CELLULAR COMMUNICATION IN CANCER PROGRAM – PROJECT SUMMARY/ABSTRACT The Cellular Communication in Cancer (CCC) Program studies novel signaling mechanisms and tumor-host interactions that drive cancer. Notable scientific accomplishments include (1) the development of innovative organoid and metastatic colonization models; (2) the implementation of new imaging approaches to detect metastases and study cancer and host cell dynamics in mice; (3) the identification of molecular pathways and antigens that correlate with disease progression, providing therapeutic and diagnostic opportunities; (4) the identification of mechanisms by which inflammation can drive cancer initiation and metastasis; (5) the discovery that cachexia via IL-6 connects hepatic ketogenesis to an immune-suppressive stress response; (6) the development of an orally bioavailable, specific inhibitor of PTP1B, an enzyme driving breast cancer metastasis; and (7) the discovery that CXCR4-signaling confers immunosuppression. The Program has three overarching research themes. First, members are identifying and targeting key signaling nodes in cancer initiation and progression using advanced model systems and approaches, including murine models of metastasis, three- dimensional organoid cultures, novel proteomics approaches, and state-of-the-art in vivo imaging methods. Second, members are elucidating the interactions between cancer cells and host cells that drive cancer initiation and progression. Third, members are working to understand cancer in the context of the whole-body. To that end, CCC Program members have initiated collaborative, interdisciplinary projects to understand the mechanisms through which (i) stress signaling, (ii) cachexia, (iii) circadian biology, (iv) chronic infection and inflammation, and (v) organismal metabolism contribute to and are affected by cancer development and progression. The roles of neural genes and synaptic signals in cancer progression are also being explored. The Program is co-led by Mikala Egeblad and Linda Van Aelst and includes 14 members. Since 2015, Program members produced a total of 145 papers (138 publications and 7 preprints). Among them, 30 (21%) resulted from intra-programmatic collaborations, 30 (21%) resulted from inter-programmatic collaborations, 118 (81%) involved collaborations with investigators at other institutions, and 60 (41%) were published in journals with an impact factor greater than 10. All 14 Program members except a newly recruited member (93%) co-authored articles with other Cold Spring Harbor Laboratory Cancer Center members. Program members are supported by 12 R01-equivalent grants among 6 members. Peer-reviewed funding increased from $2.7 million in 2015 to $3.5 million in 2020. The novel insights into signaling and tumor-host interactions that CCC Program members are making will lead to a greater understanding of cancer as a systemic disease and will inform novel diagnostic and treatment strategies.