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Tropomodulin 3 Overexpression as a Marker for Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Multi-Omics Profiling of High-Grade Serous Ovarian Cancer Reveals an Inflammation-Related Lipid Metabolism Subtype
Yuxi Zhao1, Junyi Li2, Bo Zheng3
1Department of Gynecologic Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Abstract:
Ovarian cancer is the deadliest gynecological malignancy. The main obstacle in treating high-grade serous ovarian cancer (HGSOC) is platinum resistance. The mechanistic interface between tumor metabolic reprogramming and platinum resistance remains undefined. We integrated proteomic and metabolomic profiling of 97 primary HGSOC tumors to map the molecular landscape. Unsupervised clustering identified three subtypes. Subtype 3 exhibited a higher platinum resistance rate (64.5%), as well as worse overall (p = 0.001) and recurrence-free (p = 0.0001) survival. At the molecular level, both Subtypes 2 and 3 tumors displayed phenotypes of activated lipid metabolism. However, Subtype 3 tumors were unique, exhibiting potential divergence between lipid metabolism and bioenergetics. The arachidonic acid metabolism pathway was upregulated (p = 2.0 × 10-6), and the key enzyme cyclooxygenase-2 (COX-2) was overexpressed (p < 0.001). Subtype 3 tumors exhibited an inflammation-associated state with the highest infiltration of M2-like macrophages (p = 0.007). Single-cell transcriptomics revealed increased expression of PTGS2 (encoding COX-2, p = 0.001) and CD163 (p < 2.2 × 10-16) in macrophages from platinum-resistant HGSOC. Multiplex immunofluorescence confirmed that platinum-resistant tumors had a higher proportion of COX-2+ cells in M2-like macrophages (p = 0.010). These findings define a high-risk HGSOC subtype characterized by inflammation-related lipid metabolism. This suggests targeting the arachidonic acid metabolism pathway as a way to overcome platinum resistance.
Insights
High-grade serous ovarian cancer (HGSOC) subtype 3 shows platinum resistance linked to lipid metabolism and inflammation. Targeting arachidonic acid metabolism may overcome resistance in these high-risk ovarian cancer patients.
Area of Science:
- Oncology
- Metabolomics
- Immunology
Background:
- Ovarian cancer, particularly high-grade serous ovarian cancer (HGSOC), presents a significant challenge due to platinum resistance.
- The interplay between tumor metabolic reprogramming and platinum resistance in HGSOC is not well understood.
Purpose of the Study:
- To investigate the molecular landscape of HGSOC tumors and identify subtypes associated with platinum resistance.
- To elucidate the metabolic and inflammatory mechanisms underlying platinum resistance in HGSOC.
Main Methods:
- Integrated proteomic and metabolomic profiling of 97 primary HGSOC tumors.
- Unsupervised clustering to identify tumor subtypes.
- Single-cell transcriptomics and multiplex immunofluorescence to analyze cellular composition and marker expression.
Main Results:
- Three HGSOC subtypes were identified; Subtype 3 showed significantly higher platinum resistance and poorer survival outcomes.
- Subtype 3 tumors displayed activated lipid metabolism, specifically upregulation of arachidonic acid metabolism (via COX-2) and increased M2-like macrophage infiltration.
- Platinum-resistant HGSOC tumors exhibited higher expression of PTGS2 (COX-2) and CD163 in macrophages.
Conclusions:
- A distinct high-risk HGSOC subtype (Subtype 3) is characterized by inflammation-related lipid metabolism.
- Targeting the arachidonic acid metabolism pathway, particularly COX-2, presents a potential therapeutic strategy to overcome platinum resistance in HGSOC.
