Revolutionary imaging technique uncovers metabolic differences in ovarian cancer subtypes, paving the way for early detection and personalized treatment strategies.
Study:Metabolic imaging distinguishes ovarian cancer subtypes and detects their early and variable responses to treatment. Image Credit: Explode / Shutterstock.com
A recent study published in the journal Oncogene examines the use of metabolic imaging to differentiate types of ovarian cancer.
Metabolic differences in HGSOC subtypes
Ovarian cancer remains a leading cause of cancer-related death in women throughout the world. High-grade serous ovarian cancer (HGSOC), the most common lethal ovarian cancer subtype, can be further classified into high or low oxidative phosphorylation (OXPHOS) HGSOC subtypes.
In high OXPHOS HGSOC, upregulation of the genes involved in synthesizing the components of the electron transport chain has been observed. This leads to greater oxygen uptake, which increases the cells' vulnerability to the effects of chemotherapy.
Comparatively, in low OXPHOS HGSOC, glycolysis is dominant, and low oxygen uptake is required. As a result, the low OXPHOS subtype of HGSOC is associated with poorer patient outcomes due to its inherent resistance to chemotherapy.
Gene copy number
Prior studies have used positron emission tomography (PET) measurements of 2-deoxy-2-(fluorine-18)fluoro-D-glucose (18F)FDG) uptake and 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized (1-13C) pyruvate metabolism to measure glycolysis in ovarian cancer.
HGSOC subtypes can also be distinguished through their gene copy numbers, which assess these cancer cells' mutation rate and type. Certain types of gene copy number changes signify the presence of abnormalities in the genome, such as breakage-fusion bridges.
Increased copy number is associated with slower tumor growth, as well as an increased risk of relapse after chemotherapy and low carboplatin sensitivity, which affects overall survival.
About the study
The current study determined the association between different gene copy number signatures and clinically detectable variations in glucose metabolism of HGSOC cells. The researchers also investigated whether these techniques could discern differences in carboplatin treatment responses between these subtypes.
Patient-derived organoids (PDOs) were cultured from ascitic fluid obtained from patients with advanced HGSOC. These organoids were also subcutaneously implanted into immunocompromised mice to produce xenografts for comparative studies.
Metabolic differences with MRSI
With localized 13C MRS measurements of hyperpolarized (1-13C) pyruvate metabolism, both organoids and tumor xenografts exhibited a clear metabolic difference. Low and high OXPHOS subtypes of PDO-1 and 5, as well as PDO 2 and 11, respectively, were identified.
Increased lactate labeling was associated with higher lactate dehydrogenase (LDH) activity in low OXPHOS subtypes, along with increased expression of monocarboxylate transporter 4 (MCT4). Glucose transporter 1 (GLUT1) expression was also increased in parallel with lactate labeling.
PET assessments
PET assessments indicated that FDG uptake was similar in both tumor subtypes because the enzyme hexokinase II (HKII), which is required for this step, is expressed at higher levels in the high OXPHOS subtype.
MYC vs. EGFR expression
The c-Myc gene, commonly amplified in HGSOC, facilitates glycolysis by increasing the expression of multiple enzymes, including lactate dehydrogenase A (LDHA), HKll, and GLUT1. Moreover, the c-Myc gene is upregulated by the epidermal growth factor receptor (EGFR), which is present at higher levels in 60% of ovarian cancers.
EGFR enhances aerobic glucose metabolism and advances the cell cycle stage. Thus, EGFR overexpression mediates platinum resistance in ovarian cancer cells.
The current study attributed PDO-1 and PDO-5 growth to c-Myc and EGFR gene amplification and increased expression, respectively.
Treatment responses
Chemotherapy for ovarian cancer often involves a combination treatment of paclitaxel and carboplatin. Paclitaxel sensitivity was observed in all organoids and implants. Conversely, high OXPHOS xenografts responded early to carboplatin treatment, whereas low OXPHOS grafts showed an absence of response.
Conclusions
The ability to distinguish OXPHOS activity using 13C magnetic resonance spectroscopic imaging of hyperpolarized (1-13C) pyruvate metabolism is a promising approach to distinguish tumor cells with high or low OXPHOS activity. Thus, this imaging technique has the potential to detect early treatment responses in HGSOC in the absence of gross changes in tumor volume.
Importantly, no correlation was observed between copy number abnormalities and OXPHOS activity. Furthermore, no difference in (18F) FDG uptake between tumor models was reported.
Gene copy signatures can help predict ovarian cancer and determine the type of treatment. However, different tumor deposits may have varying genomic signatures and, as a result, chemosensitivities.
Metabolic imaging overcomes some of the traditional limitations associated with tissue biopsies while also increasing the accuracy of detection of OXPHOS activity in tumors.
Journal reference:
Chia, M. L., Bulat, F., Gaunt, A., et al. (2024). Metabolic imaging distinguishes ovarian cancer subtypes and detects their early and variable responses to treatment. Oncogene. doi:10.1038/s41388-024-03231-w.