Hepatocellular carcinoma (HCC) is the leading death cause in the world. Although chemotherapy can eradicate majority of HCC cells, subpopulation of tumor propagating cells (TPCs) develop tolerance to chemotherapy and lead to relapse. Here we set out to illustrate how vascular environment regulates the emergence of chemoreistant TPCs. We have shown that aberrant activation of vascular endothelial cells induces generation of diverse signals provoking diseases. Expression of Notch ligand Jagged1 (Jag1) in tumor associated endothelial cells (TECs) stimulates juxtacrine Notch2 signaling in adjacent lymphoma cells, instigating generation of chemoresistant TPCs. Pilot studies demonstrate that TEC-expressed Jag1 stimulates Notch-dependent induction of Insulin-like growth factor 1 receptor (IGF1R) in perivascular HCC cells, instigating TPC-like chemoresistance. Thus, we propose to decode the mechanism by which TECs are subverted form a TPC-enabling niche expressing Jag1. Our preliminary data show that PARP1 activation in TECs catalyzes PARylation of Wnt component TCF4 to spur expression of its downstream target Jag1. Building on these findings, we hypothesize that activation of PARP1-TCF4-Jag1 pathway in TECs by chemotherapy feed- forward mechanism to generate and amplify chemoresistant HCC TPCs. We will use in vitro TEC-TPC co-culture model, EC-specific genetic deletion mouse model, and HCC transplantation and genetic preclinical platforms to thoroughly demonstrate the functional contribution of this tumorigenic pathway in enabling TPCs. We will also explore the therapeutic value of clinically studied PARP1 inhibitors in obviating TPCs and HCC chemoresistance. Outcome of our studies will help to reveal a previously overlooked executive influence of vascular microenvironment on instigating chemoresistance. Testing the effect of PARP1 inhibitors in abrogating tumorigenic function of TECs will also aid in devising effective approaches to circumvent HCC chemoreistance.
Project Narratvie We show that blood vessel promotes lymphoma progression by delivering blood and providing nutrients and growth factors (Cao et al Cancer Cell 2014), and we have recently found a previously unrecognized contribution of tumor blood vessel to making liver cancer cells tolerant to chemotherapy (Cao et al Cancer Cell 2016). This effect of tumor blood vessel was found to mediated by activation of an enzyme PARP1, which by stimulates production of Jagged1 molecule to enhance tumor chemoreistance. Here we aim to fully define how PARP1 stimulates Jagged1 expression in tumor blood vessel during chemotherapy, and we also plan to test whether PARP1 inhibitors being used in clinical studies will block the capacity of tumor blood vessel in promoting tumor chemoresistane.
