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Single-cell RNA sequencing revealed subclonal heterogeneity and gene signatures of gemcitabine sensitivity in pancreatic cancer

Introduction: Resistance to gemcitabine is common and critically limits its therapeutic efficacy in pancreatic ductal adenocarcinoma (PDAC). Methods: We constructed 17 patient-derived xenograft (PDX) models from PDAC patient samples and identified the most notable responder to gemcitabine by screeni...

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Autores principales: Hou, Zelin, Lin, Jiajing, Ma, Yuan, Fang, Haizhong, Wu, Yuwei, Chen, Zhijiang, Lin, Xianchao, Lu, Fengchun, Wen, Shi, Yu, Xunbin, Huang, Heguang, Pan, Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10267405/
https://www.ncbi.nlm.nih.gov/pubmed/37324492
http://dx.doi.org/10.3389/fphar.2023.1193791
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author Hou, Zelin
Lin, Jiajing
Ma, Yuan
Fang, Haizhong
Wu, Yuwei
Chen, Zhijiang
Lin, Xianchao
Lu, Fengchun
Wen, Shi
Yu, Xunbin
Huang, Heguang
Pan, Yu
author_facet Hou, Zelin
Lin, Jiajing
Ma, Yuan
Fang, Haizhong
Wu, Yuwei
Chen, Zhijiang
Lin, Xianchao
Lu, Fengchun
Wen, Shi
Yu, Xunbin
Huang, Heguang
Pan, Yu
author_sort Hou, Zelin
collection PubMed
description Introduction: Resistance to gemcitabine is common and critically limits its therapeutic efficacy in pancreatic ductal adenocarcinoma (PDAC). Methods: We constructed 17 patient-derived xenograft (PDX) models from PDAC patient samples and identified the most notable responder to gemcitabine by screening the PDX sets in vivo. To analyze tumor evolution and microenvironmental changes pre- and post-chemotherapy, single-cell RNA sequencing (scRNA-seq) was performed. Results: ScRNA-seq revealed that gemcitabine promoted the expansion of subclones associated with drug resistance and recruited macrophages related to tumor progression and metastasis. We further investigated the particular drug-resistant subclone and established a gemcitabine sensitivity gene panel (GSGP) (SLC46A1, PCSK1N, KRT7, CAV2, and LDHA), dividing PDAC patients into two groups to predict the overall survival (OS) in The Cancer Genome Atlas (TCGA) training dataset. The signature was successfully validated in three independent datasets. We also found that 5-GSGP predicted the sensitivity to gemcitabine in PDAC patients in the TCGA training dataset who were treated with gemcitabine. Discussion and conclusion: Our study provides new insight into the natural selection of tumor cell subclones and remodeling of tumor microenvironment (TME) cells induced by gemcitabine. We revealed a specific drug resistance subclone, and based on the characteristics of this subclone, we constructed a GSGP that can robustly predict gemcitabine sensitivity and prognosis in pancreatic cancer, which provides a theoretical basis for individualized clinical treatment.
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spelling pubmed-102674052023-06-15 Single-cell RNA sequencing revealed subclonal heterogeneity and gene signatures of gemcitabine sensitivity in pancreatic cancer Hou, Zelin Lin, Jiajing Ma, Yuan Fang, Haizhong Wu, Yuwei Chen, Zhijiang Lin, Xianchao Lu, Fengchun Wen, Shi Yu, Xunbin Huang, Heguang Pan, Yu Front Pharmacol Pharmacology Introduction: Resistance to gemcitabine is common and critically limits its therapeutic efficacy in pancreatic ductal adenocarcinoma (PDAC). Methods: We constructed 17 patient-derived xenograft (PDX) models from PDAC patient samples and identified the most notable responder to gemcitabine by screening the PDX sets in vivo. To analyze tumor evolution and microenvironmental changes pre- and post-chemotherapy, single-cell RNA sequencing (scRNA-seq) was performed. Results: ScRNA-seq revealed that gemcitabine promoted the expansion of subclones associated with drug resistance and recruited macrophages related to tumor progression and metastasis. We further investigated the particular drug-resistant subclone and established a gemcitabine sensitivity gene panel (GSGP) (SLC46A1, PCSK1N, KRT7, CAV2, and LDHA), dividing PDAC patients into two groups to predict the overall survival (OS) in The Cancer Genome Atlas (TCGA) training dataset. The signature was successfully validated in three independent datasets. We also found that 5-GSGP predicted the sensitivity to gemcitabine in PDAC patients in the TCGA training dataset who were treated with gemcitabine. Discussion and conclusion: Our study provides new insight into the natural selection of tumor cell subclones and remodeling of tumor microenvironment (TME) cells induced by gemcitabine. We revealed a specific drug resistance subclone, and based on the characteristics of this subclone, we constructed a GSGP that can robustly predict gemcitabine sensitivity and prognosis in pancreatic cancer, which provides a theoretical basis for individualized clinical treatment. Frontiers Media S.A. 2023-06-01 /pmc/articles/PMC10267405/ /pubmed/37324492 http://dx.doi.org/10.3389/fphar.2023.1193791 Text en Copyright © 2023 Hou, Lin, Ma, Fang, Wu, Chen, Lin, Lu, Wen, Yu, Huang and Pan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Hou, Zelin
Lin, Jiajing
Ma, Yuan
Fang, Haizhong
Wu, Yuwei
Chen, Zhijiang
Lin, Xianchao
Lu, Fengchun
Wen, Shi
Yu, Xunbin
Huang, Heguang
Pan, Yu
Single-cell RNA sequencing revealed subclonal heterogeneity and gene signatures of gemcitabine sensitivity in pancreatic cancer
title Single-cell RNA sequencing revealed subclonal heterogeneity and gene signatures of gemcitabine sensitivity in pancreatic cancer
title_full Single-cell RNA sequencing revealed subclonal heterogeneity and gene signatures of gemcitabine sensitivity in pancreatic cancer
title_fullStr Single-cell RNA sequencing revealed subclonal heterogeneity and gene signatures of gemcitabine sensitivity in pancreatic cancer
title_full_unstemmed Single-cell RNA sequencing revealed subclonal heterogeneity and gene signatures of gemcitabine sensitivity in pancreatic cancer
title_short Single-cell RNA sequencing revealed subclonal heterogeneity and gene signatures of gemcitabine sensitivity in pancreatic cancer
title_sort single-cell rna sequencing revealed subclonal heterogeneity and gene signatures of gemcitabine sensitivity in pancreatic cancer
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10267405/
https://www.ncbi.nlm.nih.gov/pubmed/37324492
http://dx.doi.org/10.3389/fphar.2023.1193791
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