Identifying mechanisms of osteosarcoma chemoresistance that arise from the lung metastatic niche

A therapy preventing the emergence of lung metastasis in adolescents with osteosarcoma could save more than 70% of the lives currently lost to this disease. This would represent the most significant improvement in outcome for osteosarcoma since the advent of chemotherapy in the 1960s. The primary cause for treatment failure in metastatic osteosarcoma is the emergence of resistance. Metastatic recurrence commonly follows a pattern of initial response to treatment followed by late development of metastatic lesions, often years after completion of therapy. Metastatic recurrences are inherently resistant to chemotherapy. Our lab has determined that tumor-derived IL6 and CXCL8 are critical for the survival of the small group of osteosarcoma cells that survive the stresses associated with metastasis. We now suspect those same cells that initially start growing in metastatic lesions are the same cells that make them recur after chemotherapy, making lesions resistant to treatment.

Our lab is hyper-focused on teasing out interactions between lung cells and tumor cells that help osteosarcoma tumors grow in the lung. We have identified signals produced by both lung cells and osteosarcoma tumor cells that create an environment favorable for tumor cell growth within the lung. This process starts when pulmonary epithelial cells release a signal called IL1. The IL1 signal provokes tumor cells that have traveled to the lung, causing them to produce large amounts of IL6 (although only a small number of the tumor’s cells can respond in this way). These IL1-responsive cells stop dividing when they reach the lung, which initially perplexed us (how would an event that stops proliferation help metastases form?), though we now suspect that this may be why metastatic lesions respond so poorly to chemo. If chemotherapy targets rapidly dividing cells, then an interaction that stops tumor cells from proliferating (again, a small subset of the tumor cells) would protect those cells from the effects of chemotherapy. In this proposal, we intend to test this hypothesis.
To do this, we will do two primary experiments. First, we will determine whether IL1-responsive osteosarcoma cells are those that survive the early stresses associated with metastasis. Second, we will expose metastatic lesions to chemotherapy and determine how the stresses of chemotherapy alter the metastatic tumors. We anticipate that chemotherapy will kill the rapidly dividing tumor cells, but leave the slowly-dividing cells behind, making them again look like the very early metastatic lesions. If this holds true, then therapies targeting the IL1-responsive cells might eliminate metastatic lesions, when combined with chemotherapy.