Chemotherapy enhances HMGA1 secretion through the mutant p53-CK2 axis in pancreatic ductal adenocarcinoma cells.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal cancers, with limited therapeutic options and a dismal prognosis. A critical driver of its progression is mutant p53 (mutp53), which reshapes the tumor microenvironment (TME) by modulating the secretion of key signaling molecules. Given the potential of secretome profiling to reveal novel biomarkers and druggable targets, we investigated the role of the mutp53-driven secretome in PDAC cells and its implications for disease progression. Through mass-spectrometry (MS) analysis, we identified a set of secreted proteins modulated by mutp53, with the nuclear high mobility group A1 (HMGA1) serving as a central regulator. HMGA1 is a transcription factor involved in several cellular processes and found to be upregulated in different tumors, but its extracellular role in cancer remains largely unexplored. We demonstrate that mutp53-driven HMGA1 secretion promotes PDAC cell hyperproliferation, where HMGA1 deficiency significantly impairs tumor growth highlighting a critical role of this protein in tumor aggressiveness. Notably, we discovered that chemotherapy enhances HMGA1 secretion specifically in TP53-mutant PDAC cells through a mechanism dependent on Casein Kinase 2 (CK2) activity. To unravel the downstream oncogenic signaling triggered by secreted HMGA1, we conducted phosphoproteomic analysis, identifying hyperphosphorylation of Nucleophosmin 1 (NPM1), as a pivotal event that further amplifies tumor cell proliferation. Collectively, our findings reveal that a panel of chemotherapeutic agents stimulate a novel mutp53-dependent CK2-HMGA1-NPM1 axis that fuels PDAC aggressiveness in an autocrine/paracrine manner. Targeting this pathway at multiple levels emerges as a promising therapeutic strategy to counteract mutp53-driven tumor progression andimprove patient outcomes.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Culture Fluid

DISEASE(S): Pancreatic Cancer

SUBMITTER: Marcello Manfredi  

LAB HEAD: Marcello Manfredi

PROVIDER: PXD062127 | Pride | 2025-11-10

REPOSITORIES: Pride