Deciphering the contribution of the aged alveolar niche to lung cancer evolution

Despite aging being a major risk factor for lung cancer incidence, most preclinical and clinical studies do not take aging into account. Thus, our understanding of how aging affects lung cancer progression, evolution and therapy response remains limited. The diversity of subpopulations of tumor cells, and their therapeutic responses are shaped by their complex interactions with the host. Our published studies support this, revealing a causal link between the systemic metabolic reprogramming driven by aging and lung cancer progression and immune evasion, putting aging and the changes it causes in the host at the center stage coordinating cancer evolution. Recently, we showed that beyond systemic changes, alterations in the composition and functional state of old lung tumor microenvironment (TME) shape niche signaling and drive divergent lines of lung cancer evolution resulting in age-dependent intrinsic differences in prognosis upon treatment with standard of care therapies. Yet, the age-driven niche-signaling mechanisms that fuel this divergent evolution remain unknown. Importantly, we have identified a damage-associated state of alveolar epithelial cells (alveolar differentiation intermediates, or ADIs) that accumulate within the NSCLC TME and the adjacent lung as a key difference between NSCLC in young versus old animals and patients. Strikingly, ADIs’ preferential accumulation within the old TME dominates the communication between NSCLC cells and the TME through ADI-produced ligands linked to stemness induction. Thus, in this research program we propose that the emergence of ADIs in the old lung TME shapes the niche signaling that NSCLC cells and the other TME cellular components are exposed to. We posit that these changes steer NSCLC evolution towards a primitive stem-like state with higher grade tumors that confer resistance to chemotherapies. We will leverage multiple model systems (human and mouse cancer cells lines, AT2-derived organoids and in vivo mouse models) combined with high throughput single cell technologies and mass spectrometry to characterize the mechanism that underlies the age-induced ADI accumulation within NSCLC TME (Aim 1) and determine the contribution of ADIs to the evolution of the primitive stem-like state of NSCLC (Aim 2). Consequently, the proposed studies will put forward defined roles for aging in NSCLC biology and inducing the evolution of chemoresistance states that confer poor prognosis, thereby bringing awareness to the need of tailoring treatments to the specific age and biology of the patient. Our studies will also unveil for the first-time normal alveolar cells as major regulators of the NSCLC progression. Moreover, they will also put forward age-specific targets and pathways for subsequent studies with the ultimate goal of leveraging this information therapeutically to improve outcomes of the most common and vulnerable NSCLC patient population: the elderly. Project Number: 1R21AG100933-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Ana da silva Gomes | Institution: H. LEE MOFFITT CANCER CTR & RES INST, TAMPA, FL | Award Amount: $463,375 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 BTC-F (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11353625