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
  • 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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