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<p>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 alters the tumor microenvironment (TME) by influencing crucial pro-tumoral signaling factors. 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 <i>TP53</i>-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 proliferation in an autocrine/paracrine manner. Targeting this pathway at multiple levels emerges as a promising therapeutic strategy to counteract mutp53-driven tumor progression and improve patient outcomes.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • Federica Danzi,
  • Giovanna Butera,
  • Damien Sutton,
  • Matthew D. Perricone,
  • Yushu Hu,
  • Adriana Celesia,
  • Marcello Manfredi,
  • Jessica Brandi,
  • Narges Pourmandi,
  • Noah S. Nelson,
  • Lin Lin,
  • Michele Bevere,
  • Raffaella Pacchiana,
  • Antonio Pea,
  • Roberto Salvia,
  • Aldo Scarpa,
  • Claudio Luchini,
  • Daniela Cecconi,
  • Stefano Ugel,
  • Costas A. Lyssiotis,
  • Alessandra Fiore,
  • Massimo Donadelli

摘要

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 alters the tumor microenvironment (TME) by influencing crucial pro-tumoral signaling factors. 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 proliferation in an autocrine/paracrine manner. Targeting this pathway at multiple levels emerges as a promising therapeutic strategy to counteract mutp53-driven tumor progression and improve patient outcomes.