Abstract A29: Cooption of the reactive stroma by brain metastasis relies on protease inhibitors

Abstract

Abstract Metastatic cancer cells are known to get benefit from the interaction with their microenvironment. The presence of metastatic cells in a target organ induces changes in the stroma. This reactive stroma is very evident in the brain, where cancer cells are ubiquitously associated with reactive glia. Since reactive astrocytes are known sources not only of trophic factors but also deleterious signals, we hypothesized that the ability of metastatic cells to develop in a target organ requires the ability to neutralize these deleterious signals. We detected reactive astrocytes in the proximity of brain metastasis producing plasminogen activators (tPA and uPA), which activate Plasmin, one of the main proteases in the brain. Plasmin activity in the brain acts as a deleterious factor to metastatic cells in this organ. Cancer cells selected in vivo for their ability to metastasize in the brain overexpress Serine Protease Inhibitors (SERPINs) that block Plasmin activation. Moreover, a significant cohort of human brain metastasis samples from both lung and breast adenocarcinoma scored positive for specific members of the SERPIN family. When the cancer cells were depleted of SERPINs their brain metastatic activity was significantly reduced in all experimental models, including breast and lung adenocarcinoma xenografts and syngeneic mouse models. Brain metastatic cells are sensitive to Plasmin activated killer cytokines (sFASL), and their ability to survive and to grow in the brain depends on genes whose products are inactivated by Plasmin cleavage (VEGFA and L1CAM). The cooption of SERPINs by brain metastatic cells is required to avoid the deleterious consequences of the reactive stroma and subsequently benefit from the interaction with the microenvironment. Citation Format: Manuel Valiente, Derek J. Lee, Anna Obenauf, Jason T. Huse, Jamie E. Chaft, Mark G. Kris, Edi Brogi, Joan Massagué. Cooption of the reactive stroma by brain metastasis relies on protease inhibitors. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A29.