Oncogenic and tumor-suppressive forces converge on a progenitor-orchestrated niche to shape early tumorigenesis

Reyes, José, Del Priore, Isabella, Chaikovsky, Andrea C, Pasnuri, Nikhita, Elhossiny, Ahmed M, Krause, Tobias, Moorman, Andrew, Snopkowski, Catherine, Takizawa, Meril, Burdziak, Cassandra, Ratnayeke, Nalin, Masillioni, Ignas, Ho, Yu-Jui, Chaligné, Ronan, Romesser, Paul B, Filliol, Aveline, Nawy, Tal, Morris, John P, Zhao, Zhen, Di Magliano, Marina Pasca, Alonso-Curbelo, Direna, Pe'er, Dana, Lowe, Scott W (June 2025) Oncogenic and tumor-suppressive forces converge on a progenitor-orchestrated niche to shape early tumorigenesis. bioRxiv. ISSN 2692-8205 (Submitted)

PDF 10.1101.2025.06.10.656791.pdf - Submitted Version Available under License Creative Commons Attribution. Download (16MB)

Abstract

The transition from benign to malignant growth is a pivotal yet poorly understood step in cancer progression that marks the shift from a pathologically inert condition to a clinically lethal disease. Here, we integrate lineage tracing, single-cell and spatial transcriptomics to visualize the molecular, cellular and tissue-level events that promote or restrain malignancy during the tumor initiation in mouse models of pancreatic ductal adenocarcinoma (PDAC). We identify a discrete progenitor-like population of KRAS-mutant cells that co-activates oncogenic and tumor-suppressive programs-including p53, CDKN2A, and SMAD4-engaging senescence-like responses and remodeling their microenvironment, ultimately assembling a niche that mirrors invasive PDAC. KRAS inhibition depletes progenitor-like cells and dismantles their niche. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state as the convergence point of cancer-driving mutations, plasticity, and tissue remodeling-revealing a critical window for intercepting malignancy at its origin.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
CSHL Authors:	Zhao, Zhen
Communities:	CSHL labs > Zhao lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	12 June 2025
Date Deposited:	28 Oct 2025 16:06
Last Modified:	28 Oct 2025 16:06
PMCID:	PMC12259082
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/41991

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