Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the RAS pathway. Finally, through intratumoral dissection and the direct manipulation of RAS gene dosage, we identify a suite of RAS-regulated secreted and membrane-bound proteins that may represent potential candidates for therapeutic intervention in patients with PDAC. SIGNIFICANCE: Accurate modeling of the molecular subtypes of pancreatic cancer is crucial to facilitate the generation of effective therapies. We report the development of an intraductal organoid transplantation model of pancreatic cancer that models the progressive switching of subtypes, and identify stochastic and RAS-driven mechanisms that determine subtype specification.

Interleukin (IL)-4 and IL-13 are known as pleiotropic Th2 cytokines with a wide range of biological properties and functions especially in immune responses. In addition, increasing activities have also been determined in oncogenesis and tumor progression of several malignancies. It is now generally accepted that IL-4 and IL-13 can exert effects on epithelial tumor cells through corresponding receptors. Type II IL-4 receptor (IL-4Rα/IL-13Rα1), predominantly expressed in non-hematopoietic cells, is identified to be the main target for both IL-4 and IL-13 in tumors. Moreover, IL-13 can also signal by binding to the IL-13Rα2 receptor. Structural similarity due to the use of the same receptor complex generated in response to IL-4/IL-13 results in overlapping but also distinct signaling pathways and functions. The aim of this review was to summarize knowledge about IL-4 and IL-13 and their receptors in pancreatic cancer in order understand the implication of IL-4 and IL-13 and their receptors for pancreatic tumorigenesis and progression and for developing possible new diagnostic and therapeutic targets.

Exogenous interleukin-4 (IL-4) has been demonstrated to affect the growth of different human malignancies including pancreatic cancer cells. The aim of our study was to determine the role of endogenously expressed IL-4-receptor-α-chain (IL-4Rα) in pancreatic cancer cells. IL-4Rα-suppression was achieved by generating Capan-1 cells stably expressing shRNA targeting IL-4Rα. The malignant phenotype was characterized by assessing growth properties, directional and non-directional cell movement in vitro and tumor growth in vivo. Signaling pathways were analyzed upon IL-4 and IL-13 stimulation of wildtype (WT) and control-transfected cells compared to IL-4Rα-knockdown cells. Silencing of IL-4Rα resulted in reduced anchorage-dependent cell growth (p < 0.05) and reduced anchorage-independent colony size (p < 0.001) in vitro. Moreover, cell movement and migration was inhibited. IL-4 and IL-13 stimulation of Capan-1-WT cells induced activation of similar pathways like stimulation with Insulin-like growth factor (IGF)-I. This activation was reduced after IL-4Rα downregulation while IGF-I signaling seemed to be enhanced in knockdown-clones. Importantly, IL-4Rα silencing also significantly suppressed tumor growth in vivo. The present study indicates that endogenously expressed IL-4 and IL-4Rα contribute to the malignant phenotype of pancreatic cancer cells by activating diverse pro-oncogenic signaling pathways. Addressing these pathways may contribute to the treatment of the disease.

Interleukin (IL)-4 and -13 are structurally and functionally related cytokines sharing common receptor subunits. They regulate immune responses and, moreover, are involved in the pathogenesis of a variety of human neoplasms. Three different receptors have been described for IL-4, but only IL-4 receptor type II (IL-4Rα/IL-13Rα1) is expressed in solid tumors. While IL-13 can also bind to three different receptors, IL-13 receptor type I (IL-4Rα/IL-13Rα1/IL-13Rα2) and type II (IL-4Rα/IL-13Rα1) are expressed in solid tumors. After receptor binding, IL-4 and IL-13 can mediate tumor cell proliferation, survival, and metastasis in gastric or colon cancer. This review summarizes the results about the role of IL-4/IL-13 and their receptors in gastric and colon cancer.

The management of pancreatic cancer has dramatically changed since the first major randomized trial published in 2001 by the European Study Group for Pancreatic Cancer (ESPAC) stimulated the development of multimodality oncosurgical therapies. ESPAC-1 demonstrated a survival improvement from upfront surgery of only 8%, increasing to 21% 5-year survival for 5-fluorouracil/folinic acid but only 10.8% for chemoradiotherapy. ESPAC-4 has shown a 5-year survival rate of 30% for all patients without restriction of 30% using a combination of gemcitabine and capecitabine, rising to 40% in those with an R0 resection margin, or nearly 50% in those with N0 lymph node status. In selected patients with favorable prognostic features mFOLFIRINOX can produce a 50% 5-year survival rate but with added toxicity. While a positive resection margin is associated with an increased likelihood of local recurrence, this of itself is not the contributor to reduced survival, but rather reflects the increased probability of systemic disease. Thus, strategies aimed at local control, may reduce subsequent local progression, but will not improve overall survival. Neoadjuvant chemotherapy is increasingly utilized in cases of borderline resectable or locally advanced pancreatic cancer, but there is still a lack of proof of concept studies. High-quality evidence from randomized controlled trials to identify the indications and benefits of neoadjuvant therapy in pancreatic cancer are required. The use of patient-derived tumor organoids may predict response to chemotherapy which could open a new opportunity in pancreatic cancer treatment, stratifying patients into treatment groups based on their response to these therapies in the laboratory.

The c-Jun N-terminal protein kinases (JNKs) JNK1 and JNK2 can act as either tumor suppressors or pro-oncogenic kinases in human cancers. The isoform-specific roles for JNK1 and JNK2 in human pancreatic cancer are still unclear, the question which should be addressed in this project. Human pancreatic cancer cell lines MIA PaCa-2 and PANC-1 clones were established either expressing either JNK1 or -2 shRNA in a stable manner. Basal anchorage-dependent and –independent cell growth, single-cell movement, and invasion using the Boyden chamber assay were analyzed. Xenograft growth was assessed using an orthotopic mouse model. All seven tested pancreatic cancer cell lines expressed JNKs as did human pancreatic cancer samples determined by immunohistochemistry. Pharmacological, unspecific JNK inhibition (SP600125) reduced cell growth of all cell lines but PANC-1. Especially inhibition of JNK2 resulted in overall increased oncogenic potential with increased proliferation and invasion, associated with alterations in cytoskeleton structure. Specific inhibition of JNK1 revealed opposing functions. Overall, JNK1 and JNK2 can exert different functions in human pancreatic cancer and act as counter players for tumor invasion. Specifically modulating the activity of JNKs may be of potential therapeutic interest in the future.

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Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new therapeutic approaches are urgently needed. Protein kinases are key regulatory players in basically all stages of development, maintaining physiologic functions but also being involved in pathogenic processes. c-Jun N-terminal kinases (JNK) and p38 kinases, representatives of the mitogen-activated protein kinases, as well as the casein kinase 1 (CK1) family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors, DNA damage, and others. In their physiologic roles, they are responsible for the regulation of cell cycle progression, cell proliferation and differentiation, and apoptosis. Dysregulation of the underlying pathways consequently has been identified in various cancer types, including pancreatic cancer. Pharmacological targeting of those pathways has been the field of interest for several years. While success in earlier studies was limited due to lacking specificity and off-target effects, more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising in vitro results. Consequently, targeting of JNK, p38, and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases. However, further studies are warranted, especially involving in vivo investigation and clinical trials, in order to advance inhibition of stress-activated kinases to the field of translational medicine.