Researcher: Erkan, Murat Mert
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Erkan, Murat Mert
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Publication Metadata only Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase(Nature Publishing Group (NPG), 2018) Ruess, Dietrich A.; Heynen, Guus J.; Ciecielski, Katrin J.; Ai, Jiaoyu; Berninger, Alexandra; Kabacaoglu, Derya; Goerguelue, Kivanc; Dantes, Zahra; Woermann, Sonja M.; Diakopoulos, Kalliope N.; Karpathaki, Angeliki F.; Kowalska, Marlena; Kaya-Aksoy, Ezgi; Song, Liang; van der Laan, Eveline A. Zeeuw; Lopez-Alberca, Maria P.; Nazare, Marc; Reichert, Maximilian; Saur, Dieter; Hopt, Ulrich T.; Sainz, Bruno, Jr.; Birchmeier, Walter; Schmid, Roland M.; Lesina, Marina; Alguel, Hana; N/A; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors(1). Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways(1-7). Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro(8). Here, we report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumors. Genetic deletion of Ptpn11 profoundly inhibited tumor development in mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumors delayed tumor progression but was not sufficient to achieve tumor regression. However, SHP2 was necessary for resistance mechanisms upon blockade of MEK. Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. Our data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers.Publication Metadata only Contemporary strategies to improve the outcome in locally advanced pancreatic cancer(Edizioni Medico Scientifiche, 2017) Schneider, Rick; Spath, Christoph; Nitsche, Ulrich; Kleeff, Jorg; Erkan, Murat Mert; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; Koç University Hospital; 214689Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of less than 7%. After many years of basic and clinical research efforts, pancreatic cancer patients presenting with locally advanced, unresectable tumors remain a therapeutic challenge. Despite the lack of high quality randomized controlled trials, perioperative/neoadjuvant treatment strategies seem to be beneficial in these patients. At present the FOLFIRINOX regimen, which was established in the palliative setting, is increasingly recognized as the backbone of neoadjuvant therapy for locally advanced PDAC. Surgical resection follows the same principles and guidelines as upfront surgery specifically regarding the extent of resection including lymphadenectomy, vascular resections and multivisceral resections. Because of the limited diagnostic accuracy of restaging after neoadjuvant treatment, an adjusted intraoperative strategy is necessary to minimize the risk of debulking procedures and maximize the chance of a potential curative resection. Locally advanced PDAC requires a multidisciplinary and individualized treatment approach, and further research efforts for novel and innovative therapies. This article provides an updated overview on strategies to improve the outcome in locally advanced PDAC.Publication Metadata only A subset of metastatic pancreatic ductal adenocarcinomas depends quantitatively on oncogenic Kras/Mek/Erk-induced hyperactive mTOR signalling(BMJ Publishing Group, 2016) Kong, Bo; Wu, Weiwei; Cheng, Tao; Schlitter, Anna Melissa; Qian, Chengjia; Bruns, Philipp; Jian, Ziying; Jaeger, Carsten; Regel, Ivonne; Raulefs, Susanne; Behler, Nora; Irmler, Martin; Beckers, Johannes; Friess, Helmut; Siveke, Jens T.; Tannapfel, Andrea; Hahn, Stephan A.; Theis, Fabian J.; Esposito, Irene; Kleeff, Joerg; Michalski, Christoph W.; N/A; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689Objective Oncogenic Kras-activated robust Mek/Erk signals phosphorylate to the tuberous sclerosis complex (Tsc) and deactivates mammalian target of rapamycin (mTOR) suppression in pancreatic ductal adenocarcinoma (PDAC); however, Mek and mTOR inhibitors alone have demonstrated minimal clinical antitumor activity. Design We generated transgenic mouse models in which mTOR was hyperactivated either through the Kras/Mek/Erk cascade, by loss of Pten or through Tsc1 haploinsufficiency. Primary cancer cells were isolated from mouse tumours. Oncogenic signalling was assessed in vitro and in vivo, with and without single or multiple targeted molecule inhibition. Transcriptional profiling was used to identify biomarkers predictive of the underlying pathway alterations and of therapeutic response. Results from the preclinical models were confirmed on human material. Results Reduction of Tsc1 function facilitated activation of Kras/Mek/Erk-mediated mTOR signalling, which promoted the development of metastatic PDACs. Single inhibition of mTOR or Mek elicited strong feedback activation of Erk or Akt, respectively. Only dual inhibition of Mek and PI3K reduced mTOR activity and effectively induced cancer cell apoptosis. Analysis of downstream targets demonstrated that oncogenic activity of the Mek/Erk/Tsc/mTOR axis relied on Aldh1a3 function. Moreover, in clinical PDAC samples, ALDH1A3 specifically labelled an aggressive subtype. Conclusions These results advance our understanding of Mek/Erk-driven mTOR activation and its downstream targets in PDAC, and provide a mechanistic rationale for effective therapeutic matching for Aldh1a3-positive PDACs.Publication Metadata only Kif20a inhibition reduces migration and invasion of pancreatic cancer cells(Academic Press Inc Elsevier Science, 2015) Stangel, Daniela; Buchholz, Malte; Gress, Thomas; Michalski, Christoph; Raulefs, Susanne; Friess, Helmut; Kleeff, Joerg; N/A; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689Background: The Translational Genome Research Network in Pancreatic Cancer performed a meta-analysis of publicly available various high-throughput gene analysis panels to identify drugable targets. There, the most differentially expressed gene between normal and cancerous pancreas was Kif20a. The aim of the study was to verify this expression pattern and further characterize Kif20a in pancreatic cancer. Materials and methods: Detailed expression analyses were carried out in pancreatic tissues and in a wide panel of pancreatic cells including ductal adenocarcinoma (PDAC) and neuroendocrine-cancer cell lines as well as immortalized human pancreatic ductal epithelial and primary stellate cells using quantitative real-time polymerase chain reaction, immunohistochemistry, immunofluorescence, and immunoblot analyses. Effects on proliferation, apoptosis, and cell cycle were assessed by MTT assays, caspase-cleavage assays, and fluorescence-activated cell sorting analysis after Kif20a silencing. Cell motility was assessed by migration and invasion assays as well as time-lapse microscopy. Results: Mean Kif20a messenger RNA expression was 18.4-fold upregulated in PDAC tissues compared with that in the normal pancreas. In line, neuroendocrine-cancer cell lines display a 1.6-fold increase and ductal adenocarcinoma cell lines a 11-fold increase of Kif20a messenger RNA (P = 0.009) in comparison with primary stellate cells. A 7.3-fold over-expression was also found in immortalized pancreatic ductal epithelial cells. Kif20a silencing with small interfering RNA molecules resulted in an inhibition of proliferation, motility, and invasion of pancreatic cancer cell lines. Conclusions: Targeting Kif20a reduces proliferation, migration, and invasion of pancreatic cancer cells. Together with its significant overexpression in PDAC, this makes it a potential target for diagnostic and interventional purposes. (C) 2015 Elsevier Inc. All rights reserved.Publication Metadata only Histopathologic infiltration pattern predicts metastasis and progression better than pT-Stage and grade in well-differentiated pancreatic neuroendocrine tumors: a proposal for an infiltration-based morphologic grading system(SPRINGERNATURE, 2021) Reid, Michelle; Culci, Pelin Bağcı; Balcı, Serdar; Demirtaş, Deniz; Pehlivanoğlu, Burçin; Saka, Burcu; Memiş, Bahar; Bozkurtlar, Emine; Leblebici, Can Berk; Corobea, Adelina Birceanu; Xue, Yue; Sökmensüer, Cenk; Scarpa, Aldo; Luchini, Claudio; Baştürk, Olca; Taşkın, Orhun Çığ; Armutlu, Ayşe; Erkan, Murat Mert; Kapran, Yersu; Adsay, Nazmi Volkan; Faculty Member; Teaching Faculty; Faculty Member; Faculty Member; Faculty Member; School of Medicine; School of Medicine; School of Medicine; School of Medicine; School of Medicine; Koç University Hospital; 166686; 133567; 214689; 168101; 