Abstract Lung cancer disproportionately affects individuals of African ancestry (AA), particularly men, who experience 12% higher incidence and 15% higher death rates than European ancestry men. The causes of this disparity remain unclear; while smoking is the most substantial risk factor for lung cancer, AA men do not smoke more than other groups. Despite the lack of understanding of the increased lung cancer risk and death rates of the AA population, the tools to study lung cancer in this group lag far behind; there are very limited in vitro models to study lung cancer in AA individuals. Lung adenocarcinoma (LUAD), which originates in the alveolar epithelium, is the most common histological subtype of lung cancer in all population groups. Immortalized human alveolar epithelial cells (ihAEC) are therefore key tools for studying the etiology and development of LUAD, as well as effects of environmental exposures. In addition to ihAECs, patient-derived xenografts (PDXs), in which human tumors are implanted and grown in immunodeficient mice, and in vitro cultured LUAD cell lines, are valuable tools to study lung adenocarcinoma. To address the shortage of these models developed from AA patients, we are taking a 3-pronged approach. We are collecting non-tumor and LUAD tissues from AA lung cancer patients with full consent. When sufficient non-tumor tissue is available, we isolate alveolar epithelial cells and use a CRISPR/Cas9-based gene-delivery approach to generate ihAEC lines. We direct genomic integration of simian virus 40 large-tumor antigen (SV40 LgT) and human telomerase reverse transcriptase (TERT) genes into the adeno-associated virus integration site 1 (AAVS1), a safe harbor region that prevents inserted genes from being silenced. When sufficient LUAD tumor tissue is available, we implant tumor sections subcutaneously in immunodeficient mice. Tumors that grow are explanted for a new round of propagation in mice as well as in vitro culture. To date one PDX has been established, and cells are in culture from non-tumor and tumor tissue; further characterization is in progress. The development of new ihAEC lines, PDXs, and LUAD cell lines will provide valuable tools for studying responses to environmental exposures, carcinogen detoxification processes, oncogenic transformation, and for testing novel therapies in ancestry-appropriate models. This work is an important step towards minimizing lung cancer health disparities caused by the absence of diverse model systems. Supported by grants U54CA233396, U54CA233444, and U54CA233465 from the National Institutes of Health (NIH)/National Cancer Institute (NCI), and the Norris Comprehensive Cancer Center core grant, award number P30CA014089 from the NIH/NCI. Citation Format: Karla E. Gonzalez, Bianca Dal Bo, Chunli Yan, Donna Loza, Matthew A. Gladstone, Anthony W. Kim, Scott M. Atay, Takashi Harano, W Dean Wallace, Ben Y. Tew, Bodour Salhia, Beiyun Zhou, Kweku Ofosu-Asante, Kyle R. Philips, Benjamin J. Ryder, Desmond Kwakye, Chase A. Lilly, Yong Huang, Nazarius S. Lamango, Ite A. Offringa. Ensuring diverse in vitro lung cancer models: Development of alveolar epithelial cell lines, patient-derived xenografts, and lung adenocarcinoma cell lines from individuals of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3407.

