2. Academic Validation
  3. Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity

Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity

  • Cell Stem Cell. 2025 Dec 4;32(12):1869-1885.e8. doi: 10.1016/j.stem.2025.10.005.
Jin Young Lee 1,  Nabora Reyes 2,  Sang-Ho Woo 3,  Nancy C Allen 3,  Tsukasa Kadota 3,  Andrew Lechner 3,  Ritusree Biswas 3,  Sakshi Goel 4,  Fia Stratton 4,  Chaoyuan Kuang 4,  Tatsuya Tsukui 5,  Vincent Auyeung 5,  Aaron S Mansfield 6,  Lindsay M LaFave 4,  Tien Peng 7
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Physiology and Biophysics, College of Medicine, Inha University, Incheon 22212, Republic of Korea. Electronic address: [email protected].
  • 2 Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Cell and Developmental Biology, School of Biological Sciences, University of California, San Diego, San Diego, CA 92093, USA.
  • 3 Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 4 Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • 5 Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
  • 6 Department of Oncology, Division of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA.
  • 7 Department of Medicine, Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].
PMID: 41187746 DOI: 10.1016/j.stem.2025.10.005
Abstract

Senescence has been demonstrated to either inhibit or promote tumorigenesis. Resolving this paradox requires spatial mapping and functional characterization of senescent cells in the native tumor niche. Here, we identify p16Ink4a+ cancer-associated fibroblasts enriched with senescent phenotypes that promote fatty acid uptake and utilization by aggressive lung adenocarcinoma (LUAD) driven by Kras and p53 mutations. Furthermore, rewiring of lung Cancer metabolism by p16Ink4a+ cancer-associated fibroblasts also alters tumor cell identity to a highly plastic/dedifferentiated state associated with progression in murine and human LUAD. Our ex vivo senolytic screening platform identifies XL888, an HSP90 Inhibitor, that clears p16Ink4a+ cancer-associated fibroblasts in vivo. XL888 administration after establishment of advanced LUAD significantly reduces tumor burden concurrent with the loss of plastic tumor cells. Our study identifies a druggable component of the tumor stroma that fulfills the metabolic requirement of tumor cells to acquire a more aggressive phenotype.

Keywords

cancer-associated fibroblasts; lung adenocarcinoma; p16(INK4a); senescence; senolytics; spatial transcriptomics; tumor cell plasticity; tumor metabolism; tumor microenvironment.

Figures
Products