Senescent Fibroblasts in the Tumor Niche Rewire Lung Cancer Metabolism and Plasticity

Senescent fibroblasts are aging cells that no longer divide and protect against tumor development. Yet two decades have gone by since cell biologist Judith Campisi, PhD, paradoxically demonstrated that these same cells can promote cancer growth in a laboratory setting. Until now, it has not been clear whether this occurs inside the body. 

Using advanced genetic reporters and spatial transcriptomics in mouse and human lung adenocarcinoma, researchers from UC San Francisco have identified senescent fibroblasts within the tumor microenvironment and found that they cluster near a highly aggressive, plastic subset of tumor cells that can change identity to resist treatment. 

Through experiments using tumor organoids and adoptive transfer models, the research team discovered that these senescent fibroblasts secrete protein molecules such as APOE that reprogram tumor metabolism, fueling this plastic behavior. Strikingly, when the researchers used senolytic therapies to remove senescent fibroblasts, these highly adaptable cancer cells decreased dramatically, and aggressive tumors regressed in animal models. 

Their study published in November in Cell Stem Cell.

Lung cancer is so difficult to treat because tumor mutations keep evolving to develop drug resistance. What's exciting about this work is that we identified a druggable cell population within the stroma that supports tumor." 

Tien Peng, MD, senior author, UCSF associate professor of Pulmonary, Critical Care, Allergy and Sleep Medicine

Using a drug-discovery approach to target senescent cells, the researchers were able to selectively clear senescent fibroblasts and, in doing so, reverse the metabolic and cellular changes that drive aggressive lung cancer.

Because senescent cells exhibit distinct drug sensitivities compared to cancer cells, targeting them may provide new therapeutic avenues to counteract tumor drug resistance.

"This work not only confirms the seminal observations of Judith Campisi two decades ago in living tissue but also uncovers a potential therapeutic opportunity: targeting senescent cells in the tumor niche to block cancer adaptation and growth, offering a new path toward translating basic aging biology into clinical oncology," said Peng.