Nucleolin targeting impairs the progression of pancreatic cancer and promotes the normalization of tumor vasculature

Pancreatic cancer is a highly aggressive tumor, mostly resistant to the standard treatments. Nucleolin (NCL) is overexpressed in cancers and its inhibition impairs tumor growth. Herein we showed that NCL was overexpressed in human specimens of pancreatic ductal adenocarcinoma (PDAC) and that the overall survival significantly increased in patients with low levels of NCL. The NCL antagonist N6L strongly impaired the growth of primary tumors and liver metastasis in an orthotopic mouse model of PDAC (mPDAC). Similar anti-tumor effect of N6L has been observed in a highly angiogenic mouse model of pancreatic neuroendocrine tumor RIP-Tag2. N6L significantly inhibited both human and mouse pancreatic cell proliferation and invasion. Notably, the analysis of tumor vasculature revealed a strong increase of pericyte coverage and vessel perfusion both in mPDAC and RIP-Tag2 tumors, in parallel to an inhibition of tumor hypoxia. NCL inhibition directly affected endothelial cell (EC) activation and changed a pro-angiogenic signature. Among the vascular activators, NCL inhibition significantly decreased Ang-2 secretion and expression in ECs, in the tumor and in the plasma of mPDAC mice. As a consequence of the observed N6L-induced tumor vessel normalization, pre-treatment with N6L efficiently improved chemotherapeutic drug delivery and increased the anti-tumor properties of gemcitabine in PDAC mice. In conclusion, NCL inhibition is a new anti-pancreatic cancer therapeutic strategy that dually blocks tumor progression and normalizes tumor vasculature improving the delivery and efficacy of chemotherapeutic drugs. Moreover, we unveiled Ang-2 as a potential target and suitable response biomarker for N6L treatment in pancreatic cancer.