Taxane chemotherapy leads to breast cancer dormancy escape by stromal injury mediated IL-6/MAP2K signaling

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 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, as well as an altered tumor microenvironment with augmented pro-tumor immune signaling. 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.

Wounding the stroma: Docetaxel’s role in dormant breast cancer escape

“…Despite the growing recognition of the tumour microenvironment’s (TME) role in awakening dormant cancer cells, details of cellular communication networks remain largely unresolved [ 2 ]. In a recent report in PLOS Biology , Ganesan and colleagues illuminate a hitherto unknown mechanism of breast cancer recurrence wherein the TME drives progression [ 3 ]. The investigators provided evidence that administration of docetaxel can modify the stromal cell secretome and awaken dormant cancer cells by promoting an immunosuppressive and pro-metastatic TME conducive to cancer recurrence.…”