Roberts

Four decades of intense multinational efforts have not improved outcomes for children and teenagers with osteosarcoma. Our standard of care remains unchanged since 1982, even though 35–40% of young people so treated still die from the disease, usually from complications related to lung metastasis. Our canine companions face even more significant challenges—nearly all dogs diagnosed with osteosarcoma will eventually succumb to metastatic disease. While effective metastasis-targeting interventions could transform clinical care, our unsophisticated understanding of the mechanisms that drive lung-specific metastasis handicaps efforts to develop rational, targeted therapeutic interventions.

Focused on this problem, our laboratory has identified several tumor-host interactions occurring in the lung that appear to be critical for the development of metastatic lesions. We found that a small subpopulation of osteosarcoma cells engages with epithelial cells in the lung, triggering an IL1–IL6 paracrine loop that establishes a persisting inflammatory cytokine environment in the surrounding tissue. This subset of osteosarcoma cells has distinct characteristics: it is hypo-proliferative, hyper-secretory, p21+, and survives the stresses of dissemination to the lung. We call these metastasis-initiating cells “anchor” cells and their rapidly proliferative counterparts “growth cells.” Disseminated anchor cells trigger a wound-healing program that changes the cellular composition, extracellular matrix, and cytokine milieu of the surrounding tissues. Ironically, anchor cells also block progression to the resolution phase of the wound-healing process, creating a bona fide “wound that never heals.” The environment created by this anchor cell activity is conducive to the survival and proliferation of growth cells, which anchor cells can actively recruit to an established niche.

These data suggest that lung metastases arise through cooperation between osteosarcoma cells with distinct phenotypes. Anchor cells survive the initial stresses of the pulmonary environment, then modify that environment by invoking and manipulating the wound-healing programs of the lung. Proliferating growth cells are subsequently recruited to anchored niches to generate clinically relevant metastatic lesions. Effective treatment of metastatic disease will likely require combinations of agents that target both of these osteosarcoma subtypes, which exhibit highly divergent sensitivity to conventional therapies. Integrative development of novel approaches to treatment, instructed by these discoveries, is underway. We hope that this work will make metastatic osteosarcoma as manageable as primary disease for both kids and their dogs alike.