Lung cancer is the leading cause of cancer-related death. Adenocarcinoma (LUAD), the most common form of lung cancer, is a heterogeneous disease with high variability in histopathologic features and clinical outcomes. Atypical adenomatous hyperplasia and adenocarcinoma in situ are the premalignant lesions (PML) in LUAD pathogenesis. The molecular features of PML that lead to aggressive LUAD are poorly characterized. We hypothesized that transcriptomic changes in PML are linked to distinct clinicopathologic features that may identify aggressive PML before they become invasive LUAD. We examined lung resections from patients with early-stage LUAD where adjacent tissue contained premalignant histology. Normal, PML, and LUAD areas were laser-capture micro-dissected, and RNA was isolated and then profiled using bulk RNA-sequencing (n=41 patients, n=177 samples). We derived a set of recurrent gene modules (n=9 modules) in LUAD PML using samples from our cohort (n=80 PML samples) and three publicly available data sets (n=57 LUAD PML samples). Using these modules, we identified four PML archetypes, where the vertices of a polytope define each archetype. Based on pathway (Gene Set Enrichment Analysis, FDR <0.01) and signature enrichment, we identified the four archetypes as: normal-like, inflammation, cell adhesion, and proliferation. Analyzing the expression of published gene signatures suggests that the immune environment and epithelial cell plasticity may play different roles in different archetypes. Archetypes also differ with regard to a gene-expression signature for predicted immunotherapy response, with the proliferation archetype predicted to have a poor response, and the inflammation archetype predicted to have a good response to immunotherapy (logistic regression, p<0.05). An advantage of the archetyping approach is that archetype space is continuous, and samples from other cohorts can be placed within the PML-derived polytope based on their transcriptomic profile. We found that the PML-derived archetypes were related to clinical features in studies of LUAD. The proliferation archetype was associated with a decrease in disease free survival in multiple datasets (cox-proportional hazard model, p<0.05 for each tested cohort), and aggressive LUAD histology (linear model, p<0.05 for each tested cohort). While past studies demonstrated transcriptional differences between tumors and PML, our archetyping approach focuses on PML-specific gene expression patterns using multiple cohorts to increase the diversity of PML samples studied. Gene expression differences among archetypes were related to pathway dysregulation and prognosis. Characterizing PML based on transcriptomic features may improve our understanding of divergent mechanisms of carcinogenesis, and enable identification of aggressive PML capable of developing into invasive LUAD. Kelley Anderson, Linh Tran, Kostyantyn Krysan, Gregory A. Fishbein, William D. Wallace, Emily Green, Hanqiao Liu, Xiaohui Xiao, Gang Liu, Erin Kane, Avrum Spira, Steven M. Dubinett, Eric Burks, Sarah Mazzilli, Marc Lenburg, Jennifer Beane. Archetype analysis links heterogeneity in premalignant lesions to diverging features of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7489.

DEGs between subsolid nodule and nLung C20 NKT cells

Objective and Impact Statement: We present a panel of virtual staining neural networks for lung and heart transplant biopsies, providing rapid and high-quality histological staining results while bypassing the traditional histochemical staining process. Introduction: Allograft rejection is a common complication of organ transplantation, which can lead to life-threatening outcomes if not promptly managed. Histological examination is the gold standard method for evaluating organ transplant rejection status, as it provides detailed insights into rejection signatures at the cellular level. Nevertheless, the traditional histochemical staining process is time-consuming, costly, and labor-intensive since transplant biopsy evaluations typically necessitate multiple stains. Furthermore, once these tissue slides are stained, they cannot be reused for other ancillary tests. More importantly, suboptimal handling of very small tissue fragments from transplant biopsies may impede their effective histochemical staining, and color variations across different laboratories or batches can hinder efficient histological analysis by pathologists. Methods: To mitigate these challenges, we developed a panel of virtual staining neural networks for lung and heart transplant biopsies, which digitally convert autofluorescence microscopic images of label-free tissue sections into their bright-field histologically stained counterparts—bypassing the traditional histochemical staining process. Specifically, we virtually generated hematoxylin and eosin (H&E), Masson’s Trichrome (MT), and elastic Verhoeff-Van Gieson stains for label-free transplant lung tissue, along with H&E and MT stains for label-free transplant heart tissue. Results: Blind evaluations conducted by 3 board-certified pathologists confirmed that the virtual staining networks consistently produce high-quality histology images with high color uniformity, closely resembling their well-stained histochemical counterparts across various tissue features. The use of virtually stained images for the evaluation of transplant biopsies achieved comparable diagnostic outcomes to those obtained via traditional histochemical staining, with a concordance rate of 82.4% for lung samples and 91.7% for heart samples. Moreover, virtual staining models create multiple stains from the same autofluorescence input, eliminating structural mismatches observed between adjacent sections stained in the traditional workflow, while also saving tissue, expert time, and staining costs. Conclusion: The presented virtual staining panels provide an effective alternative to conventional histochemical staining for transplant biopsy evaluation. These virtual staining panels have the potential to enhance the clinical diagnostic workflow for organ transplant rejection and improve the performance of downstream automated models for the analysis of transplant biopsies.

