Premalignant Progression in the Lung: Knowledge Gaps and Novel Opportunities for Interception of Non-Small Cell Lung Cancer. An Official American Thoracic Society Research Statement

Abstract

Rationale: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing timely and effective intervention before cancer development. Objectives: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. Methods: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the transformation of premalignant lung lesions to advanced lung cancer. Results: This research statement identifies significant gaps in knowledge and proposes potential research questions aimed at expanding our understanding of the mechanisms underlying the progression of premalignant lung lesions to lung cancer in an effort to explore potential innovative modalities to intercept lung cancer at its nascent stages. Conclusions: The identified gaps in knowledge about the biological mechanisms of premalignant progression in the lung, together with ongoing challenges in screening, detection, and early intervention, highlight the critical need to prioritize research in this domain. Such focused investigations are essential to devise effective preventive strategies that may ultimately decrease lung cancer incidence and improve patient outcomes.

Keywords: interception; lung cancer; oncogenic transformation; premalignant progression.

Figure 1.

Underlying molecular mechanisms of oncogenic transformation, knowledge gaps, and potential tools for addressing them. Environmental exposures, mutations, DNA damage, cellular stress, and altered metabolism serve as pivotal triggers that compromise the function of alveolar type II (AT2) epithelial cells in response to lung injury. The malfunction in AT2 cell regeneration leads them into a transcriptional transition state, evolving into highly adaptable cells during the precancerous phase. Age-related AT2 dysfunction disrupts repair and regenerative processes, exacerbating lung diseases such as COPD, IPF, PH, and LC. Cutting-edge diagnostic tools such as PET scans play a crucial role in the early detection and visualization of premalignant lesions. These scans, coupled with comprehensive omics analyses, elucidate the molecular alterations underlying neoplastic transformations in the initial stages of tumorigenesis. Furthermore, ex vivo model systems, such as cocultures and organoid cultures involving stromal and epithelial cells, offer invaluable insights into the influence of the microenvironment across various stages of carcinogenesis. Complementary techniques such as digital pathology, single-cell analysis, and spatial multiomics approaches are used to investigate early clonal progression and intercellular dynamics within the tumor microenvironment. This integrated approach provides a comprehensive understanding of cellular dynamics and molecular pathways in both premalignant and malignant lesions. AI = artificial intelligence; AT1 = alveolar type I; COPD = chronic obstructive pulmonary disease; FDG = [¹⁸F]2-deoxy-2-fluoro-D-glucose; IPF = idiopathic pulmonary fibrosis; LC = lung cancer; PET = positron emission tomography; PH = pulmonary hypertension; T-SNE = t-distributed stochastic neighbor embedding; UMAP = uniform manifold approximation and projection.

Figure 2.

Roles of host precancer immune/stromal interaction in facilitating tumor development and progression. Dysregulated chronic inflammation, caused by pollution, infection, and smoke, induces aberrant expression of cytokines and accumulation of immune cells in the airways. This interplay of the immune system in chronic inflammation precedes neoplastic development and promotes lung cancer through the activation of multiple tumorigenic pathways. In addition, the interaction between immune cells and the surrounding tumor microenvironment influences host immune surveillance from early-stage tumors to invasive stages. Advanced bronchoscopy is used as a powerful tool for diagnosing and tracing the evolutionary trajectory of antitumor adaptive immune responses during lung tumor development. It also aids in exploring potential high-risk premalignant lesions, which may increase tumor invasiveness. Pattern recognition receptors (PRRs), crucial in the innate immune system for recognizing primary pathogens in inflammation, are poorly defined in the context of premalignant lung lesions. Therapeutic targeting of PRRs in preclinical lung cancer models is essential to uncover host–microbial interactions in this context. Using spatial omics approaches (spatial transcriptomics and multiplex immunohistochemistry) facilitates the definition of heterogeneity and cellular plasticity in the clinical trajectory and immunopathogenesis of premalignant lung lesions.