Metabolic Alterations in Preneoplastic Development Revealed by Untargeted Metabolomic Analysis

Abstract

Metabolic rewiring is a critical hallmark of tumorigenesis and is essential for the development of cancer. Although many key features of metabolic alteration that are crucial for tumor cell survival, proliferation and progression have been identified, these are obtained from studies with established tumors and cancer cell lines. However, information on the essential metabolic changes that occur during pre-neoplastic cell (PNC) development that enables its progression to full blown tumor is still lacking. Here, we present an untargeted metabolomics analysis of human oncogene HRASG12V induced PNC development, using a transgenic inducible zebrafish larval skin development model. By comparison with normal sibling controls, we identified six metabolic pathways that are significantly altered during PNC development in the skin. Amongst these altered pathways are pyrimidine, purine and amino acid metabolism that are common to the cancer metabolic changes that support rapid cell proliferation and growth. Our data also suggest alterations in post transcriptional modification of RNAs that might play a role in PNC development. Our study provides a proof of principle work flow for identifying metabolic alterations during PNC development driven by an oncogenic mutation. In the future, this approach could be combined with transcriptomic or proteomic approaches to establish the detailed interaction between signaling networks and cellular metabolic pathways that occur at the onset of tumor progression.

Preneoplastic cells switch to Warburg metabolism from their inception exposing multiple vulnerabilities for targeted elimination

“…In our model of tumour initiation, human HRAS G12V (thereafter HRAS) was induced in zebrafish larval keratinocytes to mimic the initial mutational event leading to PNC development (Figure 1 A Schematic). EGFP tagged PNCs can be identified from 8 hours post induction (hpi) and analysing cell proliferation suggests that enhanced PNC growth is overt from 24hpi and the proliferation rate in PNCs remains high at later times 10,11 . We therefore focused our analysis within the first 24 hours of PNC emergence to establish the earliest metabolic changes following PNC induction.…”

“…The zebrafish lines used in this study include Tg(krtt1c19e::KalTA4-ER T2 ; cmlc2::eGFP) ed201 (hereafter K19 Gal4 driver) primarily drives basal keratinocytes. Tg(krt4::KalTA4-ER T2 ; cmlc2::eGFP) ed202 (hereafter K4 Gal4 driver) primarily expressed in superficial keratinocytes 40 Tg(UAS::eGFP-HRAS G12V ; cmlc2::eGFP) ed203 (hereafter UAS:RAS) 11 . Tg(UAS::eGFP-CAAX; cmlc2::eGFP) ed204 (hereafter UAS:CAAX) 11…”

“…Tg(UAS::eGFP-CAAX; cmlc2::eGFP) ed204 (hereafter UAS:CAAX) 11 Zebrafish skin Preneoplastic cell induction and drug treatment.…”

Recent developments in data acquisition, treatment and analysis with ion mobility‐mass spectrometry for lipidomics

“…These results highlight the importance of a good and efficient data preprocessing step in lipid annotation, especially when a complex third dimension is added to the analysis. PNNL Pre-Processor has also been used in other lipidomic studies within the last 2 years for demultiplexing and saturation repair [65][66][67][68][69][70], which shows a good acceptance of the software for these studies using IM-MS.…”

Immunometabolism – The Role of Branched-Chain Amino Acids

“…In a seminal article, Sivanand and Heiden reviewed the fundamental perspectives concerning the critical role of BCAA metabolism in cancer ( 143 ). Indeed, metabolism is altered in various diseases, including cancer ( 144 , 145 ). Interestingly, Mayers et al reported elevations in circulating BCAAs during pancreatic cancer progression in humans and mouse cancer models ( 146 ).…”