In:
PLOS Biology, Public Library of Science (PLoS), Vol. 21, No. 9 ( 2023-9-12), p. e3002275-
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3002275
DOI:
10.1371/journal.pbio.3002275.g001
DOI:
10.1371/journal.pbio.3002275.g002
DOI:
10.1371/journal.pbio.3002275.g003
DOI:
10.1371/journal.pbio.3002275.g004
DOI:
10.1371/journal.pbio.3002275.g005
DOI:
10.1371/journal.pbio.3002275.g006
DOI:
10.1371/journal.pbio.3002275.g007
DOI:
10.1371/journal.pbio.3002275.g008
DOI:
10.1371/journal.pbio.3002275.s001
DOI:
10.1371/journal.pbio.3002275.s002
DOI:
10.1371/journal.pbio.3002275.s003
DOI:
10.1371/journal.pbio.3002275.s004
DOI:
10.1371/journal.pbio.3002275.s005
DOI:
10.1371/journal.pbio.3002275.s006
DOI:
10.1371/journal.pbio.3002275.s007
DOI:
10.1371/journal.pbio.3002275.s008
DOI:
10.1371/journal.pbio.3002275.s009
DOI:
10.1371/journal.pbio.3002275.s010
DOI:
10.1371/journal.pbio.3002275.s011
DOI:
10.1371/journal.pbio.3002275.s012
DOI:
10.1371/journal.pbio.3002275.s013
DOI:
10.1371/journal.pbio.3002275.s014
DOI:
10.1371/journal.pbio.3002275.s015
DOI:
10.1371/journal.pbio.3002275.s016
DOI:
10.1371/journal.pbio.3002275.s017
DOI:
10.1371/journal.pbio.3002275.s018
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2126773-X
Bookmarklink