Researchers at the University of Barcelona have cracked open one of lung cancer's most stubborn mysteries: why two seemingly similar tumors respond so differently to the same drugs. The answer lies not in the cancer cells themselves, but in the fibroblasts—ordinary, abundant cells that surround the tumor and fundamentally shape how it grows, starves, or thrives.
Lung cancer remains the leading cause of cancer-related death worldwide, and the two main types, adenocarcinoma and squamous cell carcinoma, have long presented a therapeutic puzzle. Anti-angiogenic drugs, which block the formation of new blood vessels that tumors need to expand, work effectively against adenocarcinoma but have historically failed against squamous cell carcinoma. Why? The answer, published in Cell Death & Disease and led by Professor Jordi Alcaraz at the University of Barcelona's Faculty of Medicine and Health Sciences, reveals that the tumor's neighborhood matters as much as the tumor itself.
The international research team—drawing expertise from institutions across Catalonia, the United States, the United Kingdom, and Australia—studied the molecular markers that govern blood vessel formation and oxygen deprivation in both lung cancer types. What they discovered was striking: the difference between success and failure hinges on how tumor-associated fibroblasts behave in each cancer type. "The fibroblast-rich tumor microenvironment is not merely a spectator but a key player that shapes the tumor's progression," Alcaraz explained, noting that these cells influence everything from the vascular network to oxygen availability and even immune response.
In adenocarcinoma, fibroblasts work like eager construction workers, actively promoting new blood vessel formation through a combination of vascular endothelial growth factor and TIMP-1, a previously underappreciated angiogenic factor. This abundant blood supply means the tumor enjoys higher oxygen levels and lower rates of cell death—conditions that, paradoxically, make it vulnerable to anti-angiogenic drugs that cut off its lifeline. Squamous cell carcinoma, by contrast, harbors fibroblasts that struggle with blood vessel formation. These cells appear molecularly altered, possibly from the higher tobacco exposure associated with this cancer type, resulting in tumors that are starved of oxygen and more acidic. This hostile microenvironment blocks the anti-angiogenic strategy that works so well against adenocarcinoma.
The implications are profound and personally tailored. Most lung cancer patients do not respond to immunotherapy alone, but combining it with anti-angiogenic drugs—which can normalize blood vessels and reduce immune suppression—shows promise. Until now, squamous cell carcinoma patients have been excluded from this combined approach due to its historical resistance to anti-angiogenic treatment. This research opens the door to finally including them. By understanding precisely how fibroblasts differ between the two cancer types, researchers can now design treatments that account for these biological realities rather than imposing a one-size-fits-all solution.
The study, led by UB researcher Natalia Díaz Valdivia and conducted across the Catalan Institute of Oncology, Mayo Clinic, Francis Crick Institute, and institutions in Australia, signals a shift toward genuinely personalized medicine in oncology—one where the tumor's neighborhood is as important as its genetic code.