Defining Roles of Metabolic Reprogramming in Pancreatic Tumorigenesis and Tumor Maintenance

Pancreatic cancer is the third leading cause of cancer-related deaths in the United States. Nearly all pancreatic tumors harbor mutations in oncogenic KRAS. Unfortunately, KRAS is difficult to target therapeutically, despite decades of efforts. As such, KRAS-dependent pathways remain promising targets for the development of new therapeutics. Pancreatic cancer extensively reprograms cellular metabolism to support uncontrolled growth and proliferation. Mutations in oncogenic KRAS drive metabolic rewiring that PDA cells are dependent on to supply biosynthetic precursors and energy. Understanding the metabolic dependencies of tumorigenesis and tumor maintenance could reveal targetable vulnerabilities for disease detection and/or treatment. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM), and inhibiting pathways that maintain acinar homeostasis can accelerate tumorigenesis. During ADM, acinar cells transdifferentiate to duct-like cells, a process driven by oncogenic KRAS, and one that we hypothesized was mediated by metabolic rewiring. Transcriptomic analysis revealed global enhancement of metabolic programs in acinar cells undergoing ADM. We previously demonstrated that pancreatic cancer cells rewire glucose and glutamine metabolism to support growth and survival. Using in vitro models of ADM, we found that glutamine availability is not required for ADM. In contrast, glucose availability and intact oxidative phosphorylation are required for ADM. A more detailed analysis of the pathways downstream of glucose metabolism revealed that disrupting the oxidative pentose phosphate pathway accelerates ADM in vitro and tumorigenesis in vivo, likely due to heightened oxidative stress. Changes in redox balance can attenuate or accelerate ADM in vitro and in vivo. Redox homeostasis is also tightly regulated in pancreatic cancer cells by rewiring glutamine metabolism through a glutamate oxaloacetate transaminase 1 (GOT1)-dependent pathway. GOT1 inhibition disrupts redox homeostasis in pancreatic cancer cells. These insights were leveraged in PDA, where we demonstrate that radiotherapy potently enhanced the effect of GOT1 inhibition on tumor growth. Understanding the metabolic pathways that contribute to pancreatic tumorigenesis and tumor maintenance, such as redox homeostasis, could provide biomarkers for diagnosis of early disease or development of better therapeutics for treating pancreatic cancer.PHDCancer BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163123/1/barbnels_1.pd

Current advances in systems and integrative biology

Systems biology has gained a tremendous amount of interest in the last few years. This is partly due to the realization that traditional approaches focusing only on a few molecules at a time cannot describe the impact of aberrant or modulated molecular environments across a whole system. Furthermore, a hypothesis-driven study aims to prove or disprove its postulations, whereas a hypothesis-free systems approach can yield an unbiased and novel testable hypothesis as an end-result. This latter approach foregoes assumptions which predict how a biological system should react to an altered microenvironment within a cellular context, across a tissue or impacting on distant organs. Additionally, re-use of existing data by systematic data mining and re-stratification, one of the cornerstones of integrative systems biology, is also gaining attention. While tremendous efforts using a systems methodology have already yielded excellent results, it is apparent that a lack of suitable analytic tools and purpose-built databases poses a major bottleneck in applying a systematic workflow. This review addresses the current approaches used in systems analysis and obstacles often encountered in large-scale data analysis and integration which tend to go unnoticed, but have a direct impact on the final outcome of a systems approach. Its wide applicability, ranging from basic research, disease descriptors, pharmacological studies, to personalized medicine, makes this emerging approach well suited to address biological and medical questions where conventional methods are not ideal

Blood Vessel Tortuosity Selects against Evolution of Agressive Tumor Cells in Confined Tissue Environments: a Modeling Approach

Cancer is a disease of cellular regulation, often initiated by genetic mutation within cells, and leading to a heterogeneous cell population within tissues. In the competition for nutrients and growth space within the tumors the phenotype of each cell determines its success. Selection in this process is imposed by both the microenvironment (neighboring cells, extracellular matrix, and diffusing substances), and the whole of the organism through for example the blood supply. In this view, the development of tumor cells is in close interaction with their increasingly changing environment: the more cells can change, the more their environment will change. Furthermore, instabilities are also introduced on the organism level: blood supply can be blocked by increased tissue pressure or the tortuosity of the tumor-neovascular vessels. This coupling between cell, microenvironment, and organism results in behavior that is hard to predict. Here we introduce a cell-based computational model to study the effect of blood flow obstruction on the micro-evolution of cells within a cancerous tissue. We demonstrate that stages of tumor development emerge naturally, without the need for sequential mutation of specific genes. Secondly, we show that instabilities in blood supply can impact the overall development of tumors and lead to the extinction of the dominant aggressive phenotype, showing a clear distinction between the fitness at the cell level and survival of the population. This provides new insights into potential side effects of recent tumor vasculature renormalization approaches