Background— Deficiencies of iron-sulfur (Fe-S) clusters, metal complexes that control redox state and mitochondrial metabolism, have been linked to pulmonary hypertension (PH), a deadly vascular disease with poorly defined molecular origins. The BolA Family Member 3 (BOLA3) regulates Fe-S biogenesis, and mutations in BOLA3 result in multiple mitochondrial dysfunction syndrome, a fatal disorder associated with PH. The mechanistic role of BOLA3 in PH remains undefined. Methods— In vitro assessment of BOLA3 regulation and gain and loss of function assays were performed in human pulmonary artery endothelial cells (PAECs) using siRNA and lentiviral vectors expressing the mitochondrial isoform of BOLA3. Polymeric nanoparticle 7C1 was utilized for lung endothelial-specific delivery of BOLA3 siRNA oligonucleotides in mice. Overexpression of pulmonary vascular BOLA3 was performed by orotracheal transgene delivery of adeno-associated virus in mouse models of PH. Results— In cultured hypoxic PAECs as well as lung from human Group 1 and 3 PH patients as well as multiple rodent models of PH, endothelial BOLA3 expression was down-regulated, which involved HIF-2 α -dependent transcriptional repression via HDAC-mediated histone deacetylation. In vitro gain and loss of function studies demonstrated that BOLA3 regulated Fe-S integrity, thus modulating lipoate-containing 2-oxoacid dehydrogenases with consequent control over glycolysis and mitochondrial respiration. In contexts of siRNA knockdown and naturally occurring human genetic mutation, cellular BOLA3 deficiency down-regulated the glycine cleavage system protein H (GCSH), thus bolstering intracellular glycine content. In the setting of these alterations of oxidative metabolism and glycine levels, BOLA3 deficiency increased endothelial proliferation, survival, and vasoconstriction, while decreasing angiogenic potential. In vivo, pharmacologic knockdown of endothelial BOLA3 and targeted overexpression of BOLA3 in mice demonstrated that BOLA3 deficiency promotes histologic and hemodynamic manifestations of PH. Notably, the therapeutic effects of BOLA3 expression were reversed by exogenous glycine supplementation. Conclusions— BOLA3 acts as a crucial lynchpin connecting Fe-S-dependent oxidative respiration and glycine homeostasis with endothelial metabolic re-programming critical to PH pathogenesis. These results provide a molecular explanation for the clinical associations linking PH with hyperglycinemic syndromes and mitochondrial disorders. These findings also identify novel metabolic targets, including those involved in epigenetics, iron-sulfur biogenesis, and glycine biology, for diagnostic and therapeutic development. provide crucial support for the of central dysregulation of Fe-S integrity a biogenesis

This chapter considers the clinicopathologic features of pseudoneoplastic pulmonary and pleural lesions. They include lesions such as pulmonary hamartoma, inflammatory pseudotumor, plasma cell granuloma, Rosai-Dorfman disease, extramedullary hematopoiesis, tumefactive manifestations of lung injury, peribronchiolar metaplasia, mesothelial hyperplasia, hyaline pleural plaques, and diffuse pleural fibrosis. Because these conditions represent a broad and disparate spectrum in terms of etiology and pathogenesis, they are grouped here by their dominant proposed histogenesis. The specialized morphologic features of these lesions are discussed, with emphasis on differential diagnosis with other pathologic entities.

Abstract Immunotherapy has emerged as a breakthrough in the improvement of survival outcomes for lung adenocarcinoma (LUAD), however effective response requires the combination of blocking inhibitory signals on the tumor surface and antigen presentation to the tumor surface for proper immune recognition. Several commercially available and robust methods exist for identification of tumors displaying immune-inhibitory surface receptors, such as PD-L1, however it is currently difficult to predict effectiveness of antigen presentation on the cell surface. To address this, we utilized clinical and next-generation sequencing data from The Cancer Genome Atlas (TCGA) to identify gene signatures that are correlated to tumor mutational burden (TMB) within cancers of epithelial origins as a surrogate for neoantigen signatures. We identified LINC00261 as a top gene correlated to TMB, whose expression activates DNA damage response pathways in vitro along with resistance to cisplatin. LINC00261 expression was also significantly correlated to MHC class I and II genes involved in endogenous neoantigen presentation expression within the TCGA-LUAD cohort. This relationship was confirmed in vitro through ectopic reintroduction of LINC00261 for key MHC class II presentation genes. Interferon gamma-induced MHC gene activation in vitro was also able to induce endogenous expression of LINC00261. The staining of primary human lung cancer sections suggested that loss of LINC00261 is associated with an immunosuppressive tumor microenvironment. Taken together, our results suggest there is a mechanistic relationship in the silencing of LINC00261 in LUAD and compromised DNA repair, accumulation of mutations, and reduced antitumor immune response. Citation Format: Jonathan Castillo, Tianchun Xue, Mayela Norwood, Samantha Joseph, Alan L. Epstein, W. Dean Wallace, Anthony W. Kim, Crystal N. Marconett. LINC00261 is functionally linked to tumor DNA mutational burden and tumor immune microenvironment composition in lung adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A016.

