Cellular Mechanisms Program Summary Cellular Mechanisms (CM) is a new research program in the Masonic Cancer Center (MCC) formed when the Cell Signaling and Tumor Microenvironment Programs merged into one highly integrated program to strengthen the science of cellular mechanisms of cancer and expand opportunities for translation of research discoveries into new therapeutic modalities. The Program?s goal is to identify biological mechanisms that drive cancer development, tumor progression, and metastasis, including therapy-resistant recurrence, and then develop novel targeted therapies. The 3 integrated Aims are 1) to identify oncogenic signaling pathways within and between diverse cells in tumors that can be targeted to limit tumor growth, invasion, and metastasis; 2) to define epigenetic events in tumor transcriptomes that enhance malignancy or resistance to therapy; 3) to determine how tumors cause protumorigenic changes in the associated stroma and how ?cancerized? stroma and tumor-reactive host cells impact tumor progression, invasion, migration, and metastasis. The Program is co-led by Drs. Carol Lange and James McCarthy and has 45 members, representing 19 departments and 8 schools or colleges. For the last budget year, CM members were supported by $4.8 million in direct costs from the National Cancer Institute; cancer-focused, sponsored funding from all sources totaled over $10.7 million (direct costs). Since 2013, CM members have published 1027 papers, 8% of which resulted from intraprogrammatic collaborations, 22% from interprogrammatic collaborations, and 82% from external collaborations; 89 were published in journals with an impact score of 10 or higher. Since 2013, 221 clinical trials across all clinical research categories have opened under this programmatic area and have accrued 1132 subjects. The MCC has provided substantial value to the program, including recruitment of 5 new faculty and funding of $1.08M in pilot projects that have led to over $5.5 million in externally funded grants. CM members use all 10 MCC Shared Resources. In addition, the MCC was instrumental in supporting the 2nd annual Regional Midwest Tumor Microenvironment Meeting in May of 2015, which hosted 132 attendees from 7 academic institutions. Members of this well-integrated interdisciplinary Program bring complimentary expertise to identifying how tumor and host cell interactions impact tumor progression, elucidating the complexities of metastatic and hormone-refractory disease, and determining how deregulation of signaling inputs to transcriptional control might be exploited to improve therapy. The study of targetable factors related to stroma remodeling and fibrosis is also a research strength. Novel therapies are being developed using antibodies, recombinant toxins, small molecules, and medicinal chemistry/fragment-based drug design to target signaling pathways and alter tumor metabolism. Program members have substantial interactions with the Immunology and Genetic Mechanisms Programs. The CM Program fulfills key components of the Cellular and Molecular Therapeutics and Biomarker Discovery (SPG1 and SPG4) MCC Strategic Scientific Priorities.