News Article | June 28, 2017
Follicular lymphoma is an incurable cancer that affects over 200,000 people worldwide every year. A form of non-Hodgkin lymphoma, follicular lymphoma develops when the body starts making abnormal B-cells, which are white blood cells that in normal conditions fight infections. This cancer is associated with several alterations of the cell's DNA, but it has been unclear which gene or genes are involved in its development. EPFL scientists have now analyzed the genomes of more than 200 patients with follicular lymphoma, and they discover that a gene, Sestrin1, is frequently missing or malfunctioning in FL patients. The discovery opens to new treatment options and it is now published in Science Translational Medicine. One of the common features of follicular lymphoma is a genetic abnormality between two chromosomes (14 and 18). In an event known as "chromosomal translocation" the two chromosomes "swap" certain parts with each other. This triggers the activation of a gene that protects cells from dying, making cells virtually immortal -- the hallmark of a tumor. Moreover, approximately 30% of follicular lymphoma patients lose also a portion of chromosome 6, affecting multiple genes involved in suppressing the emergence of a tumor. These patients typically have poor prognosis. Another 20 % of patients have alterations causing chromosomal disorganization and the consequent malfunctioning of several genes and proteins. The bottom line is that for both group of patients it is very difficult to pinpoint which of all the affected genes are actually causing the disease. The lab of Elisa Oricchio at EPFL, with colleagues from the US and Canada, analyzed the genomes of over 200 follicular lymphoma patients. Their analyses revealed that a specific gene, Sestrin1, can be harmed by both loss of chromosome 6 and silenced in patients. Sestrin1 helps the cell defending itself against DNA damage -- for example after exposure to radiation -- and oxidative stress. In fact, Sestrin1 is part of the cell's anti-tumor mechanism that stops potentially cancerous cells from growing. Disruption of a region in chromosome 6 or epigenetic modifications of the DNA block Sestrin1 expression and these contribute to the development of Follicular Lymphoma. Beyond identifying the Sestrin1 gene as frequently altered in FL patients, the scientists demonstrated that Sestrin1 is able to suppress tumors in vivo. They showed that Sestrin1 exerts its anti-tumor effects by blocking the activity of a protein complex called mTORC1, which is well known for controlling protein synthesis as well as acting as a sensor for nutrient or energy changes in the cell. Finally, the identification of loss of Sestrin1 as a key event behind the development of follicular lymphoma is particular important because it helps identifying patients that will benefit from new therapies. Indeed, this study shows that the therapeutic efficacy of a new drug that is currently in clinical trial depends on Sestrin1. Importantly, this dependency can be extended beyond follicular lymphoma to other tumor types. This work was carried out in collaboration with the Memorial Sloan Kettering Cancer Center (New York), Cornell University, the University of Lausanne, Goodwin Research Laboratories, Trinity College Dublin, the BC Cancer Agency, the University of British Columbia, and the Princess Margaret Cancer Centre (Toronto). Swiss National Science Foundation, EPFL's Swiss Institute for Experimental Cancer Research (ISREC), the Giorgi-Cavaglieri Foundation, the National Cancer Institute, the Lymphoma Research Foundation, Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Memorial Sloan Kettering Cancer Center, the National Institutes of Health, the Starr Cancer Consortium, the Geoffrey Beene Cancer Research Center, the Leukemia and Lymphoma Society, and the Princess Margaret Cancer Centre. E. Oricchio, N. Katanayeva, M. C. Donaldson, S. Sungalee, P. P. Joyce, W. Béguelin, E. Battistello, V. R. Sanghvi, M. Jiang, Y. Jiang, M. Teater, A. Parmigiani, A. V. Budanov, F. C. Chan, S. P. Shah, R. Kridel, A. M. Melnick, G. Ciriello, H-G. Wendel. Genetic and epigenetic inactivation of SESTRIN1 controls mTORC1 and response to EZH2 inhibition in follicular lymphoma. Science Translational Medicine 9, eaak9969 (2017). DOI: 10.1126/scitranslmed.aak9969
Geismann C.,University of Kiel |
Grohmann F.,University of Kiel |
Sebens S.,2Institute for Experimental Medicine |
Wirths G.,University of Kiel |
And 11 more authors.
