Biology subjects

Zlotnik, O.

Publications and source records attributed to Zlotnik, O..

2 recordsLinked to original sources

bioRxiv2022

Disruption of integrin alpha-5/beta-1-dependent transforming growth factor beta-1signaling pathway attenuates vessel co-option in colorectal cancer liver metastases

Colorectal cancer liver metastases (CRCLM) have two major histopathological growth patterns (HGPs) including angiogenic desmoplastic HGP (DHGP) and non-angiogenic replacement HGP (RHGP). The RHGP lesions obtain their blood supply through vessel co-option, where the cancer cells hijack the pre-existing blood vessels of the surrounding liver tissue. Consequently, anti-angiogenic therapies are less efficacious in CRCLM patients with RHGP lesions. Recently, we identified a positive correlation between the expression of Angiopoietin1 (Ang1) and the development of vessel co-opted CRCLM lesions in vivo. However, the mechanisms underlying Ang1 upregulation in vessel co-opting CRCLM lesions are unclear. Herein, we demonstrated that transforming growth factor {beta}1 (TGF{beta}1) modulates the expression of Ang1 in hepatocytes in vitro. Significantly, pharmaceutical inhibition of integrin alpha-5/beta-1 (ITG5{beta}1) through ATN-161 impaired TGF{beta}1-dependent Ang1 expression in vitro and in vivo. Moreover, blocking ITG5{beta}1 attenuated the formation of vessel co-opting lesions. Furthermore, treatment with ATN-161 significantly improved survival in tumour-bearing mice. Taken together, our results suggest the molecular mechanism of Ang1 upregulation in vessel co-opting CRCLM and targeting this pathway may serve as promising therapeutic strategy to overcome the development of vessel co-option in CRCLM.

cancer biology↗

bioRxiv2020

Transient cell-in-cell formation underlies tumor resistance to immunotherapy

Despite the remarkable success of immunotherapy in cancer, most patients will develop resistant tumors. While the main conceptual paradigm suggests that relapsed clones emerge through a process of clonal selection and immunoediting, currently little evidence directly demonstrates this process in epithelial cancers. To study this process, we established several mouse models in which tumors drastically regress following immunotherapy, yet resistant tumors relapse within a few weeks of treatment cessation. Whole exome analyses indicated that relapsed tumors share hundreds of neo-antigens with the primary tumors and are comparably killed by reactive T cells. Examination of tumor cells that survive immunotherapies revealed that they structure a transient cell-in-cell formation, which is impenetrable to immune-derived cytotoxic compounds and to chemotherapies. This formation is mediated predominantly by a cell-membrane protein on activated T cells, which subsequently induces epidermal growth factor receptors and STAT3 phosphorylation in tumors cells. In contrast to previous reports on cell-in-cell formations, here both cells remain alive and can disseminate into single tumor cells once T cells are no longer present. Overall, this work highlights a powerful resistance mechanism which enable tumor cells to survive immune pressure and provides a new theoretical framework for combining chemotherapies and immunotherapies.

immunology↗