From breast cancer cell homing to the onset of early bone metastasis: The role of bone (re)modeling in early lesion formation

Author:

Young Sarah A. E.1ORCID,Heller Anna-Dorothea1ORCID,Garske Daniela S.1ORCID,Rummler Maximilian12ORCID,Qian Victoria1ORCID,Ellinghaus Agnes3ORCID,Duda Georg N.3ORCID,Willie Bettina M.2ORCID,Grüneboom Anika4ORCID,Cipitria Amaia156ORCID

Affiliation:

1. Department of Biomaterials, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.

2. Research Centre, Shriners Hospital for Children–Canada, Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, Canada.

3. Julius Wolff Institute, Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Germany.

4. Leibniz-Institute for Advancing Analytics – ISAS – e.V., Dortmund, Germany.

5. Group of Bioengineering in Regeneration and Cancer, Biodonostia Health Research Institute, San Sebastian, Spain.

6. IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.

Abstract

Breast cancer often metastasizes to bone, causing osteolytic lesions. Structural and biophysical changes are rarely studied yet are hypothesized to influence metastasis. We developed a mouse model of early bone metastasis and multimodal imaging to quantify cancer cell homing, bone (re)modeling, and onset of metastasis. Using tissue clearing and three-dimensional (3D) light sheet fluorescence microscopy, we located enhanced green fluorescent protein–positive cancer cells and small clusters in intact bones and quantified their size and spatial distribution. We detected early bone lesions using in vivo microcomputed tomography (microCT)–based time-lapse morphometry and revealed altered bone (re)modeling in the absence of detectable lesions. With a new microCT image analysis tool, we tracked the growth of early lesions over time. We showed that cancer cells home in all bone compartments, while osteolytic lesions are only detected in the metaphysis, a region of high (re)modeling. Our study suggests that higher rates of (re)modeling act as a driver of lesion formation during early metastasis.

Publisher

American Association for the Advancement of Science (AAAS)

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