per million per year in Europe 1 and the United States.2 Specific mutations are found in this particular type of melanoma: >80% of uveal melanoma express mutually exclusive somatic mutations in two paralog proto-oncogenes, GNAQ 3 and GNA11, 4 which encode a-subunits of heterotrimeric G-proteins involved in the MEK-ERK signaling pathway. 5 In both genes, most mutations occur at nucleotide 626 encoding a glutamine at codon 209 (Q209). The presence of these mutations does not influence the risk of metastasis in patients. 4 Uveal melanoma metastases develop mostly in the liver through hematogenous spread of cancer cells. Despite improvement of diagnosis and treatment of the primary eye tumor, there is no effective treatment of metastatic disease; the prognosis of patients with metastatic uveal melanoma is limited, and although a few patients experience extended survival, the median overall survival (OS) following metastases detection is less than 1 year. 6 Circulating tumor cells (CTCs), which are cancer cells detected in patient blood, may correspond to cancer "seeds" that initiate metastatic relapse.7 Over the past two decades, both molecular and cytological detection techniques have

Please cite this article as: Mariani P., Piperno-Neumann S., Servois V., Berry M.G., Dorval T., Plancher C., Couturier J., Levy-Gabriel C., Lumbroso-Le Rouic L., Desjardins L., Salmon R.J. Surgical management of liver metastases from uveal melanoma:16 years'experience at the Institut Curie., European Journal of Surgical Oncology (2009Oncology ( ), doi: 10.1016Oncology ( /j.ejso.2009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Purpose: Uveal melanoma is the most common primary intraocular malignant tumor in adults and is defined by a poor natural outcome, as 50% of patients die from metastases. The aim of this study was to develop and characterize a panel of human uveal melanoma xenografts transplanted into immunodeficient mice.Experimental Design: Ninety tumor specimens were grafted into severe combined immunodeficient mice, and 25 transplantable xenografts were then established (28%). Relationship between tumor graft and clinical, biological, and therapeutic features of the patients included were investigated. Characterization of 16 xenografts included histology, molecular analyses by immunohistochemistry, genetic alteration analysis (single-nucleotide polymorphism), and specific tumor antigen expression by quantitative reverse transcription-PCR. Pharmacologic characterization (chemosensitivity) was also done in four models using two drugs, temozolomide and fotemustine, currently used in the clinical management of uveal melanoma.Results: Take rate of human uveal melanoma was 28% (25 of 90). Tumor take was independent of size, histologic parameters, or chromosome 3 monosomy but was significantly higher in metastatic tumors. Interestingly, in vivo tumor growth was prognostic for a lower metastasis-free survival in patients with primary tumors. A high concordance between the patients' tumors and their corresponding xenografts was found for all parameters tested (histology, genetic profile, and tumor antigen expression). Finally, the four xenografts studied displayed different response profiles to chemotherapeutic agents.Conclusions: Based on these results, this panel of 16 uveal melanoma xenografts represents a useful preclinical tool for both pharmacologic and biological assessments. Clin Cancer Res; 16(8); 2352-62. ©2010 AACR.Uveal melanoma is the most common primary intraocular malignant tumor in adults. Despite the increased diagnostic accuracy and the development of conservative and effective treatments on primary tumor sites, such as plaque radiotherapy and photon beam therapy, the mortality remains stable and 50% of patients die from metastases that frequently involve the liver. Chemotherapy, such as oral temozolomide and intra-arterial fotemustine used at the metastatic stage, induces very low response rates, 14.3% and 36%, respectively, and a median survival time of 6.7 and 15 months (1-3). No postoperative adjuvant therapies are currently available to decrease the risk of metastases. Several prognostic factors of disseminated relapse after initial ophthalmologic treatment have been determined, including location with respect to the equator, monosomy 3, and retinal detachment (4). However, no effect of these prognostic markers on patient care can be envisaged in the absence of effective systemic therapies.The growing body of knowledge about molecular and genetics events involved in oncogenesis and tumor progression has led to the identification of new therapeutic targets and therapeutic agents. Preclinical investigatio...

Uveal melanoma (UM) is the most common primary tumor of the eye in adults. There is no standard adjuvant treatment to prevent metastasis and no effective therapy in the metastatic setting. We have established a unique panel of 7 UM cell lines from either patient's tumors or patient-derived tumor xenografts (PDXs). This panel recapitulates the molecular landscape of the disease in terms of genetic alterations and mutations. All the cell lines display GNAQ or GNA11 activating mutations, and importantly four of them display BAP1 (BRCA1 associated protein-1) deficiency, a hallmark of aggressive disease. The mTOR pathway was shown to be activated in most of the cell lines independent of AKT signaling. mTOR inhibitor Everolimus reduced the viability of UM cell lines and significantly delayed tumor growth in 4 PDXs. Our data suggest that mTOR inhibition with Everolimus, possibly in combination with other agents, may be considered as a therapeutic option for the management of uveal melanoma.