Cell Death and Disease | Year: 2014
Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with an overall life expectancy of 6 months despite current therapies. NF-?B signalling has been shown to be critical for this profound cell-autonomous resistance against chemotherapeutic drugs and death receptor-induced apoptosis, but little is known about the role of the c-Rel subunit in solid cancer and PDAC apoptosis control. In the present study, by analysis of genome-wide patterns of c-Rel-dependent gene expression, we were able to establish c-Rel as a critical regulator of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in PDAC. TRAIL-resistant cells exhibited a strong TRAIL-inducible NF-?B activity, whereas TRAIL-sensitive cells displayed only a small increase in NF-?B-binding activity. Transfection with siRNA against c-Rel sensitized the TRAIL-resistant cells in a manner comparable to siRNA targeting the p65/RelA subunit. Gel-shift analysis revealed that c-Rel is part of the TRAIL-inducible NF-?B complex in PDAC. Array analysis identified NFATc2 as a c-Rel target gene among the 12 strongest TRAIL-inducible genes in apoptosis-resistant cells. In line, siRNA targeting c-Rel strongly reduced TRAIL-induced NFATc2 activity in TRAIL-resistant PDAC cells. Furthermore, siRNA targeting NFATc2 sensitized these PDAC cells against TRAILinduced apoptosis. Finally, TRAIL-induced expression of COX-2 was diminished through siRNA targeting c-Rel or NFATc2 and pharmacologic inhibition of COX-2 with celecoxib or siRNA targeting COX-2, enhanced TRAIL apoptosis. In conclusion, we were able to delineate a novel c-Rel-, NFATc2- and COX-2-dependent antiapoptotic signalling pathway in PDAC with broad clinical implications for pharmaceutical intervention strategies. © 2014 Macmillan Publishers Limited. All rights reserved.
PubMed | University of Tübingen, Institute for Experimental Cancer Research, Institute for Experimental Medicine, Institute of Clinical Molecular Biology and 2 more.
Type: | Journal: Cell death & disease | Year: 2014
Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest malignancies with an overall life expectancy of 6 months despite current therapies. NF-B signalling has been shown to be critical for this profound cell-autonomous resistance against chemotherapeutic drugs and death receptor-induced apoptosis, but little is known about the role of the c-Rel subunit in solid cancer and PDAC apoptosis control. In the present study, by analysis of genome-wide patterns of c-Rel-dependent gene expression, we were able to establish c-Rel as a critical regulator of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in PDAC. TRAIL-resistant cells exhibited a strong TRAIL-inducible NF-B activity, whereas TRAIL-sensitive cells displayed only a small increase in NF-B-binding activity. Transfection with siRNA against c-Rel sensitized the TRAIL-resistant cells in a manner comparable to siRNA targeting the p65/RelA subunit. Gel-shift analysis revealed that c-Rel is part of the TRAIL-inducible NF-B complex in PDAC. Array analysis identified NFATc2 as a c-Rel target gene among the 12 strongest TRAIL-inducible genes in apoptosis-resistant cells. In line, siRNA targeting c-Rel strongly reduced TRAIL-induced NFATc2 activity in TRAIL-resistant PDAC cells. Furthermore, siRNA targeting NFATc2 sensitized these PDAC cells against TRAIL-induced apoptosis. Finally, TRAIL-induced expression of COX-2 was diminished through siRNA targeting c-Rel or NFATc2 and pharmacologic inhibition of COX-2 with celecoxib or siRNA targeting COX-2, enhanced TRAIL apoptosis. In conclusion, we were able to delineate a novel c-Rel-, NFATc2- and COX-2-dependent antiapoptotic signalling pathway in PDAC with broad clinical implications for pharmaceutical intervention strategies.
PubMed | Albert Ludwigs University of Freiburg, Institute for Experimental Cancer Research, Leiden University, University of Southampton and 2 more.
Type: Journal Article | Journal: Blood | Year: 2015
B-cell antigen receptor (BCR) expression is a key feature of most B-cell lymphomas, but the mechanisms of BCR signal induction and the involvement of autoantigen recognition remain unclear. In follicular lymphoma (FL) B cells, BCR expression is retained despite a chromosomal translocation that links the antiapoptotic gene BCL2 to the regulatory elements of immunoglobulin genes, thereby disrupting 1 heavy-chain allele. A remarkable feature of FL-BCRs is the acquisition of potential N-glycosylation sites during somatic hypermutation. The introduced glycans carry mannose termini, which create potential novel binding sites for mannose-specific lectins. Here, we investigated the effect of N-linked variable-region glycosylation for BCR interaction with cognate antigen and with lectins of different origins. N-glycans were found to severely impair BCR specificity and affinity to the initial cognate antigen. In addition, we found that lectins from Pseudomonas aeruginosa and Burkholderia cenocepacia bind and stimulate FL cells. Human exposure to these bacteria can occur by contact with soil and water. In addition, they represent opportunistic pathogens in susceptible hosts. Understanding the role of bacterial lectins might elucidate the pathogenesis of FL and establish novel therapeutic approaches.
