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Item Clinically Actionable Strategies for Studying Neural Influences in Cancer(CELL PRESS, 2020-01-01) Demir, Ihsan Ekin; Reyes, Carmen Mota; Alrawashdeh, Wasfi; Ceyhan, Guralp O.; Deborde, Sylvie; Friess, Helmut; Gorgulu, Kivanc; Istvanffy, Rouzanna; Jungwirth, David; Kuner, Rohini; Maryanovich, Maria; Na'ara, Shorook; Renders, Simon; Saloman, Jami L.; Scheff, Nicole N.; Steenfadt, Hendrik; Stupakov, Pavel; Thiel, Vera; Verma, Divij; Yilmaz, Bengi Su; White, Ruth A.; Wang, Timothy C.; Wong, Richard J.; Frenette, Paul S.; Gil, Ziv; Davis, Brian M.Neuro-glial activation is a recently identified hallmark of growing cancers. Targeting tumor hyperinnervation in preclinical and small clinical trials has yielded promising antitumor effects, highlighting the need of systematic analysis of neural influences in cancer (NIC). Here, we outline the strategies translating these findings from bench to the clinic.Item Future directions in preclinical and translational cancer neuroscience research(NATURE PORTFOLIO, 2020-01-01) Demir, Ihsan Ekin; Reyes, Carmen Mota; Alrawashdeh, Wasfi; Ceyhan, Gueralp O.; Deborde, Sylvie; Friess, Helmut; Goerguelue, Kivanc; Istvanffy, Rouzanna; Jungwirth, David; Kuner, Rohini; Maryanovich, Maria; Na'ara, Shorook; Renders, Simon; Saloman, Jami L.; Scheff, Nicole N.; Steenfadt, Hendrik; Stupakov, Pavel; Thiel, Vera; Verma, Divij; Yilmaz, Bengi Su; White, Ruth A.; Wang, Timothy C.; Wong, Richard J.; Frenette, Paul S.; Gil, Ziv; Davis, Brian M.; Res, Neural Influences Can N.I.C. IntRecent advances in cancer neuroscience necessitate the systematic analysis of neural influences in cancer as potential therapeutic targets in oncology. Here we outline recommendations for future preclinical and translational research in this field.Item Indirect cholinergic activation slows down pancreatic cancer growth and tumor-associated inflammation(BMC, 2020-01-01) Pfitzinger, Paulo L.; Fangmann, Laura; Wang, Kun; Demir, Elke; Guerlevik, Engin; Fleischmann-Mundt, Bettina; Brooks, Jennifer; D'Haese, Jan G.; Teller, Steffen; Hecker, Andreas; Jesinghaus, Moritz; Jaeger, Carsten; Ren, Lei; Istvanffy, Rouzanna; Kuehnel, Florian; Friess, Helmut; Ceyhan, Guralp Onur; Demir, Ihsan EkinBackground Nerve-cancer interactions are increasingly recognized to be of paramount importance for the emergence and progression of pancreatic cancer (PCa). Here, we investigated the role of indirect cholinergic activation on PCa progression through inhibition of acetylcholinesterase (AChE) via clinically available AChE-inhibitors, i.e. physostigmine and pyridostigmine. Methods We applied immunohistochemistry, immunoblotting, MTT-viability, invasion, flow-cytometric-cell-cycle-assays, phospho-kinase arrays, multiplex ELISA and xenografted mice to assess the impact of AChE inhibition on PCa cell growth and invasiveness, and tumor-associated inflammation. Survival analyses were performed in a novel genetically-induced, surgically-resectable mouse model of PCa under adjuvant treatment with gemcitabine+/-physostigmine/pyridostigmine (n = 30 mice). Human PCa specimens (n = 39) were analyzed for the impact of cancer AChE expression on tumor stage and survival. Results We discovered a strong expression of AChE in cancer cells of human PCa specimens. Inhibition of this cancer-cell-intrinsic AChE via pyridostigmine and physostigmine, or administration of acetylcholine (ACh), diminished PCa cell viability and invasion in vitro and in vivo via suppression of pERK signaling, and reduced tumor-associated macrophage (TAM) infiltration and serum pro-inflammatory cytokine levels. In the novel genetically-induced, surgically-resectable PCa mouse model, adjuvant co-therapy with AChE blockers had no impact on survival. Accordingly, survival of resected PCa patients did not differ based on tumor AChE expression levels. Patients with higher-stage PCa also exhibited loss of the ACh-synthesizing enzyme, choline-acetyltransferase (ChAT), in their nerves. Conclusion For future clinical trials of PCa, direct cholinergic stimulation of the muscarinic signaling, rather than indirect activation via AChE blockade, may be a more effective strategy.Item Molecular Profiling in Pancreatic Cancer: Current Role and Its Impact on Primary Surgery(KARGER, 2019-01-01) Mota Reyes, Carmen; Dogruoez, Alper; Istvanffy, Rouzanna; Friess, Helmut; Ceyhan, Gueralp O.; Demir, Ihsan EkinBackground: The advent of next-generation