Abstract
Lung tumors activate OCN+ osteoblasts in distant bone stroma to supply tumor-infiltrating neutrophils.
Major finding: Lung tumors activate OCN+ osteoblasts in distant bone stroma to supply tumor-infiltrating neutrophils.
Concept: Lung tumors promote recruitment of SiglecFhi neutrophils that are associated with poor survival.
Impact: A cross-talk between lung tumors and nonmalignant bone facilitates tumor progression.
Myeloid cells including neutrophils can infiltrate tumors to promote growth, and an increased abundance is associated with poor clinical outcomes. Many of the tumor-infiltrating myeloid cells are obtained from circulating precursors produced in distant tissues such as the bone marrow. Bone marrow contains cells that regulate hematopoiesis and immune cell fate, including osteoblasts, which are bone-forming cells that also have a have a role in hematopoiesis. However, how tumor growth might be affected by bone dynamics at distant sites is unknown, prompting Engblom, Pfirschke, and colleagues to investigate the role of lung tumors on bone homeostasis. In the KP mouse model of lung adenocarcinoma driven by Kras activation and Trp53 loss, mice bearing lung tumors had increased bone activity, which was observed across bone sites. These mice do not develop metastasis, indicating that primary lung tumors can modulate bone stromal activity. Similarly, bone density was elevated in 35 patients with KRAS+ non–small cell lung cancer without bone metastases. Lung tumors enhanced bone density by increasing the number and activity of osteocalcin (OCN)-positive osteoblasts, which induced bone formation and mineralization. These OCN+ osteoblasts promoted lung tumor growth by inducing the release of SiglecFhi neutrophils, a tumor-promoting subset that infiltrated the lung tumors to enhance tumor growth. Consistent with this finding, the presence of a SiglecFhi neutrophil gene signature was associated poor survival in patients with lung adenocarcinoma. The circulating soluble form of the receptor for advanced glycation end products (sRAGE) was upregulated in tumor-bearing mice and promoted osteoblast activity, suggesting that tumors may secrete sRAGE to activate OCN+ osteoblasts and promote the release of SiglecFhi neutrophils to facilitate tumor growth. In addition to elucidating a cross-talk between lung tumors and normal bone that supports tumor growth, these findings suggest the potential for OCN+ bone marrow cells and SiglecFhi neutrophils as biomarkers and therapeutic targets in patients with cancer.
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