Angiocrine signals regulate quiescence and therapy resistance in bone metastasis
Amit Singh, Vimal Veeriah, Pengjun Xi, Rossella Labella, Junyu Chen, Sara G. Romeo, Saravana K. Ramasamy, Anjali P. Kusumbe
Amit Singh, Vimal Veeriah, Pengjun Xi, Rossella Labella, Junyu Chen, Sara G. Romeo, Saravana K. Ramasamy, Anjali P. Kusumbe
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Research Article Bone biology Vascular biology

Angiocrine signals regulate quiescence and therapy resistance in bone metastasis

Abstract

Bone provides supportive microenvironments for hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) and is a frequent site of metastasis. While incidences of bone metastases increase with age, the properties of the bone marrow microenvironment that regulate dormancy and reactivation of disseminated tumor cells (DTCs) remain poorly understood. Here, we elucidate the age-associated changes in the bone secretome that trigger proliferation of HSCs, MSCs, and DTCs in the aging bone marrow microenvironment. Remarkably, a bone-specific mechanism involving expansion of pericytes and induction of quiescence-promoting secretome rendered this proliferative microenvironment resistant to radiation and chemotherapy. This bone-specific expansion of pericytes was triggered by an increase in PDGF signaling via remodeling of specialized type H blood vessels in response to therapy. The decline in bone marrow pericytes upon aging provides an explanation for loss of quiescence and expansion of cancer cells in the aged bone marrow microenvironment. Manipulation of blood flow — specifically, reduced blood flow — inhibited pericyte expansion, regulated endothelial PDGF-B expression, and rendered bone metastatic cancer cells susceptible to radiation and chemotherapy. Thus, our study provides a framework to recognize bone marrow vascular niches in age-associated increases in metastasis and to target angiocrine signals in therapeutic strategies to manage bone metastasis.

Authors

Amit Singh, Vimal Veeriah, Pengjun Xi, Rossella Labella, Junyu Chen, Sara G. Romeo, Saravana K. Ramasamy, Anjali P. Kusumbe

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Figure 1

Niche-dependent perturbation of HSC and MSC quiescence in aging.

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Niche-dependent perturbation of HSC and MSC quiescence in aging. (A) FAC...
(A) FACS quantification (as shown in contour plots) of HSCs in young (n = 7 replicates) and aged (n = 7 replicates ) long bones (left panel). Data represent mean ± SD; 2-tailed unpaired t test. G0 and G1 phases separated by staining with Pyronin Y, which preferentially binds to RNA, and Hoechst 33342, which in turn binds to A-T base pairs. The lower right panel shows flow cytometric quantification of quiescent HSPCs. Data represent mean ± SD (n = 6 replicates); 2-tailed unpaired t test. (B) Schematic representation of the experimental strategy. The graph shows the frequency of the young Tomato+ donor-derived HSCs, B cells, T cells, and myeloid cells in the BM of the young and aged recipients after 16 weeks following transplantation. Data represent mean ± SD (n = 7 replicates); 2-tailed unpaired t test. YN, young niche, determined by quantification in bones from young mice; AN, aged niche, determined by quantification in bones from aged mice. (C) Representative FACS plots from young and aged mouse bones show the gating strategy for identifying quiescent (G0) MSCs, which is based on Hoechst and Pyronin Y staining. The lower left panel shows FACS quantification of MSCs based on PDGFRα+Sca-1+CD45–Ter119–CD31– expression in the young and aged mice. The lower right panel shows the quantification of quiescent (G0) MSCs in young and aged bones based on Hoechst and Pyronin Y staining. Data represent mean ± SD (n = 6 replicates); 2-tailed unpaired t tests. (D) Schematic illustration of the transplantation strategy for Tomato+ PKH67+ MSCs in the young and aged recipients. The upper bar graph shows FACS-based quantification of total Tomato+ donor PDGFRα+Sca-1+CD45–Ter119–CD31– MSCs in young and aged mouse bones 10 weeks after transplantation. The bar graph in the lower panel shows the quantification of label retaining the MSCs 10-weeks post transplantation. The data represent the mean ± SD (n = 6 replicates), and 2-tailed unpaired t tests. **P < 0.01, ***P < 0.001, ****P < 0.0001.