Hypoxia inducible factor signaling in breast tumors controls spontaneous tumor dissemination in a site-specific manner

Rachelle W. Johnson,Lawrence A. Vecchi,Lauren Himmel,Vera M. Todd,Katherine P. Snow,Miranda E. Clements,Christopher Pinelli,Marjan Rafat,Cayla D. Ontko

doi:10.1038/s42003-021-02648-3

Abstract

Hypoxia is a common feature in tumors and induces signaling that promotes tumor cell survival, invasion, and metastasis, but the impact of hypoxia inducible factor (HIF) signaling in the primary tumor on dissemination to bone in particular remains unclear. To better understand the contributions of hypoxia inducible factor 1 alpha (HIF1α), HIF2α, and general HIF pathway activation in metastasis, we employ a PyMT-driven spontaneous murine mammary carcinoma model with mammary specific deletion of Hif1α, Hif2α, or von Hippel-Lindau factor (Vhl) using the Cre-lox system. Here we show that Hif1α or Hif2α deletion in the primary tumor decreases metastatic tumor burden in the bone marrow, while Vhl deletion increases bone tumor burden, as hypothesized. Unexpectedly, Hif1α deletion increases metastatic tumor burden in the lung, while deletion of Hif2α or Vhl does not affect pulmonary metastasis. Mice with Hif1α deleted tumors also exhibit reduced bone volume as measured by micro computed tomography, suggesting that disruption of the osteogenic niche may be involved in the preference for lung dissemination observed in this group. Thus, we reveal that HIF signaling in breast tumors controls tumor dissemination in a site-specific manner.

Highlights

Hypoxia is a common feature in tumors and induces signaling that promotes tumor cell survival, invasion, and metastasis, but the impact of hypoxia inducible factor (HIF) signaling in the primary tumor on dissemination to bone in particular remains unclear
Clinical evidence from breast cancer patients shows that high HIF1α levels in primary tumors correlate with poor patient outcomes[25,26,27,28], and a hypoxic transcriptomic signature in tumor cells is associated with bone metastasis[29,30]
Tumor cells were detected by flow cytometry of bone marrow from the tibiae and femora from Hif1αf/f polyoma middle T antigen (PyMT)+ and Hif1α−/− PyMT+ mice based on epithelial cell adhesion molecule (EpCAM) positivity

Summary

Introduction

Hypoxia is a common feature in tumors and induces signaling that promotes tumor cell survival, invasion, and metastasis, but the impact of hypoxia inducible factor (HIF) signaling in the primary tumor on dissemination to bone in particular remains unclear. Hif1α deletion increases metastatic tumor burden in the lung, while deletion of Hif2α or Vhl does not affect pulmonary metastasis. Clinical evidence from breast cancer patients shows that high HIF1α levels in primary tumors correlate with poor patient outcomes[25,26,27,28], and a hypoxic transcriptomic signature in tumor cells is associated with bone metastasis[29,30]. We generated three transgenic mouse models of spontaneous mouse mammary carcinoma with tumor-specific deletion of Hif1α, Hif2α, and Vhl and evaluated the effects of HIF modulation on tumor dissemination to multiple distant sites using highly sensitive detection techniques that have been optimized to detect low levels of disseminated tumor burden[40]. This study highlights the ability of HIF signaling to differentially modulate metastasis to certain sites

Methods

Results

Conclusion