PTHrP induces breast cancer bone metastases via microbial-dependent expansion of TNF/IL-17–producing T cells

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Abstract

Bone metastases are a frequent complication of breast cancer, leading to reduced quality of life and increased morbidity. By intratibially injecting PyMT breast cancer cells in mice, we showed that the presence in the gut microbiome of segmented filamentous bacteria (SFB), a taxon that induces IL-17–producing Th17 cells and TNF-α (TNF)–producing T cells (TNF+ T cells), accelerated intraosseous tumor growth. SFB increased the activity of parathyroid hormone–related protein (PTHrP), a known driver of breast cancer bone metastasis produced by breast cancer cells. SFB promoted the PTHrP-induced expansion of intestinal Th17 cells and TNF+ T cells, their migration to bone marrow (BM) in tumor-bearing bones, and the BM expression of TNF, IL-17, and RANKL, cytokines that promote bone resorption. Demonstrating the functional relevance of IL-17 and TNF, silencing of either IL-17 or TNF blunted the growth of bone lesions in SFB+ mice. Thus, the abundance of SFB in the microbiome of mice and of SFB-like taxa in humans may determine the potency of PTHrP and the rate of growth of bone metastasis in breast cancer. Targeting the gut microbiota may represent a novel therapeutic strategy for breast cancer bone metastasis.

Authors

Nand K. Roy, Subhashis Pal, Hamid Y. Dar, Sanchiti Patil, M. Neale Weitzmann, Roberto Pacifici