2. Academic Validation
  3. Oncogenic and tumor-suppressive forces converge on a progenitor-orchestrated niche to shape early tumorigenesis

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

  • bioRxiv. 2025 Jun 12:2025.06.10.656791. doi: 10.1101/2025.06.10.656791.
José Reyes 1 2,  Isabella Del Priore 1 3,  Andrea C Chaikovsky 1,  Nikhita Pasnuri 2 4,  Ahmed M Elhossiny 5,  Tobias Krause 4,  Andrew Moorman 4,  Catherine Snopkowski 4,  Meril Takizawa 4,  Cassandra Burdziak 2,  Nalin Ratnayeke 1,  Ignas Masillioni 4,  Yu-Jui Ho 1,  Ronan Chaligné 4,  Paul B Romesser 6,  Aveline Filliol 1,  Tal Nawy 2,  John P Morris 4th 1 7 8,  Zhen Zhao 1 9,  Marina Pasca Di Magliano 10 11,  Direna Alonso-Curbelo 1 12,  Dana Pe'er 2 13,  Scott W Lowe 1 13
Affiliations

Affiliations

  • 1 Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
  • 2 Computational and Systems Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
  • 3 Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
  • 4 Single-cell Analytics Innovation Lab, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
  • 5 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
  • 6 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
  • 7 Department of Pharmacology, The University of North Carolina at Chapel Hill Medical School, Chapel Hill, NC, USA.
  • 8 Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
  • 9 Cold Spring Harbor Laboratory; New York, NY, USA.
  • 10 Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
  • 11 Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
  • 12 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  • 13 Howard Hughes Medical Institute, Chevy Chase, MD, USA.
PMID: 40661354 DOI: 10.1101/2025.06.10.656791
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.

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