Lascano V.,University of Amsterdam |
Zabalegui L.F.,Institute Of Genetique Moleculaire Of Montpellier |
Zabalegui L.F.,Montpellier University |
Cameron K.,University of Amsterdam |
And 12 more authors.
Cell Death and Differentiation | Year: 2012
The tumor necrosis factor (TNF) family member APRIL (A proliferation inducing ligand) is a disease promoter in B-cell malignancies. APRIL has also been associated with a wide range of solid malignancies, including colorectal cancer (CRC). As evidence for a supportive role of APRIL in solid tumor formation was still lacking, we studied the involvement of APRIL in CRC. We observed that ectopic APRIL expression exacerbates the number and size of adenomas in ApcMin mice and in a mouse model for colitis-associated colon carcinogenesis. Furthermore, knockdown of APRIL in primary spheroid cultures of colon cancer cells and both mouse and human CRC cell lines reduced tumor clonogenicity and in vivo outgrowth. Taken together, our data therefore indicate that both tumor-derived APRIL and APRIL produced by non-tumor cells is supportive in colorectal tumorigenesis. © 2012 Macmillan Publishers Limited. All rights reserved.
Schafer H.,Laboratory of Molecular Gastroenterology and Hepatology |
Geismann C.,Laboratory of Molecular Gastroenterology and Hepatology |
Heneweer C.,Clinic for Diagnostic Radiology |
Egberts J.-H.,Clinic of General Surgery and Thoracic Surgery |
And 8 more authors.
Carcinogenesis | Year: 2012
Pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis, representing one risk factor for PDAC, are characterized by a marked desmoplasia enriched of pancreatic myofibroblasts (PMFs). Thus, PMFs are thought to essentially promote pancreatic tumorigenesis. We recently demonstrated that the adhesion molecule L1CAM is involved in epithelial-mesenchymal transition of PMF-cocultured H6c7 human ductal epithelial cells and that L1CAM is expressed already in ductal structures of chronic pancreatitis with even higher elevation in primary tumors and metastases of PDAC patients. This study aimed at investigating whether PMFs and L1CAM drive malignant transformation of pancreatic ductal epithelial cells by enhancing their tumorigenic potential. Cell culture experiments demonstrated that in the presence of PMFs, H6c7 cells exhibit a profound resistance against death ligand-induced apoptosis. This apoptosis protection was similarly observed in H6c7 cells stably overexpressing L1CAM. Intrapancreatic inoculation of H6c7 cells together with PMFs (H6c7co) resulted in tumor formation in 7/8 and liver metastases in 6/8 severe combined immunodeficiency (SCID) mice, whereas no tumors and metastases were detectable after inoculation of H6c7 cells alone. Likewise, tumor outgrowth and metastases resulted from inoculation of L1CAM-overexpressing H6c7 cells in 5/7 and 3/7 SCID mice, respectively, but not from inoculation of mock-transfected H6c7 cells. Treatment of H6c7co tumor-bearing mice with the L1CAM antibody L1-9.3/2a inhibited tumor formation and liver metastasis in 100 and 50%, respectively, of the treated animals. Overall, these data provide new insights into the mechanisms of how PMFs and L1CAM contribute to malignant transformation of pancreatic ductal epithelial cells in early stages of pancreatic tumorigenesis. © The Author 2011. Published by Oxford University Press. All rights reserved.
Meincke M.,University of Kiel |
Tiwari S.,Institute for Experimental Cancer Research |
Hattermann K.,University of Kiel |
Kalthoff H.,Institute for Experimental Cancer Research |
Mentlein R.,University of Kiel
Clinical and Experimental Metastasis | Year: 2011
The chemokine CXCL12/SDF-1 and its receptors CXCR4 and CXCR7 play a major role in tumor invasion, proliferation and metastasis. Since both receptors are overexpressed on distinct tumor cells and on the tumor vasculature, we evaluated their potential as targets for detection of cancers by molecular imaging. We synthesized conjugates of CXCL12 and the near-infrared (NIR) fluorescent dye IRDye ®800CW, tested their selectivity, sensitivity and biological activity in vitro and their feasibility to visualize tumors in vivo. Purified CXCL12-conjugates detected in vitro as low as 500 A764 human glioma cells or MCF-7 breast cancer cells that express CXCR7 alone or together with CXCR4. Binding was time- and concentration-dependent, and the label could be competitively displaced by the native peptide. Control conjugates with bovine serum albumin or lactalbumin failed to label the cells. In mice, the conjugate distributed rapidly. After 1-92 h, subcutaneous tumors of human MCF-7 and A764 cells in immunodeficient mice were detected with high sensitivity. Background was observed in particular in liver within the first 24 h, but also skull and hind limbs yielded some background. Overall, fluorescent CXCL12-conjugates are sensitive and selective probes to detect solid and metastatic tumors by targeting tumor cells and tumor vasculature. © 2011 The Author(s).
