ISS: Leveraging Microgravity to Study Immunomechanics in Cancer-Myeloid Organoids

The unique low gravity environment of the International Space Station (ISS) offers advantageous opportunities for gaining new insights into human health and disease. On Earth, diseases such as cancer are often studied in flat layers of growing cells that do not reproduce the complex, three-dimensional behavior of human physiology. This award supports research to grow three-dimensional models of the brain cancer on the ISS in order to better mimic how these tumors form within the brain, and to study interactions between cancer and immune cells. Opportunities will be provided for K-12 teachers to learn how to demonstrate simulated space experiments in their classrooms, for high school students to learn how to conduct these experiments themselves in a university laboratory setting, and for college students to learn in the classroom about how space impacts human physiology. This will lay important groundwork for training the next generation of space scientists and engineers. Unlike ground-based organoid cultures, which are subject to settling, sedimentation, disassociation, and heterogeneity due to Earth’s gravitational forces, organoids grown in microgravity conditions are more uniform, larger, complex, and consistently reproducible. Here, novel cancer-myeloid organoids (CMOs) will be generated on-ground vs. on-orbit to mimic and study the tumor microenvironment of glioblastoma (GBM), the deadliest primary brain tumor in adults. The GBM microenvironment is dominated by myeloid cells, such as resident brain microglia and infiltrating monocytes and macrophages, which often exist in a tumor-supporting (i.e., anti-inflammatory, or “M2-like”) phenotypic and functional state. GBM are further plagued by the effects of a tumor growth-induced mechanical force known as solid stress. It is hypothesized here that solid stress promotes tumor supporting behavior in myeloid cells. In turn, because myeloid cells comprise up to 50% of the GBM microenvironment, it is further posited that they directly contribute to tumor solid stress generation. By utilizing robust CMOs that are grown in the microgravity environment of the ISS, novel cellular and molecular mechanisms underlying these “immunomechanical” relationships will be revealed, which are not readily discoverable in limitation-plagued Earth-grown organoids. First, flight ready CMO seeds (i.e., micro-organoids) will be generated from different mixtures of GBM and myeloid cell types with varied functional polarization states spanning from tumor-supporting to tumor-combating (i.e., pro-inflammatory, or “M1-like”). The extracellular environment will also be tuned to mimic tumor confinement by the host-organ (i.e., the brain). Next, following a successful launch, an established passive containment system for organoid cultures on the ISS will be used to sustain and promote CMO growth for up to 30-45 days on-orbit. Finally, upon return after splashdown, the CMOs will be subjected to downstream analysis including histology, transcriptomics, proteomics, and mechanical force evaluations. These data will be integrated to derive novel immunomechanical signatures of the microgravity CMOs vs. ground controls, which advance fundamental knowledge of brain cancer for further studies and future interventions. The PI has developed plans for outreach and train the next generation of space scientists and engineers. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.