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A Novel Assessment of Metabolic Pathways in Peritoneal Metastases from Low-Grade Appendiceal Mucinous Neoplasms

  • Peritoneal Surface Malignancy
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

There is a paucity of targeted therapies for patients with pseudomyxoma peritonei (PMP) secondary to low-grade appendiceal mucinous neoplasms (LAMNs). Dysregulated metabolism has emerged as a hallmark of cancer, and the relationship of metabolomics and cancer is an area of active scientific exploration. We sought to characterize phenotypic differences found in peritoneal metastases (PM) derived from LAMN versus adenocarcinoma.

Methods

Tumors were washed with phosphate-buffered saline (PBS), microdissected, then dissociated in ice-cold methanol dried and reconstituted in pyridine. Samples were derivatized in tert-butyldimethylsilyl (TBDMS) and subjected to gas chromatography-coupled mass spectrometry. Metabolites were assessed based on a standard library. RNA sequencing was performed, with pathway and network analyses on differentially expressed genes.

Results

Eight peritoneal tumor samples were obtained and analyzed: LAMNs (4), and moderate to poorly differentiated adenocarcinoma (colon [1], appendix [3]). Decreases in pyroglutamate, fumarate, and cysteine in PM from LAMNs were found compared with adenocarcinoma. Analyses showed the differential gene expression was dominated by the prevalence of metabolic pathways, particularly lipid metabolism. The gene retinol saturase (RETSAT), downregulated by LAMN, was involved in the multiple metabolic pathways that involve lipids. Using network map**, we found IL1B signaling to be a potential top-level modulation candidate.

Conclusions

Distinct metabolic signatures may exist for PM from LAMN versus adenocarcinoma. A multitude of genes are differentially regulated, many of which are involved in metabolic pathways. Additional research is needed to identify the significance and applicability of targeting metabolic pathways in the potential development of novel therapeutics for these challenging tumors.

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Acknowledgments

This work was supported by NIH RO1GM132142 and R01CA244360 (MK).

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Authors and Affiliations

  1. Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA

    Eric A. Hanse PhD, Tianhong Wang BS & Mei Kong PhD

  2. Department of Pathology and Laboratory Medicine, University of California, Irvine, Orange, CA, USA

    Delia Tifrea PhD, MA

  3. Department of Surgery, Division of Surgical Oncology, University of California, Irvine, Orange, CA, USA

    Maheswari Senthil MD & Oliver S. Eng MD

  4. Department of Surgery, Division of Surgical Oncology, Ohio State University, Columbus, OH, USA

    Alex C. Kim MD, PhD

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  1. Eric A. Hanse PhD
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  2. Tianhong Wang BS
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  4. Maheswari Senthil MD
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  7. Oliver S. Eng MD
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Contributions

EAH, OSE, and MK conceived the project. MK and OSE supervised the project. EAH conducted all experiments and analyzed the data, and EAH and OE wrote the manuscript. TW provided technical assistance with the metabolomic experiments and technical assistance with RNASeq data. DT provided tumor samples, and MS and ACK provided valuable clinical advice.

Corresponding author

Correspondence to Oliver S. Eng MD.

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Disclosures

Eric A. Hanse, Tianhong Wang, Delia Tifrea, Maheswari Senthil, Alex C. Kim, Mei Kong, and Oliver S. Eng have no relevant financial disclosures to declare.

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Hanse, E.A., Wang, T., Tifrea, D. et al. A Novel Assessment of Metabolic Pathways in Peritoneal Metastases from Low-Grade Appendiceal Mucinous Neoplasms. Ann Surg Oncol 30, 5132–5141 (2023). https://doi.org/10.1245/s10434-023-13587-0

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