Lung cancer is one of the most aggressive cancers and the leading cause of cancer mortality in the US, mainly due to the lack of early detection. Meanwhile, gene expression profiling can identify molecular responses to carcinogen exposure and tumorigenesis. We have previously identified lung cancer-associated gene expression alterations in the normal bronchial airway epithelium of ever smokers with and without lung cancer. These alterations are the basis of a diagnostic test that is useful in clinical decision-making in patients with suspect lung cancer. Despite this success, further improvements in early lung cancer diagnosis are needed, along with a better understanding of airway biology during the initiation and development of lung cancer. Towards these goals, for the first aim of my thesis, I explored whether normal-appearing bronchial airway gene expression reflects lung cancer histologic subtypes. Genes differentially expressed in the bronchial airway between patients with lung squamous cell carcinoma and lung adenocarcinoma were identified and confirmed in independent data. Using a method developed based on independent component analysis (ICA), cell type-specific gene modules were derived from airway single-cell RNA-sequencing data and shown to be altered between lung cancer subtypes. Secondly, I sought to investigate whether integrating the bronchial airway molecular biomarker with radiomic features (i.e., quantitative features derived from radiographic images) could yield a better diagnosis for lung cancer screening. Using clinical variables, molecular signatures, and radiomic imaging features, I built and tested an integrated biomarker to improve discrimination between malignant and benign Indeterminate Pulmonary Nodules (IPNs). Finally, as COVID-19 became a pandemic during my thesis work, I sought to utilize large-scale genomic data from multiple cohorts to investigate possible clinical risk factors related to SARS-CoV-2 entry and disease severity. My analysis showed that smoking affects the expression of host genes involved in SARS-CoV-2 entry differently in the nasal and bronchial airways. The work has implications about how smoking might modulate SARS-CoV-2 infection and COVID-19 disease severity. Collectively, this work leverages computational approaches to identify airway biology associated with lung cancer subtypes, improve the diagnosis of lung cancer in patients with IPNs, and reveal relationship between smoking and SARS-CoV-2 infection. / 2024-02-18T00:00:00Z

Lung cancer is the leading cause of cancer-related death worldwide. Exclusively found in citrus peels, the inhibitory effects of polymethoxyflavones (PMFs) on 3 human non-small cell lung cancer cells have been investigated. Results showed that monodemethylated PMFs at 5-position potently inhibited lung cancer cells than those of their permethoxylated counterparts. The inhibition of cancer cells caused by monodemethylated PMFs was associated with both extensive cell cycle arrest and apoptosis as a result of modulation of key oncogenic signaling proteins. Treatment with different bioactive compounds in combination may enhance inhibitory effects on lung cancer due to their synergistic interaction among these agents. Results showed that both nobiletin/atorvastatin (NBT/ATST) and tangeretin/atorvastatin (TAN/ATST) co-treatments at low doses exerted strong synergy as confirmed by isobologram analysis, and also produced much stronger inhibitory effects on lung cancer cells in comparison to those produced by NBT, TAN, or ATST alone at higher doses. Flow cytometry analysis showed both NBT/ATST and TAN/ATST co-treatments significantly induced cell cycle arrest and apoptosis, and these molecular events were involved with prenylation of RhoA which subsequently resulted in alteration of key signaling proteins. Supplementation of mevalonate or geranylgeranyl pyrophosphate significantly counteracted the effects caused by NBT/ATST. Inhibitory effects of metabolites of PMFs against lung cancer cells were significantly stronger than those produced by their parental compounds. Treatments of PMFs significantly inhibited lung tumorsphere formation and aldehyde dehydrogenase bright cells implicating the potential utilization of these compounds to target lung cancer stem cells.

