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Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape

A major cause of cancer recurrence following chemotherapy is cancer dormancy escape. Taxane-based chemotherapy is standard of care in breast cancer treatment aimed at killing proliferating cancer cells. Here, we demonstrate that docetaxel injures stromal cells, which release protumor cytokines, IL-6...

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Autores principales: Ganesan, Ramya, Bhasin, Swati S., Bakhtiary, Mojtaba, Krishnan, Upaasana, Cheemarla, Nagarjuna R., Thomas, Beena E., Bhasin, Manoj K., Sukhatme, Vikas P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10497165/
https://www.ncbi.nlm.nih.gov/pubmed/37699010
http://dx.doi.org/10.1371/journal.pbio.3002275
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author Ganesan, Ramya
Bhasin, Swati S.
Bakhtiary, Mojtaba
Krishnan, Upaasana
Cheemarla, Nagarjuna R.
Thomas, Beena E.
Bhasin, Manoj K.
Sukhatme, Vikas P.
author_facet Ganesan, Ramya
Bhasin, Swati S.
Bakhtiary, Mojtaba
Krishnan, Upaasana
Cheemarla, Nagarjuna R.
Thomas, Beena E.
Bhasin, Manoj K.
Sukhatme, Vikas P.
author_sort Ganesan, Ramya
collection PubMed
description A major cause of cancer recurrence following chemotherapy is cancer dormancy escape. Taxane-based chemotherapy is standard of care in breast cancer treatment aimed at killing proliferating cancer cells. Here, we demonstrate that docetaxel injures stromal cells, which release protumor cytokines, IL-6 and granulocyte colony stimulating factor (G-CSF), that in turn invoke dormant cancer outgrowth both in vitro and in vivo. Single-cell transcriptomics shows a reprogramming of awakened cancer cells including several survival cues such as stemness, chemoresistance in a tumor stromal organoid (TSO) model, as well as an altered tumor microenvironment (TME) with augmented protumor immune signaling in a syngeneic mouse breast cancer model. IL-6 plays a role in cancer cell proliferation, whereas G-CSF mediates tumor immunosuppression. Pathways and differential expression analyses confirmed MEK as the key regulatory molecule in cancer cell outgrowth and survival. Antibody targeting of protumor cytokines (IL-6, G-CSF) or inhibition of cytokine signaling via MEK/ERK pathway using selumetinib prior to docetaxel treatment prevented cancer dormancy outgrowth suggesting a novel therapeutic strategy to prevent cancer recurrence.
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spelling pubmed-104971652023-09-13 Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape Ganesan, Ramya Bhasin, Swati S. Bakhtiary, Mojtaba Krishnan, Upaasana Cheemarla, Nagarjuna R. Thomas, Beena E. Bhasin, Manoj K. Sukhatme, Vikas P. PLoS Biol Research Article A major cause of cancer recurrence following chemotherapy is cancer dormancy escape. Taxane-based chemotherapy is standard of care in breast cancer treatment aimed at killing proliferating cancer cells. Here, we demonstrate that docetaxel injures stromal cells, which release protumor cytokines, IL-6 and granulocyte colony stimulating factor (G-CSF), that in turn invoke dormant cancer outgrowth both in vitro and in vivo. Single-cell transcriptomics shows a reprogramming of awakened cancer cells including several survival cues such as stemness, chemoresistance in a tumor stromal organoid (TSO) model, as well as an altered tumor microenvironment (TME) with augmented protumor immune signaling in a syngeneic mouse breast cancer model. IL-6 plays a role in cancer cell proliferation, whereas G-CSF mediates tumor immunosuppression. Pathways and differential expression analyses confirmed MEK as the key regulatory molecule in cancer cell outgrowth and survival. Antibody targeting of protumor cytokines (IL-6, G-CSF) or inhibition of cytokine signaling via MEK/ERK pathway using selumetinib prior to docetaxel treatment prevented cancer dormancy outgrowth suggesting a novel therapeutic strategy to prevent cancer recurrence. Public Library of Science 2023-09-12 /pmc/articles/PMC10497165/ /pubmed/37699010 http://dx.doi.org/10.1371/journal.pbio.3002275 Text en © 2023 Ganesan et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Ganesan, Ramya
Bhasin, Swati S.
Bakhtiary, Mojtaba
Krishnan, Upaasana
Cheemarla, Nagarjuna R.
Thomas, Beena E.
Bhasin, Manoj K.
Sukhatme, Vikas P.
Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape
title Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape
title_full Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape
title_fullStr Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape
title_full_unstemmed Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape
title_short Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape
title_sort taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10497165/
https://www.ncbi.nlm.nih.gov/pubmed/37699010
http://dx.doi.org/10.1371/journal.pbio.3002275
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