Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Shiau, Carina, Su, Jennifer, Guo, Jimmy A., Hong, Theodore S., Wo, Jennifer Y., Jagadeesh, Karthik A., Hwang, William L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
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
_version_ 1784800443738619904
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
work_keys_str_mv AT shiaucarina treatmentassociatedremodelingofthepancreaticcancerendotheliumatsinglecellresolution
AT sujennifer treatmentassociatedremodelingofthepancreaticcancerendotheliumatsinglecellresolution
AT guojimmya treatmentassociatedremodelingofthepancreaticcancerendotheliumatsinglecellresolution
AT hongtheodores treatmentassociatedremodelingofthepancreaticcancerendotheliumatsinglecellresolution
AT wojennifery treatmentassociatedremodelingofthepancreaticcancerendotheliumatsinglecellresolution
AT jagadeeshkarthika treatmentassociatedremodelingofthepancreaticcancerendotheliumatsinglecellresolution
AT hwangwilliaml treatmentassociatedremodelingofthepancreaticcancerendotheliumatsinglecellresolution