In Situ Profiling Reveals Metabolic Alterations in the Tumor Microenvironment of Ovarian Cancer After Chemotherapy

Authors

Sara Corvigno
Sunil Badal
Meredith L Spradlin
Michael Keating
Igor Pereira
Elaine Stur
Emine Bayraktar
Katherine I Foster
Nicholas W Bateman
Waleed Barakat
Kathleen M Darcy
Thomas P Conrads
G Larry Maxwell
Philip L Lorenzi
Susan K Lutgendorf
Yunfei Wen
Li Zhao
Premal H Thaker
Michael J Goodheart
Jinsong Liu
Nicole Fleming
Sanghoon Lee
Livia S Eberlin
Anil K Sood

Publication Date

11-3-2023

Journal

NPJ Precision Oncology

Abstract

In this study, we investigated the metabolic alterations associated with clinical response to chemotherapy in patients with ovarian cancer. Pre- and post-neoadjuvant chemotherapy (NACT) tissues from patients with high-grade serous ovarian cancer (HGSC) who had poor response (PR) or excellent response (ER) to NACT were examined. Desorption electrospray ionization mass spectrometry (DESI-MS) was performed on sections of HGSC tissues collected according to a rigorous laparoscopic triage algorithm. Quantitative MS-based proteomics and phosphoproteomics were performed on a subgroup of pre-NACT samples. Highly abundant metabolites in the pre-NACT PR tumors were related to pyrimidine metabolism in the epithelial regions and oxygen-dependent proline hydroxylation of hypoxia-inducible factor alpha in the stromal regions. Metabolites more abundant in the epithelial regions of post-NACT PR tumors were involved in the metabolism of nucleotides, and metabolites more abundant in the stromal regions of post-NACT PR tumors were related to aspartate and asparagine metabolism, phenylalanine and tyrosine metabolism, nucleotide biosynthesis, and the urea cycle. A predictive model built on ions with differential abundances allowed the classification of patients' tumor responses as ER or PR with 75% accuracy (10-fold cross-validation ridge regression model). These findings offer new insights related to differential responses to chemotherapy and could lead to novel actionable targets.

Keywords

Cancer metabolism, Cancer, Oncology

DOI

10.1038/s41698-023-00454-0

PMID

37923835

PMCID

PMC10624842

PubMedCentral® Posted Date

November 2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes