The five year survival rate for lung cancer is ~20% despite improved screening methods and advances in treatment. Tumor metastasis is one of the major causes of death in cancer patients. Besides the dysregulated signaling in tumor cells, the survival of dislodged circulating tumors from detachment-induced apoptosis (anoikis) and immune attack in the blood depends on a crosstalk between the tumor and support cells in the tumor microenvironment, including blood platelets. Lung cancer patients with high platelet count are often associated with worst survival and a lower efficacy towards chemotherapeutic agents. Although platelets are a determinant in tumor metastasis, current anti-platelet therapy (aspirin and clopidogrel) with an established role in cardiovascular disease, has challenges when deployed for the management of cancer. Therefore, new approaches to better understand the platelet-cancer crosstalk is needed to identify novel platelet targets. Interestingly, platelets from cancer subjects have quantitative changes in the proteome. It is currently unknown if the cancer-induced changes in platelet protein(s) merely serve as a biomarker(s) or promote disease progression. This critical unanswered problem in the field has the potential to provide new insights into disease mechanisms that are influenced by platelets. Recent studies suggest a role for the catalytic subunit of protein phosphatase 1 (PP1c) in the platelet-cancer crosstalk. Our preliminary studies revealed that the platelets isolated from human lung cancer patients and mice with experimental lung cancer show increased PP1cα protein compared to the non-cancer controls. Importantly, conditional deletion of PP1cα in platelets showed reduced tumor burden in an experimental model of lung cancer metastasis. Our overarching hypothesis is that platelet PP1cα facilitates lung cancer metastasis by reducing detachment-induced apoptosis (anoikis) and/or promoting an immunosuppressive milieu. This proposal will determine how platelet PP1cα promotes lung cancer metastasis using novel mice models and investigators with expertise in platelet phosphatases, cancer biology, platelet-cancer cross talk and immunology of lung cancer. In Aim 1, we will investigate the role of platelet PP1cα in lung cancer survival and metastasis. Aim 2 will determine the role of platelet PP1cα on immune responses to lung cancer. This work could lead to studies wherein simultaneous blockade of platelet/extracellular PP1cα along with immune check points may provide exclusive opportunities to optimize cancer immunotherapy.