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Malignancies arising from mutation of tumor suppressors have unexplained tissue proclivity. For example, BAP1 encodes a widely expressed deubiquitinase for histone H2A, but germline mutations are predominantly associated with uveal melanomas and mesotheliomas. We show that BAP1 inactivation causes apoptosis in mouse embryonic stem cells, fibroblasts, liver, and pancreatic tissue but not in melanocytes and mesothelial cells. Ubiquitin ligase RNF2, which silences genes by monoubiquitinating H2A, promoted apoptosis in BAP1-deficient cells by suppressing expression of the prosurvival genes Bcl2 and Mcl1. In contrast, BAP1 loss in melanocytes had little impact on expression of prosurvival genes, instead inducing Mitf Thus, BAP1 appears to modulate gene expression by countering H2A ubiquitination, but its loss only promotes tumorigenesis in cells that do not engage an RNF2-dependent apoptotic program., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Axl is expressed in various types of cancer and is involved in multiple processes of tumorigenesis, including promoting tumor cell growth, migration, invasion, metastasis as well as angiogenesis. To evaluate further the mechanisms involved in the expression/activation of Axl in various aspects of tumorigenesis, especially its roles in modulating tumor stromal functions, we have developed a phage-derived mAb (YW327.6S2) that recognizes both human and murine Axl. YW327.6S2 binds to both human and murine Axl with high affinity. It blocks the ligand Gas6 binding to the receptor, downregulates receptor expression, inhibits receptor activation and downstream signaling. In A549 non-small-cell lung cancer (NSCLC) and MDA-MB-231 breast cancer models, YW327.6S2 attenuates xenograft tumor growth and potentiates the effect of anti-VEGF treatment. In NSCLC models, YW327.6S2 also enhances the effect of erlotinib and chemotherapy in reducing tumor growth. Furthermore, YW327.6S2 reduces the metastasis of MDA-MB-231 breast cancer cells to distant organs. YW327.6S2 induces tumor cell apoptosis in NSCLC, reduces tumor-associated vascular density and inhibits the secretion of inflammatory cytokines and chemokines from tumor-associated macrophages in the breast cancer model. In conclusion, anti-Axl mAb can enhance the therapeutic efficacy of anti-VEGF, EGFR small-molecule inhibitors as well as chemotherapy. Axl mAb affects not only tumor cells but also tumor stroma through its modulation of tumor-associated vasculature and immune cell functions. [ABSTRACT FROM AUTHOR]