In situ profiling reveals metabolic alterations in the tumor microenvironment of ovarian cancer after chemotherapy

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.

Seeing is Believing: Developing Multimodal Metabolic Insights at the Molecular Level

“…It can also be used for tissue histology due to the chemical contrast of intrinsic metabolites . MALDI-MSI offers comprehensive molecular insights across a wide mass spectrum, spanning small molecules to large proteins, , by generating detailed 2D ion images of specific compounds that may have otherwise not been detected in the fingerprint region of the SRS imaging. The capacity to correlate chemotypes in tissue regions through MSI renders it valuable for investigating disease progression, discovering biomarkers, and enhancing diagnostic precision. Neuroscience: SRS microscopy can perform real-time imaging of dynamic processes such as (de)­myelination in single cells, as well as the visualization of small molecules such as glucose or neurotransmitters. , It can generate high spatial-resolution quantification maps of intracellular, pathophysiological protein aggregates. , On the other hand, MALDI-MSI can assist in detailed lipid and metabolic profiling at different time points during neurological processes .…”

“…114 It can also be used for tissue histology due to the chemical contrast of intrinsic metabolites. 173 MALDI-MSI offers comprehensive molecular insights across a wide mass spectrum, spanning small molecules to large proteins, 174,175 by generating detailed 2D ion images of specific compounds that may have otherwise not been detected in the fingerprint region of the SRS imaging. The capacity to correlate chemotypes in tissue regions through MSI renders it valuable for investigating disease progression, discovering biomarkers, and enhancing diagnostic precision.…”