286248N/APublication Metadata only DNA methylation pattern of TM6SF2 influences NAFLD progression in genotype-dependent manner(Elsevier, 2019) Adalı, Gupse; Dayangaç, Murat; N/A; N/A; N/A; N/A; N/A; N/A; Ulukan, Bürge; Yiğit Alpdoğan, Buket; Yılmaz, Onur; Cömert, Melis Cansu; Erkan, Murat Mert; Zeybel, Müjdat; PhD Student; Researcher; Undergraduate Student; Undergraduate Student; Faculty Member; Faculty Member; Graduate School of Health Sciences; N/A; School of Medicine; School of Medicine; School of Medicine; School of Medicine; N/A; N/A; N/A; N/A; 214689; 214694N/APublication Metadata only Evaluation and pathologic classification of choledochal cysts clinicopathologic analysis of 84 cases from the west(Lippincott Williams & Wilkins, 2021) Hacıhasanoğlu, Ezgi; Muraki, Takashi; Pehlivanoğlu, Burçin; Memiş, Bahar; Mittal, Pardeep; Polito, Humbert; Everett, Rhonda; Sarmiento, Juan; Kooby, David; Maithel, Shishir K.; Baştürk, Olca; Reid, Michelle D.; N/A; Meriçöz, Çisel Aydın; Saka, Burcu; Erkan, Murat Mert; Adsay, Nazmi Volkan; Faculty Member; Faculty Member; Faculty Member; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; School of Medicine; School of Medicine; School of Medicine; 162418; 222921; 214689; 286248Choledochal cyst (CC) is believed to be a mostly Asian disorder. As a clinically defined entity, its pathologic correlates are poorly characterized. Eighty-four resected CCs from the West were reanalyzed. After applying established Japanese criteria, 9/66 with available imaging were disqualified and 10/39 with preoperative cyst typing had to be recategorized. None had been diagnosed with, or evaluated for, pancreatobiliary maljunction, but on retrospective analysis of radiologic images, 12/66 were found to have pancreatobiliary maljunction. The clinical findings were: F/M=5.7; mean age, 48; most (77%) presented with abdominal pain; mean size, 2.9 cm; choledocholithiasis 11%. Gross/histologic examination revealed 3 distinct pathology-based categories: (I) Cystic dilatation of native ducts (81%). (II) Double bile duct (13%), almost all of which were found in women (10/11); all were diagnosed by pathologic examination, and not preoperative diagnosis. (III) Gastrointestinal (GI) duplication type (6%). Microscopic findings of the entire cohort included mucosal-predominant lymphoplasmacytic inflammation (50%), follicular cholangitis (7%), mucosal hyperplasia (43%; 13% with papillae), intestinal metaplasia (10%), BilIN-like hyperplasia (17%), erosion/ulceration (13%), and severe dysplasia-mimicking atypia including "detachment atypia" and micropapillary degeneration (11%). Carcinomatous changes were seen in 14 cases (17%) (high-grade dysplasia/carcinoma in situ in 7, intraductal papillary neoplasm 1, and invasive carcinoma 6); and 13/14 of these occurred in pathologic category I, all with cyst size >1 cm. In conclusion, diagnostic imaging guidelines used in Asia are not routinely used (but should be adopted) in the West. Pathologically, cases designated as CC are classifiable in 3 groups: category 1 (dilated native duct type), more prone to carcinomatous change; category 2, double-duct phenomenon (all but 1 being female in this study); and category 3, GI-type duplication. Overall, 17% of CCs show carcinomatous change (50% of them invasive). CC specimens should be carefully examined with this classification and submitted entirely for assessment of at-risk mucosa and cancerous transformation.Publication Metadata only Pancreatobiliary maljunction-associated gallbladder cancer is as common in the West, shows distinct clinicopathologic characteristics and offers an invaluable model for anatomy-induced reflux-associated physio-chemical carcinogenesis(Lippincott Williams and Wilkins (LWW), 2022) Muraki, Takashi; Pehlivanoglu, Burcin; Memis, Bahar; Reid, Michelle D.; Uehara, Takeshi; Basturk, Olca; Pernicka, Jennifer Golia; Klimstra, David S.; Jarnagin, William R.; Ito, Tetsuya; Hasebe, Osamu; Okaniwa, Shinji; Horigome, Naoto; Hisa, Takeshi; Mittal, Pardeep; Sarmiento, Juan M.; Maithel, Shishir K.; Koshiol, Jill; Tsai, Susan; Evans, Douglas; N/A; Erkan, Murat Mert; Adsay, Nazmi Volkan; Faculty Member; Faculty