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Treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution
Pancreatic ductal adenocarcinoma (PDAC) is one of the most treatment refractory and lethal malignancies. The diversity of endothelial cell (EC) lineages in the tumor microenvironment (TME) impacts the efficacy of antineoplastic therapies, which in turn remodel EC states and distributions. Here, we p...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9524152/ https://www.ncbi.nlm.nih.gov/pubmed/36185212 http://dx.doi.org/10.3389/fonc.2022.929950 |
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author | Shiau, Carina Su, Jennifer Guo, Jimmy A. Hong, Theodore S. Wo, Jennifer Y. Jagadeesh, Karthik A. Hwang, William L. |
author_facet | Shiau, Carina Su, Jennifer Guo, Jimmy A. Hong, Theodore S. Wo, Jennifer Y. Jagadeesh, Karthik A. Hwang, William L. |
author_sort | Shiau, Carina |
collection | PubMed |
description | Pancreatic ductal adenocarcinoma (PDAC) is one of the most treatment refractory and lethal malignancies. The diversity of endothelial cell (EC) lineages in the tumor microenvironment (TME) impacts the efficacy of antineoplastic therapies, which in turn remodel EC states and distributions. Here, we present a single-cell resolution framework of diverse EC lineages in the PDAC TME in the context of neoadjuvant chemotherapy, radiotherapy, and losartan. We analyzed a custom single-nucleus RNA-seq dataset derived from 37 primary PDAC specimens (18 untreated, 14 neoadjuvant FOLFIRINOX + chemoradiotherapy, 5 neoadjuvant FOLFIRINOX + chemoradiotherapy + losartan). A single-nucleus transcriptome analysis of 15,185 EC profiles revealed two state programs (ribosomal, cycling), four lineage programs (capillary, arterial, venous, lymphatic), and one program that did not overlap significantly with prior signatures but was enriched in pathways involved in vasculogenesis, stem-like state, response to wounding and hypoxia, and endothelial-to-mesenchymal transition (reactive EndMT). A bulk transcriptome analysis of two independent cohorts (n = 269 patients) revealed that the lymphatic and reactive EndMT lineage programs were significantly associated with poor clinical outcomes. While losartan and proton therapy were associated with reduced lymphatic ECs, these therapies also correlated with an increase in reactive EndMT. Thus, the development and inclusion of EndMT-inhibiting drugs (e.g., nintedanib) to a neoadjuvant chemoradiotherapy regimen featuring losartan and/or proton therapy may be most effective in depleting both lymphatic and reactive EndMT populations and potentially improving patient outcomes. |
format | Online Article Text |
id | pubmed-9524152 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95241522022-10-01 Treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution Shiau, Carina Su, Jennifer Guo, Jimmy A. Hong, Theodore S. Wo, Jennifer Y. Jagadeesh, Karthik A. Hwang, William L. Front Oncol Oncology Pancreatic ductal adenocarcinoma (PDAC) is one of the most treatment refractory and lethal malignancies. The diversity of endothelial cell (EC) lineages in the tumor microenvironment (TME) impacts the efficacy of antineoplastic therapies, which in turn remodel EC states and distributions. Here, we present a single-cell resolution framework of diverse EC lineages in the PDAC TME in the context of neoadjuvant chemotherapy, radiotherapy, and losartan. We analyzed a custom single-nucleus RNA-seq dataset derived from 37 primary PDAC specimens (18 untreated, 14 neoadjuvant FOLFIRINOX + chemoradiotherapy, 5 neoadjuvant FOLFIRINOX + chemoradiotherapy + losartan). A single-nucleus transcriptome analysis of 15,185 EC profiles revealed two state programs (ribosomal, cycling), four lineage programs (capillary, arterial, venous, lymphatic), and one program that did not overlap significantly with prior signatures but was enriched in pathways involved in vasculogenesis, stem-like state, response to wounding and hypoxia, and endothelial-to-mesenchymal transition (reactive EndMT). A bulk transcriptome analysis of two independent cohorts (n = 269 patients) revealed that the lymphatic and reactive EndMT lineage programs were significantly associated with poor clinical outcomes. While losartan and proton therapy were associated with reduced lymphatic ECs, these therapies also correlated with an increase in reactive EndMT. Thus, the development and inclusion of EndMT-inhibiting drugs (e.g., nintedanib) to a neoadjuvant chemoradiotherapy regimen featuring losartan and/or proton therapy may be most effective in depleting both lymphatic and reactive EndMT populations and potentially improving patient outcomes. Frontiers Media S.A. 2022-09-16 /pmc/articles/PMC9524152/ /pubmed/36185212 http://dx.doi.org/10.3389/fonc.2022.929950 Text en Copyright © 2022 Shiau, Su, Guo, Hong, Wo, Jagadeesh and Hwang 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 | Oncology Shiau, Carina Su, Jennifer Guo, Jimmy A. Hong, Theodore S. Wo, Jennifer Y. Jagadeesh, Karthik A. Hwang, William L. Treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution |
title | Treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution |
title_full | Treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution |
title_fullStr | Treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution |
title_full_unstemmed | Treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution |
title_short | Treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution |
title_sort | treatment-associated remodeling of the pancreatic cancer endothelium at single-cell resolution |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9524152/ https://www.ncbi.nlm.nih.gov/pubmed/36185212 http://dx.doi.org/10.3389/fonc.2022.929950 |
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