Pancreatic cancer-associated diabetes is an "exosomopathy"

Diabetes may be a consequence of pancreatic cancer, preceding cancer diagnosis. The underlying mechanism is the release of exosomes delivering adrenomedullin to β cells, inducing endoplasmic reticulum stress and perturbations in the unfolded protein response, leading to β-cell dysfunction and death. This knowledge could lead to improved diagnostic strategies for pancreatic cancer

p38 MAPK in pancreatic cancer: finding a protective needle in the haystack

Activated p38 MAPK alpha (pp38α) is a good prognostic marker in pancreatic ductal adenocarcinoma that could be used to personalize therapy. pp38α suppresses JNK-mediated proliferation, both in vitro and in vivo. These findings support the testing of combination therapies that include JNK targeting and/or suppressing negative regulators of pp38α

Update on Diabetes Mellitus

Diabetes mellitus is a complex multi-system disorder that may be classified as autoimmune mediated type 1 diabetes, or as insulin resistance associated type 2 diabetes. In type 1 diabetes, there is selective loss of the beta cells within the endocrine islets, as a consequence of T-cell and cytokine mediated destruction of these cells, perhaps in conjunction with destruction of the peri-islet Schwann cells. In type 2 diabetes, the etiology of the resistance ranges from post-receptor defects in the insulin signaling pathway to excessive production of adipocyte derived cytokines that antagonize insulin action to mitochondrial defects that interfere with glucose disposal. Proteome based technologies are providing new insights into these defects

Pancreatic Cancer Center: Providing the Research Tools Necessary to Advance Pancreatic Cancer Patient Care

poster abstractThere were approximately 43,000 new cases of pancreatic ductal adenocarcinoma (PDAC) in the U.S. in 2010, and approximately 37,000 deaths. PDAC thus constitutes the fourth leading cause of cancer deaths, and PDAC patients have a dismal 5-year survival rate of 6%; approximately 75% of patients die within the first year after diagnosis. PDAC is notoriously resistant to chemotherapy and radiation and even with our best treatment options, a complete margin-negative surgical resection, few patients achieve long-term survival. Despite these statistics, surprisingly only a small number of NCI-designated cancer centers have a specialized pancreatic cancer program. The creation of the IUPUI Signature Center for Pancreatic Cancer Research has been the foundation for putting IUPUI, the IU School of Medicine, Purdue University and the IU Simon Cancer Center at the forefront of pancreatic cancer treatment and research across the nation. The Signature Center, comprised of basic, translational and clinical researchers, represents the continuum of the disease from biological / molecular investigation to clinical trials. Funding from the Signature Center Initiative is being utilized to develop genetically engineered mouse models, generate orthotopic pancreatic cancer mouse models as well as provide funding for peer reviewed pilot projects. Establishment and characterization of these in vivo models provides the groundwork to be used by all members in their translational research projects; support of pilot projects provides preliminary data and identification of projects to be used in a SPORE application. Additionally, work has begun on a web portal to promote and educate both patients and clinicians about the IUSCC Pancreas Cancer Clinic which became operational in 2010. Taken together these activities provide the infrastructure to support pancreas cancer research at IU across the continuum of bench to bedside to practice. The availability of these resources to all members promotes inter-disciplinary collaborations aimed at increasing our understanding of pancreatic cancer so that advancements can be made in diagnosis, prevention and treatment of this malignancy

Designer hydrogels: Shedding light on the physical chemistry of the pancreatic cancer microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer mortality in the United States, with a 5-year survival of ∼8%. PDAC is characterized by a dense and hypo-vascularized stroma consisting of proliferating cancer cells, cancer-associated fibroblasts, macrophages and immune cells, as well as excess matrices including collagens, fibronectin, and hyaluronic acid. In addition, PDAC has increased interstitial pressures and a hypoxic/acidic tumor microenvironment (TME) that impedes drug delivery and blocks cancer-directed immune mechanisms. In spite of increasing options in targeted therapy, PDAC has mostly remained treatment recalcitrant. Owing to its critical roles on governing PDAC progression and treatment outcome, TME and its interplay with the cancer cells are increasingly studied. In particular, three-dimensional (3D) hydrogels derived from or inspired by components in the TME are progressively developed. When properly designed, these hydrogels (e.g., Matrigel, collagen gel, hyaluronic acid-based, and semi-synthetic hydrogels) can provide pathophysiologically relevant compositions, conditions, and contexts for supporting PDAC cell fate processes. This review summarizes recent efforts in using 3D hydrogels for fundamental studies on cell-matrix or cell-cell interactions in PDAC