Member; Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM); School of Medicine; School of Medicine; 214689; 286248Objective: To determine the associations of pancreatobiliary maljunction (PBM) in the West. Background: PBM (anomalous union of common bile duct and pancreatic duct) is mostly regarded as an Asian-only disorder, with 200X risk of gallbladder cancer (GBc), attributed to reflux of pancreatic enzymes. Methods: Radiologic images of 840 patients in the US who underwent pancreatobiliary resections were reviewed for PBM and contrasted with 171 GBC cases from Japan. Results: Eight % of the US GBCs (24/300) had PBM (similar to Japan; 15/171, 8.8%), in addition to 1/42 bile duct carcinomas and 5/33 choledochal cysts. None of the 30 PBM cases from the US had been diagnosed as PBM in the original work-up. PBM was not found in other pancreatobiliary disorders. Clinicopathologic features of the 39 PBM-associated GBCs (US:24, Japan:15) were similar; however, comparison with non-PBM GBCs revealed that they occurred predominantly in females (F/M = 3); at younger (<50-year-old) age (21% vs 6.5% in non-PBM GBCs; P = 0.01); were uncommonly associated with gallstones (14% vs 58%; P < 0.001); had higher rate of tumor-infiltrating lymphocytes (69% vs 44%; P = 0.04); arose more often through adenoma-carcinoma sequence (31% vs 12%; P = 0.02); and had a higher proportion of nonconventional carcinomas (21% vs 7%; P = 0.03). Conclusions: PBM accounts for 8% of GBCs also in the West but is typically undiagnosed. PBM-GBCs tend to manifest in younger age and often through adenoma-carcinoma sequence, leading to unusual carcinoma types. If PBM is encountered, cholecystectomy and surveillance of bile ducts is warranted. PBM-associated GBCs offer an invaluable model for variant anatomy-induced chemical (reflux-related) carcinogenesis.Publication Metadata only Metabolically reprograming pancreatic stellate cells using a novel nanomedicine for the treatment of pancreatic cancer(Lippincott Williams and Wilkins (LWW), 2018) Sharbeen, G.; Akerman, A.; McCarroll, J.; Boyer, C.; Holst, J.; Youkhana, J.; Davis, T. P.; Goldstein, D.; Phillips, P. A.; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689N/APublication Metadata only Hippo pathway elements co-localize with occludin: a possible sensor system in pancreatic epithelial cells(Taylof & Francis, 2015) Cravo, Ana Santos; Carter, Edward; Harvey, Emma; Furutani-Seiki, Makoto; Mrsny, Randall; N/A; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689External adherens junction-based cell-cell contacts involving E-cadherin interactions function to sense planar cell status and modulate epithelial cell proliferation through Hippo (Hpo) and non-canonical Wnt pathways signaling. We hypothesized these regulatory processes should also be sensitive to a similar cell-cell contact sensor associated with apical-basal polarity events at epithelial surfaces. We used 2 human pancreatic cancer cell lines to explore this hypothesis: one with the capacity to form functional tight junction structures and polarize (HPAFII) and one lacking this capacity (AsPc1).Occludin (Ocln), a tetraspanning protein associated with TJ structures and capable of establishing external cell-cell contacts, was observed to partially co-localize with Hpo elements YAP (c-yes associated protein) and TEAD (TEA-dependent), which function to drive a proliferative transcription program. Treatment with dobutamine, known to affect YAP, was shown to suppress proliferation in an Ocln-dependent manner. Blockade of protein kinase C-zeta (PKC-z) diminished transepithelial electrical resistance (TER) of HPAFII monolayers that was not corrected by dobutamine treatment while the loss of TER resulting from inhibition of ROCK1could be partially recovered. Examination of normal and cancerous human pancreatic biopsies showed that the cellular localization of Ocln, c-Yes, YAP, and TEAD were similar to HPAFII for normal cells and AsPc1 for cancerous cells. Together, these results suggest a link between Hpo and signals emanating from cell-cell contacts involving Ocln that may regulate pancreatic cell proliferation through the coordination of planar cell polarity with apical-basal polarity events.