PXD062127-1

PXD062127 is an original dataset announced via ProteomeXchange.

Title	Chemotherapy enhances HMGA1 secretion through the mutant p53-CK2 axis in pancreatic ductal adenocarcinoma cells.
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-11-10
AnnouncementXML	Submission_2025-11-09_16:15:37.006.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marcello Manfredi
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	TripleTOF 5600

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-21 09:42:56	ID requested
⏵ 1	2025-11-09 16:15:38	announced

Danzi F, Butera G, Sutton D, Perricone MD, Hu Y, Celesia A, Manfredi M, Brandi J, Pourmandi N, Nelson NS, Lin L, Bevere M, Pacchiana R, Pea A, Salvia R, Scarpa A, Luchini C, Cecconi D, Ugel S, Lyssiotis CA, Fiore A, Donadelli M, Chemotherapy enhances HMGA1 secretion through the mutant p53-CK2 axis in pancreatic ductal adenocarcinoma cells. Cell Death Dis, 16(1):766(2025) [pubmed]

10.1038/s41419-025-08082-1;

submitter keyword: TP53, mass spectrometry,Pancreatic ductal adenocarcinoma, supernatants, tumor microenvironment

Marcello Manfredi
contact affiliation	Dipartimento di medicina Traslazionale, Università del Piemonte Orientale
contact email	marcello.manfredi@uniupo.it
lab head
Marcello Manfredi
contact affiliation	University of Eastern Piedmont
contact email	marcello.manfredi@uniupo.it
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD062127
     1. Label: PRIDE project
     2. Name: Chemotherapy enhances HMGA1 secretion through the mutant p53-CK2 axis in pancreatic ductal adenocarcinoma cells.