Anticancer treatments enhance CK2-mediated HMGA1 secretion in mutant p53-pancreatic ductal adenocarcinoma (PDAC) cells with oncogenic activity

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. In this tumor type mutant p53 (mutp53) has a key role in altering the secretion of many signaling molecules, thus manipulating the tumor microenvironment (TME) to drive tumorigenesis. Since an extensive characterization of cancer secretome may lead to the identification of biomarkers and druggable targets for tumor treatment, we focused our study on the role of mutp53-dependent secretome in PDAC cells. Through mass-spectrometry (MS) analysis, we detected secreted proteins modulated by mutp53 and, among them, we selected the nuclear high mobility group A1 (HMGA1) for further studies. HMGA1 is a transcription factor involved in several cellular processes and found to be upregulated in different tumors, but its function in cancer remains unclear. We demonstrated that mutp53-dependent secretion of HMGA1 promotes PDAC cells hyperproliferation in vitro suggesting a critical role of this protein in tumor aggressiveness. This observation is also confirmed by our in vivo data showing that HMGA1 deficiency significantly affects tumor progression. Moreover, we showed that chemotherapy increases HMGA1 secretion only in cells harboring mutp53 with a mechanism that relies on the activity of the Casein kinase 2 (CK2). Lastly, given that mutp53-driven secreted proteins may act in an autocrine or paracrine manner stimulating crucial anabolic and oncogenic pathways, we analyzed which pathways are activated by the secreted HMGA1 by performing phosphoproteomic analysis. Overall, our study uncovers a novel mutp53-dependent CK2-HMGA1-NPM1 signaling axis activated by a range of chemotherapeutic agents, which drives PDAC proliferation through autocrine/paracrine mechanisms. Targeting this pathway at multiple levels represents might provide new therapeutic opportunities to counteract mutp53-driven tumor progression and improve clinical outcomes in PDAC patients.