Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition

Reyes, José, Del Priore, Isabella, Chaikovsky, Andrea C, Pasnuri, Nikhita, Elhossiny, Ahmed M, Park, Jin, Weiler, Philipp, Krause, Tobias, Moorman, Andrew, Snopkowski, Catherine, Takizawa, Meril, Burdziak, Cassandra, Ratnayeke, Nalin, Masilionis, Ignas, Ho, Yu-Jui, Chaligné, Ronan, Romesser, Paul B, Filliol, Aveline, Nawy, Tal, Morris, John P, Zhao, Zhen, Pasca Di Magliano, Marina, Alonso-Curbelo, Direna, Pe'er, Dana, Lowe, Scott W (May 2026) Oncogenic and tumor-suppressive forces converge on a progenitor niche at the benign-to-malignant transition. Cell, 189 (10). 2875-2897.e53. ISSN 0092-8674

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Abstract

The benign-to-malignant transition is a defining step in cancer progression. To investigate when and how malignancy initiation occurs and tissue reorganization proceeds, we combine single-cell and spatial transcriptomic profiling in mouse models of pancreatic ductal adenocarcinoma (PDAC) that capture spontaneous p53 loss. Among Kras-mutant cells, we find that oncogenic and tumor-suppressive programs, including those controlled by p53, CDKN2A, and SMAD4, are co-activated in a discrete progenitor-like population, engaging senescence-like responses. Using a framework we developed for spatial analysis, we show that a niche centered on these cells undergoes stepwise remodeling during tumor progression, mirroring invasive PDAC. Transient KRAS inhibition depletes progenitor-like cells and dismantles their niche, delaying malignancy initiation. Conversely, p53 suppression enables progenitor cell expansion, epithelial-mesenchymal reprogramming, and immune-privileged niche formation. These findings position the progenitor-like state at the convergence of cancer-driving mutations, plasticity, and tissue remodeling, revealing a critical window for intercepting malignancy.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
diseases & disorders > cancer > cancer types > pancreatic cancer
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Zhao lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 14 May 2026
Date Deposited: 22 May 2026 12:16
Last Modified: 22 May 2026 12:16
PMCID: PMC13173668
Related URLs:
URI: https://repository.cshl.edu/id/eprint/42207

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