The Evolution of PGD Addiction in Human Pancreatic Cancer

University Of Miami School Of Medicine, Coral Gables FL

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Abstract

PROJECT SUMMARY (ABSTRACT) Distant metastasis causes most cancer deaths. That is especially true for patients with pancreatic cancer. These patients develop hundreds to thousands of metastatic tumors that appear suddenly and progress rapidly. This stage of the disease is rapidly lethal, poorly understood, and understudied. Long-term Objectives: Characterize what supports and/or accelerates metastatic outgrowth in pancreatic cancer in patients and use this knowledge to identify new treatment targets. Research Design: This proposal is designed to deeply characterize metabolic adaptations that activate an enzyme called PGD in metastatic pancreatic cancer. Sugar (glucose) activates PGD to stimulate metastatic outgrowth in sites such as the liver where glucose is available. Experiments will investigate how import of sugar into pancreatic cells is maximized during metastatic outgrowth to abnormally activate PGD and other pro-tumorigenic enzymes. Understanding how cancer cells use glucose to activate PGD and how PGD then promotes tumor growth is important: it could lead to the first effective treatment strategies against the most common and most lethal stage of disease progression. Research Methods: Experiments will use primary and metastatic pancreatic cancer cells and tissues that were collected from patients who died of the disease. Three-dimensional experimental platforms and genetically engineered mouse models (GEMMs) will facilitate investigation into how these cancers rapidly form metastatic tumors. Experiments will specifically focus on how pancreatic cancer cells that colonize liver and lungs learn to maximize import of glucose and metabolize it into chemicals that support metastatic outgrowth. Aim 1: Evaluate how PGDhigh cooperates with protein folding to reprogram metastatic chromatin. Aim 1 will examine how PGD maximizes protein synthesis to accelerate metastatic outgrowth, and how efficient protein synthesis maximizes glucose import to mutually activate PGD. A malignant byproduct of this process is excess production of “epigenetic” metabolites that attach to DNA packaging proteins (chromatin). Aim 2: Define how HATs influence mitochondrial metabolism to reprogram metastatic chromatin. Aim 2 will investigate how epigenetic “writers” (histone acetyltransferases: HATs) tune mitochondrial respiration rates to stimulate import of excess glucose that is then catabolized into the epigenetic metabolites that HATs themselves use to reprogram chromatin for rapid metastatic outgrowth. Aim 3: Engineer transgenic mice to develop widely metastatic PDAC resembling human disease. Aim 3 will develop new genetically engineered mouse models that naturally develop widely metastatic pancreatic cancer. This will provide my lab and others with a live experimental system to model metastatic pancreatic cancer in a manner that more closely resembles how the disease behaves in patients.