Ubiquitous Aberration in Cholesterol Metabolism across Pancreatic Ductal Adenocarcinoma.

Venugopal Gunda,Gopalakrishnan Natarajan,Ramakanth Chirravuri-Venkata,Zeljka Korade,Karoly Mirnics,Kavita Mallya,Jyoti B Kaushal,Satyanarayana Rachagani,Paul M Grandgenett,Thiago C Genaro-Mattos,Surinder K Batra

doi:10.3390/metabo12010047

Venugopal Gunda, Gopalakrishnan Natarajan + Show 9 more

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https://doi.org/10.3390/metabo12010047

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Abstract

Pancreatic cancer (PC) is characterized by metabolic deregulations that often manifest as deviations in metabolite levels and aberrations in their corresponding metabolic genes across the clinical specimens and preclinical PC models. Cholesterol is one of the critical metabolites supporting PC, synthesized or acquired by PC cells. Nevertheless, the significance of the de novo cholesterol synthesis pathway has been controversial in PC, indicating the need to reassess this pathway in PC. We utilized preclinical models and clinical specimens of PC patients and cell lines and utilized mass spectrometry-based sterol analysis. Further, we also performed in silico analysis to corroborate the significance of de novo cholesterol synthesis pathway in PC. Our results demonstrated alteration in free sterol levels, including free cholesterol, across in vitro, in vivo, and clinical specimens of PC. Especially, our sterol analyses established consistent alterations in free cholesterol across the different PC models. Overall, this study demonstrates the significance and consistency in deviation of cholesterol synthesis pathway in PC while showing the aberrations in sterol metabolite intermediates and the related genes using preclinical models, in silico platforms, and the clinical specimens.

Highlights

Cholesterol is a vital structural component of cellular membranes and plays a key role in various biological processes involving physiology and disease progression, including cancer [1,2]
Pancreatic malignancies are histologically well-characterized exocrine lesions that can progress from three precursor lesions, namely, intraductal papillary mucinous-neoplasms (IPMNs), intraductal papillary-mucinous adenomas (IPMAs), and pancreatic intraepithelial neoplasms (PanINs), to pancreatic ductal adenocarcinoma (PDAC) through oncogenic transformation and mutations in tumor suppressor genes (Figure 1A)
The cholesterol biosynthesis pathway plays a significant role in cellular metabolism as it provides cholesterol and other sterol intermediates required for multiple metabolic pathways associated with sterols [41,51]

Summary

Introduction

Cholesterol is a vital structural component of cellular membranes and plays a key role in various biological processes involving physiology and disease progression, including cancer [1,2]. Due to the cellular utilization of free cholesterol as a membrane constituent and an intermediate in sterol metabolism, free cholesterol pools become significantly decreased in cells, leading to cellular dependence on cholesterol replenishment for vital processes [3] Such striking reliance on cholesterol replenishment, including the de novo biosynthesis of cholesterol, is noticed in malignancies, wherein cancer cells exhibit prolific division and migration potential, and abnormally rely on cholesterol to maintain their proliferative and migratory competence [2,4,5,6]. In vitro and in vivo models of PC reveal an inevitable association between cholesterol synthesis and growth, survival, as well as therapy response of PC, which is strongly supported by retrospective survival analyses [12]

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