Scholer N.,Institute for Experimental Cancer Research |
Langer C.,University of Ulm |
Dohner H.,University of Ulm |
Buske C.,Institute for Experimental Cancer Research |
And 2 more authors.
Experimental Hematology | Year: 2010
Recently, expression patterns of microRNAs in body fluids underscored their potential as noninvasive biomarkers for various diseases. Here we summarize the current works describing microRNAs in blood cells or serum as biomarkers and the applied methodologies of small RNA purification and detection. Future challenges and the required research relating to optimization of working with microRNAs in serum will also be discussed. © 2010 ISEH - Society for Hematology and Stem Cells.
Schafer H.,Laboratory of Molecular Gastroenterology and Hepatology |
Dieckmann C.,Laboratory of Molecular Gastroenterology and Hepatology |
Korniienko O.,Institute for Experimental Cancer Research |
Moldenhauer G.,German Cancer Research Center |
And 6 more authors.
Cancer Letters | Year: 2012
The adhesion molecule L1CAM (CD171) accounts for enhanced motility, invasiveness and chemoresistance of tumor cells and represents a novel marker for various tumor entities including pancreatic and ovarian carcinoma. Recently, we showed that L1CAM inhibition increases the apoptotic response of tumor cells towards cytostatic drugs pointing to the potential of L1CAM to serve as a chemosensitizer in anti-cancer therapy. Thus, the present study evaluated the therapeutic potential of combined treatment with L1CAM antibodies and chemotherapeutic drugs in pancreatic and ovarian carcinoma model systems. in vivo. Two L1CAM-specific antibodies (L1-14.10 and L1-9.3/2a) exhibiting high binding affinity to the L1CAM expressing pancreatic adenocarcinoma cell line Colo357 and the ovarian carcinoma cell line SKOV3ip were used for treatment. The combined therapy of SCID mice with either L1CAM antibody and gemcitabine and paclitaxel, respectively, reduced the growth of subcutaneously grown Colo357 or SKOV3ip tumors more efficiently than treatment with the cytostatic drug alone or in combination with control IgG. This was accompanied by an increased number of apoptotic tumor cells along with an elevated procaspase-8 expression. Furthermore, a lowered activation of NF-κB along with a reduced expression of VEGF and a diminished number of CD31-positive blood vessels were observed in tumors after combined therapy compared to control treatments, while the infiltration of F4/80-positive macrophages increased. Overall, these data provide new insights into the mechanism of the anti-cancer activity of L1CAM-blocking antibodies. in vivo and support the suitability of L1CAM as a target for chemosensitization and of L1CAM-interfering antibodies as an appropriate tool to increase the therapeutic response of pancreatic and ovarian carcinoma. © 2011 Elsevier Ireland Ltd.
PubMed | Institute for Experimental Cancer Research
Type: | Journal: Methods in molecular medicine | Year: 2011
Cellular transformation does not necessarily require the expression of proteins with neoantigenic properties, and for this reason, immunosurveillance does not register all tumor cells. They frequently express potentially immunogenic components, but are able to escape elimination by immune mechanisms. One explanation for this escape is poor antigen presentation by the tumor cells, resulting in little or no measurable antitumor immunity in immunocompetent hosts. T cells remain naive or even become anergic to the tumor cells. Reasons for the deficient antigen presentation by the tumor cells include the reduced or absent expression of major histocompatibility complex (MHC) molecules and the absence of tumor antigens in the groove of class I or class II MHC molecules as a consequence of defective protein processing. Other reasons are the absence or inadequate levels of expression of adhesion molecules, the absence or inadequate levels of costimulatory molecules or the expression of lymphocyte suppressive cytokines like transforming growth factor (TGF-) or interleukin 10 (IL-10) by tumor cells (1-5).