BACKGROUND AND OBJECTIVES:Neurological manifestations may occur in more than 80% of patients hospitalized with COVID-19 infection, including severe disruptions of the central nervous system (CNS), such as strokes, encephalitis, or seizures. Although the primary pathophysiological mechanism for the effects of COVID-19 in CNS remains unknown, evidence exists for both direct injury from neuroinvasion and indirect effects from disruptions in systemic inflammatory and coagulation pathways. In this study, we analyzed CNS tissue from living patients to better understand these processes.METHODS:With institutional review board approval and patient consent, samples that would be otherwise discarded from patients with active or recent (within 6 days of surgery) COVID-19 infection undergoing neurosurgical intervention were collected and tested for the presence of SARS-CoV-2 using immunohistochemistry, in situ hybridization, electron microscopy, and reverse transcription polymerase chain reaction.RESULTS:Five patients with perioperative mild-to-moderate COVID-19 infection met inclusion criteria (2 male, 3 female; mean age 38.8 ± 13.5 years). Neurosurgical diagnoses included a glioblastoma, a ruptured arteriovenous malformation, a ruptured posterior inferior cerebellar artery aneurysm, a middle cerebral artery occlusion, and a hemorrhagic pontine cavernous malformation. Samples analyzed included the frontal lobe cortex, olfactory nerve, arteriovenous malformation/temporal lobe parenchyma, middle cerebral artery, cerebellum, and cavernous malformation/brainstem parenchyma. Testing for the presence of SARS-CoV-2 was negative in all samples.CONCLUSION:The CNS is likely not a significant viral reservoir during mild-to-moderate COVID-19 infection, although direct neuroinvasion is not definitively excluded. Additional testing to help elucidate the relative contributions of direct and indirect pathways for CNS injury from COVID is warranted.

Abstract Immunotherapy has emerged as a breakthrough in the improvement of survival outcomes for lung adenocarcinoma (LUAD), however effective response requires the combination of blocking inhibitory signals on the tumor surface and antigen presentation to the tumor surface for proper immune recognition. Several commercially available and robust methods exist for identification of tumors displaying immune-inhibitory surface receptors, such as PD-L1, however it is currently difficult to predict effectiveness of antigen presentation on the cell surface. To address this, we utilized clinical and next-generation sequencing data from The Cancer Genome Atlas (TCGA) to identify gene signatures that are correlated to tumor mutational burden (TMB) within cancers of epithelial origins as a surrogate for neoantigen signatures. We identified LINC00261 as a top gene correlated to TMB, whose expression activates DNA damage response pathways in vitro along with resistance to cisplatin. LINC00261 expression was also significantly correlated to MHC class I and II genes involved in endogenous neoantigen presentation expression within the TCGA-LUAD cohort. This relationship was confirmed in vitro through ectopic reintroduction of LINC00261 for key MHC class II presentation genes. Interferon gamma-induced MHC gene activation in vitro was also able to induce endogenous expression of LINC00261. Staining of primary human lung cancer sections suggested that loss of LINC00261 is associated with an immunosuppressive tumor microenvironment. Taken together, our results suggest there is a mechanistic relationship in the silencing of LINC00261 in LUAD and compromised DNA repair, accumulation of mutations, and reduced antitumor immune response. Citation Format: Jonathan Castillo, Tianchun Xue, Mayela Norwood, Samantha Joseph, Alan L. Epstein, William D. Wallace, Anthony W. Kim, Crystal N. Marconett. LINC00261 is functionally linked to tumor DNA mutational burden and tumor immune microenvironment composition in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 180.