Purpose: The relationship between racial disparities and the health-related quality of life (HRQoL) of lung cancer patients is not well understood. The purpose of this study was to quantify the overall HRQoL of lung cancer patients and compare differences in HRQoL among racial groups in the United States. Methods: We analyzed data from the Behavioral Risk Factors Surveillance System (BRFSS), a population-based national cross-sectional study conducted by the Centers for Disease Control and Prevention. The BRFSS is conducted annually in all 50 states and collects information on demographics, health behaviors, health-related experiences, health conditions, use of medications, and use of preventive services. Three HRQoL scores (unhealthy days per month, frequent mental distress, fair/poor health) were generated using the four Healthy Days Measures questions that have been validated as HRQoL measures by previous research. Results: We found that the HRQoL measures of the Non-Hispanic Black group were not statistically different from those of the Non-Hispanic White group for any of the three measures examined. However, the Hispanic group (OR = 3.14, 95%CI=1.40 – 7.02) and Other races (OR = 1.85, 95%CI=1.04-3.27) had significantly higher odds of frequent mental distress when compared to the Non-Hispanic White group. Conclusions: Quality of life among lung cancer patients is a heavily under-researched area of the cancer survivorship experience. Rarer, is data examining specifically how racial disparities affect the quality of life of lung cancer survivors. More research is needed to examine this important topic to create a foundation for more beneficial lung cancer interventions in the future.

A high expression of stromal PDGFRβ is known to be a poor prognosis marker in several solid tumor types. However, the role of stromal PDGFRβ for non-small cell lung cancer (NSCLC) patients remains unclear. Therefore, we investigated the activation status of PDGFRβ with proximity ligation assay (PLA) by studying the interaction between the receptor and GRB2, one of PDGFRβs downstream signaling molecules. The main aim is in this study is to investigate the activation status of stromal PDGFRβ in NSCLC tissues and look into its clinical relevance for lung cancer patients. Our data revealed that PDGFRβ activation status did not affect overall survival, and was not associated to smoking, sex, age or stage of cancer. PDGFRβ activation status was higher in the histological subgroup of squamous cell carcinoma-patients compared to the adenocarcinoma subgroup. The PDGFRβ activation status showed a clear correlation to the general expression level of PDGFRβ investigated by immunohistochemistry (IHC). The correlation also showed that a high activation status required a high general expression, indicating a specific pipeline.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24288号 / 医博第4904号 / 新制||医||1061(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 山本 洋介, 教授 中本 裕士, 教授 森田 智視 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Krebs entsteht durch das Zusammenspiel von Keimbahn- und somatischen Mutationen sowie Umweltfaktoren. Für Fortschritte in Prävention, Früherkennung und Behandlung von Krebs ist es essenziell die phänotypischen Folgen dieser Mutationen und die Rolle von Umweltfaktoren bei der Steigerung des Krebsrisikos zu verstehen. In dieser Arbeit untersuche ich zunächst die Auswirkungen von Mutationen in einfachen Sequenzwiederholungsregionen (SSRs) auf das Zellwachstum in einem Hefemodell. In einem Mutationsakkumulationsexperiment in Stämmen mit defektem Mismatch-Reparatursystem zeige ich, dass die Störung von MutSβ zu einer erhöhten SSR-Mutationsrate führt, insbesondere bei SSR-Loci die länger als 8 bp sind. Meine Ergebnisse legen nahe, dass MutSβ hauptsächlich für die Reparatur an längeren Repeat-Loci verantwortlich ist. Schließlich zeige ich, dass SSR-Mutationen meist geringfügige, negative Auswirkungen auf das Zellwachstum haben. Als Nächstes untersuche ich die Auswirkungen von Zigarettenrauch auf das Transkriptom von zugänglichem Atemwegsgewebe am Beispiel des Nasenepithels von gesunden Freiwilligen und Patienten mit Verdacht auf oder diagnostiziertem Lungenkrebs. Ich stelle fest, dass Gene und biologische Funktionen, die durch das Rauchen beeinträchtigt werden, bei Patienten langsamer auf ein gesundes Ausgangsniveau zurückkehren. Zudem zeige ich, dass Patienten durch anhaltende, Rauch-assoziierte Immunveränderungen gekennzeichnet