Identifying vulnerabilities in sugar nucleotide metabolism of cancer cells

Abstract

Cancer cells exhibit elevated metabolic demands, imposing a need for metabolic reprogramming. The aim of the thesis is to identify a targetable metabolic vulnerability using an approach that leverages the altered pathways in cancer cells to induce the accumulation of inherently toxic metabolites to eliminate cancer cells selectively. Through a systematic analysis of transcriptomics and cancer dependency data, we identified UXS1, a Golgi enzyme responsible for converting UDP-glucuronic acid (UDPGA) to UDP-xylose that is conditionally essential in cells expressing high levels of its upstream enzyme UGDH. Here, we demonstrate that UGDH high cancer cells are dependent on UXS1 to prevent excess buildup of UDPGA, generated by UGDH. Excess UDPGA causes disruption of the structure and function of the Golgi, leading to aberrant protein glycosylation and improper protein trafficking of critical glycoproteins within cancer cells. We find that UGDH expression is elevated in various cancers, including lung adenocarcinoma and breast carcinoma. Furthermore, elevating UGDH expression is beneficial to cancer cells, because UDPGA functions as a substrate in the detoxification of chemotherapeutic agents. Therefore, chemo-resistant cells upregulate UGDH expression, enhancing their susceptibility to UXS1 ablation. Consequently, this study reveals the therapeutic potential of targeting UXS1 in cancer treatment, offering a novel approach to exploit the metabolism of sugar nucleotides in cancer cells.