The distinction between separate primary lung carcinomas (SPLCs) and intrapulmonary metastases (IPMs) is crucial to accurate cancer staging. Histopathology‐based classification cannot always determine the relatedness of multiple tumors taken from the lung. Recently, next‐generation sequencing (NGS) has been used for biomarker determination, but it also has the potential to inform clonality determination among multiple tumors. Here we present a patient with three lung tumors, each diagnosed as adenocarcinoma by histopathology with a differential diagnosis of SPLC versus IPM. We pursued molecular profiling by NGS, which revealed three unique mutational patterns ruling out the possibility of clonal relatedness among the cancers. Our case supports the utility of NGS in supplementing histopathological methods to distinguish between SPLCs and IPMs and to guide treatment decisions.

Abstract Lung cancer remains the leading cause of cancer-related mortality globally and continues to contribute significantly to cancer health disparities. Black/African American (B/AA) men exhibit a higher risk of lung cancer compared to White men; B/AA individuals also exhibit lower 5-year survival and stage-specific survival rates than White subjects. Biological factors, including genetic differences in cancer driver mutation, may influence this disparity. Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer across all ethnic groups, including B/AA individuals. Our study aims to characterize the main driver and co-mutation signatures of LUAD in B/AA individuals, who are significantly underrepresented in current mutational studies. We hypothesize that B/AA individuals will have a unique repertoire of cancer driver genes, which could contribute to genetic differences and response to targeted therapies compared to LUAD of White subjects. We are obtaining 100 de-identified archival formalin-fixed, paraffin-embedded (FFPE) LUAD samples from B/AA subjects from cancer registries in Florida and California. Extraction of DNA from the FFPE samples is in progress, and samples have been sent for whole exome sequencing (WES) and ancestry determination. This data will then be analyzed and compared with known LUAD mutation profiles from other ethnicities. Identification of cancer driver mutations will then inform the development of in vitro models for therapeutic testing. To date, the limited information on cancer driver genes in LUAD from B/AA subjects suggests that KRAS is the most common cancer driver gene, just like in LUAD from White subjects, and is found in ∼34% of cases. Therefore, we anticipate identifying KRAS mutations similar to this proportion based on the collection of previously published literature analyses. One key goal of this study is to obtain more information about the exact spectrum of KRAS mutations in LUAD from B/AA subjects. In addition, our work may unveil new variants of known cancer driver mutations such as KRAS, EGFR, BRAF, etc., and finally, “new” driver genes. Our efforts will address critical gaps in the understanding of lung cancer driver genes, a key step to developing personalized treatment of lung cancer and mitigating cancer health disparities between B/AA and White individuals. Supported by grants U54CA233396, U54CA233444, and U54CA233465 from the National Institutes of Health (NIH)/National Cancer Institute (NCI), the Norris Comprehensive Cancer Center core grant, award number P30CA014089 from the NIH/NCI, and by the Undergraduate Research Associates Program supported by the USC Provost. Citation Format: Davin Pan, Daniel J. Mullen, Colton Stensrud, Jose Aparicio, Christina M. Gobin, Sofia Lugo, Kweku Ofosu-Asante, Justin K. Mensah-Mamfo, Kyle R Phillips, Yong Huang, Nazarius S. Lamango, William D Wallace, Suhn K Rhie, Kristinanna M. Fredenburg, Ite A. Offringa. Identifying cancer driver mutation signatures in lung adenocarcinoma from Black/African American individuals: Addressing cancer health disparities [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C171.

Solid carcinomas are often highly heterogenous cancers, arising from multiple epithelial cells of origin. Yet, how the cell of origin influences the response of the tumor microenvironment is poorly understood. Lung adenocarcinoma (LUAD) arises in the distal alveolar epithelium which is populated primarily by alveolar epithelial type I (AT1) and type II (AT2) cells. It has been previously reported that Gramd2+ AT1 cells can give rise to a histologically-defined LUAD that is distinct in pathology and transcriptomic identity from that arising from Sftpc+ AT2 cells1,2. To determine how cells of origin influence the tumor immune microenvironment (TIME) landscape, we comprehensively characterized transcriptomic, molecular, and cellular states within the TIME of Gramd2+ AT1 and Sftpc+ AT2-derived LUAD using KRASG12D oncogenic driver mouse models. Myeloid cells within the Gramd2+ AT1-derived LUAD TIME were increased, specifically, immunoreactive monocytes and tumor associated macrophages (TAMs). In contrast, the Sftpc+ AT2 LUAD TIME was enriched for Arginase-1+ myeloid derived suppressor cells (MDSC) and TAMs expressing profiles suggestive of immunosuppressive function. Validation of immune infiltration was performed using flow cytometry, and intercellular interaction analysis between the cells of origin and major myeloid cell populations indicated that cell-type specific markers SFTPD in AT2 cells and CAV1 in AT1 cells mediated unique interactions with myeloid cells of the differential immunosuppressive states within each cell of origin mouse model. Taken together, Gramd2+ AT1-derived LUAD presents with an anti-tumor, immunoreactive TIME, while the TIME of Sftpc+ AT2-derived LUAD has hallmarks of immunosuppression. This study suggests that LUAD cell of origin influences the composition and suppression status of the TIME landscape and may hold critical implications for patient response to immunotherapy.

