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Quantification of spatial pharmacogene expression heterogeneity in breast tumors
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 disp...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9875649/ https://www.ncbi.nlm.nih.gov/pubmed/35906899 http://dx.doi.org/10.1002/cnr2.1686 |
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author | Powell, Nicholas R. Silvola, Rebecca M. Howard, John S. Badve, Sunil Skaar, Todd C. Ipe, Joseph |
author_facet | Powell, Nicholas R. Silvola, Rebecca M. Howard, John S. Badve, Sunil Skaar, Todd C. Ipe, Joseph |
author_sort | Powell, Nicholas R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9875649 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-98756492023-01-25 Quantification of spatial pharmacogene expression heterogeneity in breast tumors Powell, Nicholas R. Silvola, Rebecca M. Howard, John S. Badve, Sunil Skaar, Todd C. Ipe, Joseph Cancer Rep (Hoboken) Original Articles 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. John Wiley and Sons Inc. 2022-07-30 /pmc/articles/PMC9875649/ /pubmed/35906899 http://dx.doi.org/10.1002/cnr2.1686 Text en © 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles Powell, Nicholas R. Silvola, Rebecca M. Howard, John S. Badve, Sunil Skaar, Todd C. Ipe, Joseph Quantification of spatial pharmacogene expression heterogeneity in breast tumors |
title | Quantification of spatial pharmacogene expression heterogeneity in breast tumors |
title_full | Quantification of spatial pharmacogene expression heterogeneity in breast tumors |
title_fullStr | Quantification of spatial pharmacogene expression heterogeneity in breast tumors |
title_full_unstemmed | Quantification of spatial pharmacogene expression heterogeneity in breast tumors |
title_short | Quantification of spatial pharmacogene expression heterogeneity in breast tumors |
title_sort | quantification of spatial pharmacogene expression heterogeneity in breast tumors |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9875649/ https://www.ncbi.nlm.nih.gov/pubmed/35906899 http://dx.doi.org/10.1002/cnr2.1686 |
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