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.
Highlights
Altered metabolism is a hallmark of cancer development that underpins the uncontrolled growth and proliferation of malignant cells (Hsu and Sabatini, 2008; Hanahan and Weinberg, 2011; Pavlova and Thompson, 2016)
To achieve precise temporal control of oncogene expression, we used a tamoxifen inducible Gal4/UAS system (Figure 1A; Ramezani et al, 2015). This system relies on the combinatorial effect of two separate elements: the zebrafish optimized version of the transcription factor Gal4, KalTA4, fused to the modified ligandbinding domain of human estrogen receptor α (ERT2) expressed under the control of the krtt1c19e promoter, and the Upstream Activating Sequence (UAS) controlling the expression of eGFP
A better understanding of the cellular and molecular changes during the earliest stages of preneoplastic development would help to elucidate the mechanisms mediating the transition from normal healthy somatic cell to abnormal tumor development, FIGURE 7 | Upregulation of genes encoding metabolic enzymes at 24 h post HRASG12V induction in pre-neoplastic cell (PNC)
Summary
Altered metabolism is a hallmark of cancer development that underpins the uncontrolled growth and proliferation of malignant cells (Hsu and Sabatini, 2008; Hanahan and Weinberg, 2011; Pavlova and Thompson, 2016). Metabolic adaptation driven by different oncogenes leads to specific nutrient requirements in different types of cancer cells (Yuneva et al, 2012; Mayers et al, 2016; Ding et al, 2021). Such nutrient “addiction” could be exploited for targeted therapy (White, 2013; Alkan et al, 2018; Jin et al, 2019; Najumudeen et al, 2021)
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