A Novel Metabolic Detour for Pancreatic Cancer Survival

Abstract

BACKGROUND

Pancreatic cancer is a malignant tumor with a high mortality rate and is expected to become the second-leading cause of cancer mortality in the United States by 2030 (Park et al., 2021). The most common type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDA), which is a very aggressive form of the disease (Guo et al., 2021; Park et al., 2021). Despite tremendous efforts to develop therapeutic alternatives for PDA, surgery is currently the most effective option (Jiang et al., 2022). Thus, there is a need for developing new targets for PDA therapy, for which a fundamental understanding of PDA metabolism is essential.

Polyamine promotes the growth and survival of cancer cells by modulating various metabolic signaling pathways (Casero et al., 2018). Similar to most cancer types, PDA uses polyamines to sustain malignant tumor growth, so targeting polyamine metabolism has been proposed as a potential strategy for treating this disease (Jiang et al., 2022). Ornithine, a precursor of polyamine, is considered a non-essential amino acid that can be synthesized by obtaining building blocks (nitrogen sources) from the extracellular environment (Casero et al., 2018). In this context, investigation of de novo ornithine synthesis (DNS) could be important for understanding the PDA energy metabolism. It has been reported that PDA has high arginase activity, enhancing the conversion of arginine to ornithine (Chen et al., 2021). Meanwhile, Nada Kalaany’s group investigated the importance of the ornithine’s nitrogen donor in PDA and suggested the involvement of glutamine in DNS as a nitrogen donor (Zaytouni et al., 2017). Thus, to develop PDA therapeutics, there is a need to confirm the preference of metabolites for DNS in PDA and to investigate their molecular mechanisms.

Recently, Lee et al. (2023) revealed that glutamine-derived DNS contributes to the survival and growth of PDA using metabolic tracing methods. To prove this, genetic and pharmacological approaches were adopted in human and mouse models. The details of the findings are given below.

FINDINGS

First, to distinguish the origin of nitrogen sources that synthesize polyamine formation, the authors performed a metabolic tracing experiment using ¹⁵N(amine)-glutamine or ¹⁵N-arginine in human PDA cells. Tracing data revealed that ornithine’s main nitrogen source in PDA cells was glutamine rather than arginine. Additionally, PDA-specific glutamine-derived ornithine enhanced the production of polyamine derivatives such as putrescine and spermidine, which eventually contributed to their survival. These results imply that the production of glutamine-derived ornithine is crucial for the maintenance of PDA.

Second, to delineate the major ornithine-generating metabolic pathways, representative enzymes, such as ornithine aminotransferase (OAT), arginase (ARG)2, and glycine amidinotransferase (GATM), were silenced in PDA cells; the suppression of OAT, but not ARG2 or GATM, downregulated DNS from ¹⁵N-glutamine. These findings suggest that OAT plays an important role in polyamine synthesis and tumor growth in PDA. Thus, OAT is a potential therapeutic target for preventing polyamine generation in PDA.

Third, it has been reported that KRAS is the most prevalent oncogene in PDA (>90%), and KRAS implicated as an upstream mediator of polyamine synthesis in cancer (Kim et al., 2020; Park et al., 2021). To confirm the contribution of KRAS to glutamine-dependent polyamine production, the authors adopted KRAS-dependent or -independent PDA cells. Unlike all non-KRAS-driven PDA cell lines, the KRAS-driven ones preferred glutamine rather than arginine for DNS with polyamine synthesis. Mechanistically, using in silico analysis, the authors pinned down KLF6 as a transcriptional regulator acting downstream of KRAS, and the loss of Alf6 decreased glutamine-derived ornithine and polyamine even in KRAS-mutated PDA cells. Therefore, the authors suggest that KLF6 functions as a key determinant of DNS and polyamine synthesis in PDA. Additionally, they further addressed whether the alteration of energy metabolism, such as glutamine-derived DNS, can directly modulate the specific gene expression. To test the possibility of transcriptional modulation via alteration in metabolites, we performed assays for transposase-accessible chromatin with sequencing (ATAC-Seq) on PDA cells. ATAC-seq analysis revealed that the inhibition of OAT affected transcriptional alterations in PDA cells, implying a potential regulatory role of OAT in chromatin alteration, accompanied by related changes in the expression of certain genes. Despite these findings, further studies are needed to understand the relationship between OAT and changes in the chromatin structure.

IMPLICATIONS

Pancreatic cancer is one of the most lethal tumor types, and novel therapeutic approaches against PDA should be developed to meet unmet clinical needs (Jiang et al., 2022; Lin et al., 2022). Over the last decade, tumor energy metabolism has been a target for PDA therapeutics, but tumor metabolic plasticity has been behind their failure (Jiang et al., 2022; Park et al., 2021). To overcome this, Lee et al. (2023) performed a metabolic tracing experiment to confirm the preference of energy metabolites in PDA and found a distinct dependence of glutamine-driven ornithine for polyamine production in PDA. These findings should be helpful for novel attempts to cure PDA and further suggest a new paradigm in the field of cancer therapy using tumor energy metabolism.

As a cancer treatment strategy, cancer-specific targeting could be an ideal direction (Karagiannis and Kim, 2021; Park et al., 2021). In case of PDA, clinical treatments have been attempted with ornithine decarboxylase (ODC)1 inhibition, but failed due to the compensatory mechanism of polyamine uptake. Additionally, ODC1 might be essential for polyamine synthesis in normal cells and not specifically PDA. Interestingly, the authors demonstrated that the downregulation of OAT suppresses the level of polyamine in PDA but not in other cells, with no compensatory increases in arginine-driven polyamine in PDA. Thus, Lee et al. (2023) provided crucial clues that OAT could be a novel and attractive target for PDA-specific therapy.

Article information

References