Pancreatic Cancer Signature Center: Providing the Research Tools Necessary to Advance Pancreatic Cancer Patient Care

There were approximately 45,000 new cases of pancreatic ductal adenocarcinoma (PDAC) in the U.S. in 2013, and approximately 38,500 deaths. PDAC thus constitutes the fourth leading cause of cancer deaths in adults, and PDAC patients have a dismal 5-year survival rate of 6%. Moreover, approximately 75% of patients die within the first year after diagnosis. PDAC is notoriously resistant to chemotherapy and radiation and even with our best treatment options, a complete margin-negative surgical resection, few patients achieve long-term survival. Despite these statistics, surprisingly only a small number of NCI-designated cancer centers have a specialized pancreatic cancer program. The creation of the IUPUI Signature Center for Pancreatic Cancer Research has been the foundation for putting IUPUI, the IU School of Medicine, Purdue University and the IU Simon Cancer Center at the forefront of pancreatic cancer treatment and research across the nation. The Signature Center, comprised of basic, translational and clinical researchers, represents the continuum of the disease from biological / molecular investigation to clinical trials. Funding from the Signature Center Initiative is being utilized to develop genetically engineered mouse models, generate orthotopic pancreatic cancer mouse models, develop cancer associated fibroblast lines to be used as a shared resource as well as provide funding for peer reviewed pilot projects led by young investigators. Establishment and characterization of these cell lines and in vivo models provides the groundwork for these resources to be used by all members in their translational research projects. Support of pilot projects provides preliminary data and identification of projects to be ultimately used in a SPORE application. Additionally, work has begun on a web portal to promote and educate both patients and clinicians about the IUSCC Pancreas Cancer Clinic which became operational in 2010. Taken together, these activities provide the infrastructure to support pancreas cancer research at IU across the continuum of bench to bedside to practice. The availability of these resources to all members promotes inter-disciplinary collaborations aimed at increasing our understanding of pancreatic cancer so that advancements can be made in early diagnosis, prevention and multi-modality targeted treatment of this malignancy

Modeling Pancreatic Cancer Tumor Microenvironment using a Microfluidics Culture System

poster abstractPancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the United States, with an overall five year survival rate of 7%. This is partly due to the lack of effective models that simulate the complex PDAC tumor microenvironment and allow for high throughput drug screening. Some of the key features of the PDAC tumor microenvironment are the presence of a dense stroma which impedes effective drug delivery to the pancreatic cancer cells (PCCs), as well as the presence of cancer associated fibroblasts (CAFs) that have been shown to modulate disease progression. The objective of this project is to develop an in vitro microfluidic cell culture system that allows researchers to recapitulate the PDAC tumor environment. The system, Tumor-Microenvironment-on-Chip (T-MOC) is manufactured using a replica molding technique. The chip consist of two polydimethylsiloxane (PDMS) layers separated by a porous membrane for gas exchange. This device forms an enclosed transparent device with input channel for cell entry and inner channels which mimic fluidic transport found in vivo. To analyze the potential of the device to simulate in vivo conditions, PCCs (GFP+) and CAFs (RFP+) were co-cultured with collagen and inserted into the device. Initial data analysis indicates that the device supports the growth of PCCs and allows formation of 3D tumor spheroids. In addition, analysis of GFP and RFP intensity demonstrated the effect of CAFs on PCCs growth, which diminished PCCs growth. This provides evidence that the microfluidic device can be used to replicate tumor environment allowing for future studies to screen potential drug candidates before in vivo studies

Overview of pre-clinical and clinical studies targeting angiogenesis in pancreatic ductal adenocarcinoma

The importance of angiogenesis in pancreatic ductal adenocarcinoma (PDAC) and its therapeutic potential have been explored in both pre-clinical and clinical studies. Human PDACs overexpress a number of angiogenic factors and their cognate high-affinity receptors, and anti-angiogenic agents reduce tumor volume, metastasis, and microvessel density (MVD), and improve survival in subcutaneous and orthotopic pre-clinical models. Nonetheless, clinical trials using anti-angiogenic therapy have been overwhelmingly unsuccessful. This review will focus on these pre-clinical and clinical studies, the potential reasons for failure in the clinical setting, and ways these shortcomings could be addressed in future investigations of angiogenic mechanisms in PDAC