Metabolic Alterations in Pancreatic Cancer Progression.

Enza Vernucci,Pankaj K Singh,Audrey J Lazenby,Venugopal Gunda,Kyla Buettner,Jaime Abrego,Surendra K Shukla,Fang Yu,Benjamin J Swanson,Nina Chaika,Aneesha Dasgupta,Alysha Illies,Vikrant Rai

doi:10.3390/cancers12010002

Enza Vernucci, Pankaj K Singh + Show 11 more

Open Access

https://doi.org/10.3390/cancers12010002

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Journal: Cancers	Publication Date: Dec 18, 2019
Citations: 34	License type: CC BY 4.0

Affiliation: University of Nebraska Medical Center

Abstract

Pancreatic cancer is the third leading cause of cancer-related deaths in the USA. Pancreatic tumors are characterized by enhanced glycolytic metabolism promoted by a hypoxic tumor microenvironment and a resultant acidic milieu. The metabolic reprogramming allows cancer cells to survive hostile microenvironments. Through the analysis of the principal metabolic pathways, we identified the specific metabolites that are altered during pancreatic cancer progression in the spontaneous progression (KPC) mouse model. Genetically engineered mice exhibited metabolic alterations during PanINs formation, even before the tumor development. To account for other cells in the tumor microenvironment and to focus on metabolic adaptations concerning tumorigenic cells only, we compared the metabolic profile of KPC and orthotopic tumors with those obtained from KPC-tumor derived cell lines. We observed significant upregulation of glycolysis and the pentose phosphate pathway metabolites even at the early stages of pathogenesis. Other biosynthetic pathways also demonstrated a few common perturbations. While some of the metabolic changes in tumor cells are not detectable in orthotopic and spontaneous tumors, a significant number of tumor cell-intrinsic metabolic alterations are readily detectable in the animal models. Overall, we identified that metabolic alterations in precancerous lesions are maintained during cancer development and are largely mirrored by cancer cells in culture conditions.

Highlights

Genetic instability plays a pivotal role in pancreatic ductal adenocarcinoma (PDAC) initiation and progression [1]
To analyze metabolic and enzymatic changes that happen during pancreatic cancer development, we used the KPC mouse model
Considering that we noted significant increases in aspartate, at late stage KPC lesions, and malate, even at early stage KPC lesions, the metabolic changes could be suggestive of anaplerotic glutamine metabolism that facilitates tumor cell survival under low pH [11]

Summary

Introduction

Genetic instability plays a pivotal role in pancreatic ductal adenocarcinoma (PDAC) initiation and progression [1]. PanINs begin as low-grade lesions that, over time, allow premalignant cells to accumulate mutations. These alterations promote genetic instability and tissue disorganization, allowing histological characterization of PDAC progression from low-grade PanIN lesions to high-grade PanIN lesions in a stepwise manner before the formation of an invasive tumor mass [5]. Several studies have demonstrated that mutations in Kras alone are sufficient to initiate PanINs, but not enough to develop an invasive form of pancreatic cancer [6,7]. The cooperation between activated KRAS and inactivated tumor suppressor genes is required for progression of the disease. TP53 is one of the suppressor genes most frequently altered in pancreatic cancer [8].

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