Marine sponges interact and coexist with many different organisms. A two-sponge association between Amphimedon erina and Geodia gibberosa commonly occurs in the Florida Keys. Previous studies have only focused on the ecological influence of the association; they did not examine the cellular basis of the association. This association between A. erina and G. gibberosa was used in the development of an in vitro model to further the understanding of the cellular basis of natural sponge-sponge associations. In this study, sponge cells were cultured individually and in co-cultures and their responses related to apoptosis, cell death, and proliferation were monitored using high content imaging. Co-cultured cells of species that form sponge-sponge associations did not have the same cellular responses compared to co-cultured cells of species that do not form sponge-sponge associations. Protein expression analyses demonstrated that the model that was established does not mimic the cellular response of the association in nature, but this model can be used to test in vitro cellular interactions of sponge species that do not form associations in nature. In addition, the protein expression data that were obtained revealed that sponges use similar apoptotic pathways as humans and suggest that sponge cells may shut down cell cycling in order to repair damaged DNA. This research is a small piece to the puzzle that is sponge cell culture research.