Branched-Chain Amino Acid Catabolism - Promotes Ovarian Cancer Cell Proliferation via Phosphorylation of mTOR

Sep 23, 2026

Ovarian cancer causes substantial mortality, with high-grade serous ovarian cancer (HGSOC) driving aggressive metastatic spread from fallopian tube epithelial cells to the ovary, omentum, and peritoneal cavity. Using mass spectrometry imaging (MSI) adapted for early metastatic coculture models, the study maps metabolite changes in three-dimensional tumorigenic cell and omental tissue interfaces. Altered branched-chain amino acid (BCAA) catabolism, including increased valine consumption, is linked to heightened proliferation and mTOR signaling in tumorigenic FTE cells. These findings suggest BCAAs as a nutrient mechanism and potential therapeutic target during omental colonization, while highlighting MSI signature generation considerations such as ionization suppression.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Abstract

Significance

Introduction

RESEARCH ARTICLE [https://doi.org/10.1158/2767-9764.CRC-24-0532](https://doi.org/10.1158/2767-9764.CRC-24-0532) OPEN ACCESS Branched-Chain Amino Acid Catabolism Promotes Ovarian Cancer Cell Proliferation via Phosphorylation of mTOR Hannah J. Lusk1, Monica A. Haughan2, Tova M. Bergsten2, Joanna E. Burdette2, and Laura M. Sanchez1 􀀶 ABSTRACT Ovarian cancer is the sixth leading cause of cancer-related mortality among individuals with ovaries, and high-grade serous ovarian cancer (HGSOC) is the most common and lethal subtype. Characterized by a distinct and aggressive metastatic pattern, HGSOC can originate in the fallopian tube with the transformation of fallopian tube epithelial (FTE) cells, which metastasize to the ovary and subsequently to the omentumand peritoneal cavity. The omentum is a privileged metastatic site, and the metabolic exchange underlying omental metastasis could provide enzyme or receptor targets to block spread. In this study, we adapted amass spectrometry imaging (MSI) protocol to investigate spatial location of three-dimensional cocultures of tumorigenic FTE cells when grown in proximity to murine omental explants as a model of early metastatic colonization. Our analysis revealed several altered metabolites in tumorigenic FTE/omentum cocultures, namely changes in branched-chain amino acids (BCAA), including valine. We quantified the heightened consumption of valine, other BCAAs, and other amino acid–derived metabolites in omental cocultures using LC/MS assays. Our analysis revealed that metabolite concentrations when monitored with MSI from cell culture media in living culture systems have notable considerations for production of signatures by MSI data that induce ionization suppression. Supplementation with valine enhanced proliferation and mTOR signaling in tumorigenic FTE cells, suggesting the potential of BCAAs as a nutrient utilized by tumor cells during omental colonization and a possible target for metastasis. Significance: This study uncovers altered amino acid metabolism, specifically increased BCAA catabolism, at the interface of ovarian cancer cells andomental tissue in a coculture model of HGSOC secondary metastasis. Enhanced BCAA catabolism promotes cancer cell proliferation through mTOR signaling, presenting potential therapeutic value. These findings deepen our understanding of HGSOC pathogenesis and the metastatic tumor microenvironment, offering insights for developing new treatment strategies. Introduction Ovarian cancer is the most lethal gynecologic malignancy ( 1) . Projections indicate that in 2024, the United States will see 19,680 new cases and 12,740 deaths attributed to ovarian cancer ( 1) . Despite the term “ovarian cancer” implying a singular condition, it encompasses several histologically distinct subtypes; among them, high-grade serous ovarian cancer (HGSOC) is the most prevalent and lethal (2) . HGSOC poses challenges in diagnosis 1Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, California. 2Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, Chicago, Illinois. Corresponding Authors: Laura M. Sanchez, Department of Chemistry and Biochemistry, University of California Santa Cruz, 1156 High Street, Santa Cruz, CA 95064. E-mail: [lmsanche@ucsc.edu](lmsanche@ucsc.edu); and Joanna E. Burdette, Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois Chicago, 900 S Ashland Avenue, Chicago, IL 60607. E-mail: [joannab@uic.edu](joannab@uic.edu) [doi:](doi: 10.1158/2767-9764)[ 10.1158/2767-9764](doi: 10.1158/2767-9764) .CRC-24-0532 This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license. ©2025 The Authors; Published by the American Association for Cancer Research due to nonspecific symptoms and the absence of efficient screening methods (2–4) . Because of a lack of routine screening,

FAQs

What model and method were used to study early ovarian cancer metastasis?

The study adapted a mass spectrometry imaging (MSI) protocol to investigate spatial metabolite changes in three-dimensional cocultures of tumorigenic fallopian tube epithelial cells grown near murine omental explants.

Which metabolites were most notably altered in the coculture interface?

The analysis revealed changes in branched-chain amino acids (BCAA), including valine, alongside other amino-acid–derived metabolites.

How does valine influence tumorigenic cell behavior in this study?

Valine supplementation enhanced proliferation and increased mTOR signaling in tumorigenic FTE cells, linking BCAA catabolism to cancer cell growth during omental colonization.

Sep 23, 2026

Uploaded by River Wang