Quantification of spatial pharmacogene expression heterogeneity in breast tumors
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Published on: October 25, 2011
Nicholas R Powell1, Rebecca M Silvola1, John S Howard1
1Department of Medicine, Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Background:
Chemotherapeutic drug concentrations vary across different regions of tumors and this is thought to be involved in development of chemotherapy resistance. Insufficient drug delivery to some regions of the tumor may be due to spatial differences in expression of genes involved in the disposition, transport, and detoxification of drugs (pharmacogenes). Therefore, in this study, we analyzed the spatial expression of 286 pharmacogenes in six breast cancer tissues using the recently developed Visium spatial transcriptomics platform to (1) determine if these pharmacogenes are expressed heterogeneously across tumor tissue and (2) to determine which pharmacogenes have the most spatial expression heterogeneity.
Methods And Results:
The spatial transcriptomics technology sequences the transcriptome of 55 um diameter barcoded sections (spots) across a tissue sample. We analyzed spatial gene expression profiles of four biobank-sourced breast tumor samples in addition to two breast tumor sample datasets from 10× Genomics. We define heterogeneity as the interquartile range of read counts. Collectively, we identified 8887 spots in tumor regions, 3814 in stroma, 44 in lymphocytes, and 116 in normal regions based on pathologist annotation of the tissues. We showed statistically significant differences in expression of pharmacogenes in tumor regions compared to surrounding non-tumor regions. We also observed that the most heterogeneously expressed genes within tumor regions were involved in reactive oxygen species (ROS) handling and detoxification mechanisms. GPX4, GSTP1, MGST3, SOD1, CYP4Z1, CYB5R3, GSTK1, and NAT1 showed the most heterogeneous expression within tumor regions.
Conclusions:
The heterogeneous expression of these pharmacogenes may have important implications for cancer therapy due to their ability to impact drug distribution and efficacy throughout the tumor. Our results suggest that chemoresistance caused by expression of GPX4, GSTP1, MGST3, and SOD1 may be intrinsic, not acquired, since the heterogeneity is not specific to chemotherapy-treated samples or cell type. Additionally, we identified candidate chemoresistance pharmacogenes that can be further tested through focused follow-up studies.
Insights
Spatial differences in pharmacogene expression within tumors may drive chemotherapy resistance. This study identified key genes like GPX4 and GSTP1 with heterogeneous expression, suggesting intrinsic chemoresistance mechanisms in breast cancer.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Chemotherapeutic drug concentrations vary within tumors, potentially leading to resistance.
- Spatial heterogeneity in pharmacogene expression (genes affecting drug disposition, transport, and detoxification) may explain uneven drug delivery.
- Understanding this spatial variation is crucial for improving cancer therapy efficacy.
Purpose of the Study:
- To analyze the spatial expression of 286 pharmacogenes in breast cancer tissues.
- To determine if pharmacogene expression is heterogeneous across tumor regions.
- To identify specific pharmacogenes exhibiting the most significant spatial expression heterogeneity.
Main Methods:
- Utilized Visium spatial transcriptomics to profile gene expression in six breast cancer tissue samples.
- Defined gene expression heterogeneity by the interquartile range of read counts.
- Annotated tissue regions (tumor, stroma, lymphocytes, normal) with pathologist input.
Main Results:
- Identified significant differences in pharmacogene expression between tumor and non-tumor regions.
- Observed that genes involved in reactive oxygen species (ROS) handling and detoxification showed the highest heterogeneity within tumor regions.
- Pinpointed GPX4, GSTP1, MGST3, SOD1, CYP4Z1, CYB5R3, GSTK1, and NAT1 as the most heterogeneously expressed pharmacogenes in tumors.
Conclusions:
- Heterogeneous pharmacogene expression impacts drug distribution and efficacy, potentially causing chemoresistance.
- The identified heterogeneity suggests intrinsic, rather than acquired, chemoresistance mechanisms.
- This study identifies candidate pharmacogenes for future research into overcoming chemoresistance.
