Investigating the role of endothelial NFKBIZ signaling in tumor progression and metastasis

• Applicant: Dr. Mahak Singhal
• Subject Area: Hematology, Oncology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 510602219

Blood vessels nourish tumors with nutrients and provide passage for malignant cells to disseminate across our bodies. Additionally, blood vessel-lining endothelial cells (EC) secrete various growth factors and cytokines to modulate the tumor microenvironment to support tumor progression. Likewise, EC-derived angiocrine factors play a crucial role in setting up a conducive niche for disseminated tumor cells to colonize at a distant organ. Yet, the molecular mechanism underlying the activation of EC remains understudied. The current proposal aims at investigating molecular determinants that govern EC responsiveness to tumor progression. Here, we focus on NFκB inhibitor zeta (NFKBIZ), a member of the Nuclear factor-kappa B (NFκB) pathway, that acts as an upstream transcriptional activator for various cytokines and adhesion molecules. Our preliminary data show that deletion of Nfkbiz blunted EC responsiveness to an inflammatory stimulus, with a reduction in chemokine production and expression of adhesion molecules in Nfkbiz-deficient EC. Further, the growth of melanomas was significantly hampered in mice with EC-specific deletion of Nfkbiz. Tumors grown in Nfkbiz-deficient mice manifested a normalized intratumoral vasculature. Building on these data, we will first investigate molecular details of the endothelial NFBKIZ signaling axis with a focus on NFKBIZ interacting proteins and its downstream transcriptional target genes and trace perturbations upon tumor challenge. Secondly, the role of endothelial NFKBIZ signaling during tumor and metastatic progression will be phenotypically characterized in mice with EC-specific genetic knockout of Nfkbiz. Complementary in vivo and in vitro experiments will functionally dissect the role of endothelial NFKBIZ signaling in orchestrating host responses during tumor progression. Collectively, the experiments will yield substantial insight into molecular mechanisms through which vascular endothelium promotes tumor progression and metastasis.

• DFG Programme: Research Grants