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- Title
Taxane chemotherapy induces stromal injury that leads to breast cancer dormancy escape.
- Authors
Ganesan, Ramya; Bhasin, Swati S.; Bakhtiary, Mojtaba; Krishnan, Upaasana; Cheemarla, Nagarjuna R.; Thomas, Beena E.; Bhasin, Manoj K.; Sukhatme, Vikas P.
- 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. Cancer dormancy is a major hindrance to achieving complete clinical response in patients. This study uses a tumor stromal organoid and murine breast cancer model to reveal that chemotherapy injures stromal cells, but not dormant cancer cells directly; this stromal injury in turn invokes proinflammatory cytokine signaling and can awaken dormant cancer cells.
- Subjects
GRANULOCYTE-colony stimulating factor; BREAST cancer; DORMANCY in plants; CANCER cell proliferation; CANCER cells; CANCER relapse
- Publication
PLoS Biology, 2023, Vol 21, Issue 9, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3002275