Dissection of TRAIL-mediated signaling in pancreatic ductal adenocarcinoma cells - towards efficient anti-tumor therapy
Zusammenfassung der Projektergebnisse
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human malignancies with a mortality rate almost equivalent to its incidence rate. The only curative option is tumor resection, but nevertheless, still about 80% of the patients die from local recurrence and distant metastasis despite adjuvant chemotherapy within few years. TRAIL is a promising novel therapeutic agent for inducing apoptosis preferentially in tumor cells, without harming the normal cells. TRAIL induces cell death via binding to its plasma membrane bound receptors TRAIL-R1 and/or TRAIL-R2. However, TRAIL can also activate several non-apoptotic signaling pathways leading to proliferation, migration and invasion as well as metastasis of PDAC cells in vivo. Thus, in addition to the frequently observed resistance of tumor cells to apoptosis, the non-apoptotic signaling may limit the curative potential of the TRAIL based therapy particularly in PDAC. Our previous studies on PDAC cell lines revealed that TRAIL-R1 is the major transducer of apoptotic and non-apoptotic TRAIL-signals in this cell type. However, activation of TRAIL-R2 by receptorspecific agonistic antibodies can also lead to strong apoptotic and non-apoptotic response in these cells. The hypothesis of our project was that understanding the TRAIL-R1 and -R2-mediated signal transduction pathways will allow the selective modulation of TRAIL effects in PDAC cells. All TRAIL-induced effects are thought to be attributed to the functions of TRAIL-R1 and/or TRAIL-R2 at the cell surface. However, tumor cells express TRAIL receptors mainly in the intracellular locations, in the cytoplasm and in the nucleus. Also in PDAC, plasma membrane expression of both TRAIL-R1 and TRAIL-R2 is strongly diminished but intracellular levels are clearly enhanced compared to corresponding normal tissue. We found that intracellular TRAIL-R2 actively contributes to the establishment of the malignant phenotype in PDAC. We uncovered that nuclear TRAIL-R2 interacts with the microprocessor complex and inhibits maturation of micro RNA let-7. This TRAIL-R2 action increases the expression of HMGA2 and Lin28B and enhances cell proliferation. Correspondingly, knockdown of TRAIL-R2 resulted in reduced primary tumor growth in an orthotopic PDAC xenotransplantation model in SCID mice. In addition to the role of nuclear TRAIL-R2, we were also able to demonstrate the protumoral role of the plasma membrane TRAIL-R2 in PDAC and other tumor cells. This work has been done in collaboration with the group of Henning Walczak, London. We showed that in response to endogenous, cancer cell derived TRAIL TRAIL-R2 promotes metastasis of cells with K-Ras mutation. This holds true for PDAC cells but also for lung cancer cells and colon carcinoma cells. Concerning PDAC, using a clinically adapted orthotopic xenotransplantation model in mice we demonstrated that knockdown of TRAIL-R2 reduced recurrent tumor growth and liver metastasis. Importantly, in PDAC patients, high TRAIL-R2 expression correlated with lymph vessels invasion. Mechanistically, we identified the membrane proximal domain of TRAIL-R2 and the constitutive activation of Rac 1 as responsible for these pro-tumoral ligand-dependent functions. Summing up, both plasma membrane and nuclear TRAIL-R2 receptors, although via entirely different mechanisms, contribute to PDAC progression. This suggests that the down regulation of TRAIL-R2 expression, instead of its targeting by agonistic molecules, may offer a better therapeutic option for treatment of patients suffering from PDAC.
Projektbezogene Publikationen (Auswahl)
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Compartmentalization of TNF-related apoptosis-inducing ligand (TRAIL) death receptor functions: emerging role of nuclear TRAIL-R2. Cell Death Dis. 2014 ;5:e1390
Bertsch U, Röder C, Kalthoff H, Trauzold A
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Nuclear death receptor TRAIL-R2 inhibits maturation of let-7 and promotes proliferation of pancreatic and other tumor cells. Gastroenterology. 2014; 146:278-90
Haselmann V, Kurz A, Bertsch U, Hübner S, Olempska-Müller M, Fritsch J, Häsler R, Pickl A, Fritsche H, Annewanter F, Engler C, Fleig B, Bernt A, Röder C, Schmidt H, Gelhaus C, Hauser C, Egberts JH, Heneweer C, Rohde AM, Böger C, Knippschild U, Röcken C, Adam D, Walczak H, Schütze S, Janssen O, Wulczyn FG, Wajant H, Kalthoff H, Trauzold A
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Cancer Cell-Autonomous TRAIL-R Signaling Promotes KRAS- Driven Cancer Progression, Invasion, and Metastasis. Cancer Cell. 2015 pii: S1535- 6108(15)00064-1
von Karstedt S, Conti A, Nobis M, Montinaro A, Hartwig T, Lemke J, Legler K, Annewanter F, Campbell AD, Taraborrelli L, Grosse-Wilde A, Coy JF, El-Bahrawy MA, Bergmann F, Koschny R, Werner J, Ganten TM, Schweiger T, Hoetzenecker K, Kenessey I, Hegedüs B, Bergmann M, Hauser C, Egberts JH, Becker T, Röcken C, Kalthoff H, Trauzold A, Anderson KI, Sansom OJ, Walczak H