ABSTRACTLung adenocarcinoma (LUAD) is the most common subtype of cancer arising in the distal lung. LUAD encompasses several pathologic subtypes, each with differing clinical outcomes and biological behaviors. However, the molecular and cellular underpinnings of the different subtypes are largely unknown. Understanding which cell populations in the distal lung contribute to LUAD could provide insights into the marked heterogeneity in pathologic features, clinical presentation and responses to therapy of LUAD. Differential expression analysis of lung adenocarcinoma transcriptomes from The Cancer Genome Atlas revealed distinct alveolar epithelial type 1 (AT1) and alveolar epithelial type 2 (AT2) cell signatures within human LUAD with significantly different survival outcomes between tumors expressing AT2 and AT1 gene signatures, suggesting AT1 cells might contribute to a subset of LUAD cases. To address this, we tested the ability of AT1 cells to give rise to LUAD following induction of KrasG12D, a known oncogenic driver of human LUAD. Activation of KrasG12Din Gram-domain containing 2 (Gramd2)+AT1 cells gave rise to multiple LUAD lesions, primarily of papillary histology. In contrast, activation of KrasG12Din surfactant protein C (Sftpc+) AT2 cells resulted in LUAD lesions of lepidic histology. Immunohistochemistry established thatGramd2:KrasG12Dlesions were of primary lung origin and not metastatic events. Spatial transcriptomic profiling revealed distinct pathway alterations within Gramd2- and Sftpc-derived LUAD. Immunofluorescence confirmed differences observed in the spatial transcriptomic analysis in expression patterns and distribution of cell-specific markers depending on cell of origin, while universal upregulation of the Krt8 intermediate cell state marker was observed. Our results are consistent with Gramd2+AT1 cells serving as a putative cell of origin for LUAD and suggest that LUAD may be a collection of adenocarcinomas that share a common location within the distal lung but arise from different cells of origin.

XLSX file - 343KB, Genes associated with SCC carcinogenesis.

Lung adenocarcinoma (LUAD) is the most prevalent subtype of lung cancer and presents clinically with a high degree of biological heterogeneity and distinct clinical outcomes. The current paradigm of LUAD etiology posits alveolar epithelial type II (AT2) cells as the primary cell of origin, while the role of AT1 cells in LUAD oncogenesis remains unknown. Here, we examine oncogenic transformation in mouse Gram-domain containing 2 (Gramd2)+ AT1 cells via oncogenic KRASG12D. Activation of KRASG12D in AT1 cells induces multifocal LUAD, primarily of papillary histology. Furthermore, KRT8+ intermediate cell states were observed in both AT2- and AT1-derived LUAD, but SCGB3A2+, another intermediate cell marker, was primarily associated with AT1 cells, suggesting different mechanisms of tumor evolution. Collectively, our study reveals that Gramd2+ AT1 cells can serve as a cell of origin for LUAD and suggests that distinct subtypes of LUAD based on cell of origin be considered in the development of therapeutics.

XLS file - 32KB, MYC activity prediction and its target genes.

XLS file - 35KB, TP53 activity prediction and its target genes.

Collision tumors are a rare entity in which 2 distinct neoplastic cellular populations invade each other and coalesce to form a single focal lesion. This case report describes a pulmonary collision tumor emerging from the rapid progression of 2 large-cell carcinoma lesions of the lung, including 1 nodule with clear cell features and another with basaloid features. The collision of these 2 histologically rare nodules resulted in the biologic downstaging of disease. This report provides unique insights into the biology of pulmonary collision tumors and its implications for diagnostic staging and therapeutic management.