sequencing technologies has enabled the identification of molecular subtypes of pancreatic ductal adenocarcinoma (PDAC) with different biological traits and clinically targetable features. Summary: Although current chemotherapy trials are currently exploiting this knowledge, these molecular subtypes have not yet sufficiently caught the attention of surgeons. In fact, integration of these molecular subtypes into the timing of surgery can in theory improve patient outcome. Here, we present the molecular subtypes of PDAC from the surgeon's perspective and a clinically applicable algorithm that integrates the molecular subtyping of PDAC preoperatively into the decision of primary surgery versus neoadjuvant therapy. Furthermore, we point out the potential of ``tailored{''} (in addition to conventional) neoadjuvant treatment for exploiting the molecular subtypes of PDAC. Key Messages: We believe that for surgeons, the preoperative knowledge on the subtype of PDAC can properly guide in deciding between upfront surgery versus neoadjuvant treatment for improving patient outcome.Item Targeting the undruggable oncogenic KRAS: the dawn of hope(AMER SOC CLINICAL INVESTIGATION INC, 2022-01-01) Asimgil, Hande; Ertetik, Utku; Cevik, Nedim Can; Ekizce, Menar; Dogruoez, Alper; Goekalp, Muazzez; Arik-Sever, Elif; Istvanffy, Rouzanna; Friess, Helmut; Ceyhan, Guralp Onur; Demir, Ihsan EkinKRAS mutations are the drivers of various cancers, including non-small cell lung cancer, colon cancer, and pancreatic cancer. Over the last 30 years, immense efforts have been made to inhibit KRAS mutants and oncogenic KRAS signaling using inhibitors. Recently, specific targeting of KRAS mutants with small molecules revived the hopes for successful therapies for lung, pancreatic, and colorectal cancer patients. Moreover, advances in gene editing, protein engineering, and drug delivery formulations have revolutionized cancer therapy regimens. New therapies aim to improve immune surveillance and enhance antitumor immunity by precisely targeting cancer cells harboring oncogenic KRAS. Here, we review recent KRAS-targeting strategies, their therapeutic potential, and remaining challenges to overcome. We also highlight the potential synergistic effects of various combinatorial therapies in preclinical and clinical trials.Item Localisation analysis of nerves in the mouse pancreas reveals the sites of highest nerve density and nociceptive innervation(WILEY, 2020-01-01) Saricaoglu, Oemer Cemil; Teller, Steffen; Wang, Xiaobo; Wang, Shenghan; Stupakov, Pavel; Heinrich, Tobias; Istvanffy, Rouzanna; Friess, Helmut; Ceyhan, Gueralp O.; Demir, Ihsan EkinBackground Neuropathy and neuro-inflammation drive the severe pain and disease progression in human chronic pancreatitis and pancreatic cancer. Mice, especially genetically induced-mouse models, have been increasingly utilized in mechanistic research on pancreatic neuropathy, but the normal ``peripheral neurobiology{''} of the mouse pancreas has not yet been critically compared to human pancreas. Methods We introduced a standardized tissue-harvesting technique that preserves the anatomic orientation of the mouse pancreas and allows complete sectioning in an anterior to posterior fashion. We applied immunohistochemistry and quantitative colorimetry of all nerves from the whole organ for studying pancreatic neuro-anatomy. Key Results Nerves in the mouse pancreas appeared as ``clusters{''} of nerve trunks in contrast to singly distributed nerve trunks in the human pancreas. Nerve trunks in the mouse pancreas were exclusively found around intrapancreatic blood vessels, and around lymphoid structures. The majority of nerve trunks were located in the pancreatic head (0.15 +/- 0.08\% of tissue area) and the anterior/front surface of the corpus/body (0.17 +/- 0.27\%), thus significantly more than in the tail (0.02 +/- 0.02\%, P = .006). Nerves in the tail included a higher proportion of nociceptive fibers, but the absolute majority, ie, ca. 70\%, of all nociceptive fibers, were localized in the head. Mice heterozygous for Bdnf knockout allele (Bdnf(+/-)) exhibited enrichment of nitrergic nerve fibers specifically in the head and corpus. Conclusions \& Inferences Neuro-anatomy of the ``mesenteric type{''} mouse pancreas is highly different from the ``compact{''} human pancreas. Studies that aim at reproducing human pancreatic neuro-phenomena in mouse models should pay diligent attention to these anatomic differences.