sind. Schließlich präsentiere ich einen innovativen Lungenkrebs-Klassifikator, der durch die Berücksichtigung der nasalen Genexpression von Rauch-assoziierten Genen eindeutig bessere Ergebnisse erzielt als ein Modell, das ausschließlich auf klinischen Informationen basiert. Damit belege ich das Potenzial der Genexpression des Nasenepithels zur Verbesserung der Risikostratifizierung auf Bevölkerungsebene anhand eines nicht-invasiven Tests. / Cancer is initiated and sustained by the interplay of germline and somatic mutations and environmental factors. Understanding the phenotypic consequences of mutations and the role of environmental factors in increasing cancer risk is key to improving cancer prevention, early detection, and treatment. In this thesis, I first take advantage of a yeast model to investigate the effects of mutations in simple sequence repeat regions (SSRs) on cell growth. I describe a mutation accumulation experiment conducted in strains with a deletion of the MutSβ gene, a component of the mismatch repair system (MMR). I show that abrogating MutSβ function leads to an increased SSR mutation rate, with a bias towards deletions. I also report a drastic increase in mutation rate in SSR loci longer that 8-bp, suggesting MutSβ is primarily responsible for repair at longer repeat loci. Finally, I show that many SSR mutations have small deleterious effects on cell growth. Next, I investigate the effects of cigarette smoke on the transcriptome of an accessible airway tissue, nasal epithelium, in a cohort of healthy volunteers and patients with suspected or diagnosed lung cancer. I find that smoke injury response is strikingly different in healthy individuals and clinic patients, with genes and biological functions affected by smoking showing a slower reversal to healthy baseline level in clinic patients. I find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Finally, I show that a lung cancer classifier including nasal expression of smoke-injury-associated genes performs better than a model based exclusively on clinical information, providing evidence for the potential of nasal epithelial gene expression to improve population-level risk stratification with the use of a non-invasive test.

The epidermal growth factor receptor (EGFR)-K745_E746insIPVAIK and others with rare PVAI amino-acid insertions are exon 19 insertion mutations (<1% of all EGFR mutations), which, at the structural modeling level, resemble EGFR tyrosine kinase inhibitor (TKI)-sensitizing mutants. An important unmet clinical need is the characterization of therapeutic windows of rare exon 19 PVAI amino-acid insertions to available EGFR TKIs. A limited number of preclinical and clinical reports have studied the response of these mutants to all classes of approved EGFR TKIs. We used models of EGFR-K745_E746insIPVAIK and more typical EGFR mutations (exon 19 deletion, L858R, L861Q, G719S, A763_Y764insFQEA, other exon 20 insertion mutations) to probe representative 1st (erlotinib), 2nd (afatinib), 3rd generation (osimertinib), and EGFR exon 20 active (mobocertinib) TKIs. We used human lung-cancer derived cell lines and transduced Ba/F3 cells to measure the treatment efficacy. We also compiled outcomes of EGFR exon 19 insertion mutated lung cancers−from our institution plus the literature−treated with EGFR TKIs. Cells driven by EGFR-K745_E746insIPVAIK had sensitivity to all classes of EGFR TKIs when compared to cells driven by EGFR-wild type in proliferation assays and at the protein level. However, the therapeutic window (calculated in preclinical models as the logarithm of the 50% inhibitory concentration of EGFR mutation compared to wild-type EGFR) of EGFR-K745_E746insIPVAIK driven cells was most akin to those of cells driven by EGFR-L861Q, EGFR-G719S and EGFR- A763_Y764insFQEA than the more sensitive patterns seen with cells driven by an EGFR exon 19 deletion or EGFR-L858R. The majority of patients with lung cancers harboring EGFR- K745_E746insIPVAIK and other mutations with rare PVAI amino-acid insertions responded to clinically available EGFR TKIs (including icotinib, gefitinib, erlotinib, afatinib and osimertinib), with heterogeneous periods of progression-free survival. This is the largest preclinical/clinical report to highlight that EGFR- K745_E746insIPVAIK and other mutations with rare exon 19 PVAI amino-acid insertions are sensitive to clinically available TKIs; in a pattern that mostly resembles the outcomes of models with EGFR-L861Q, EGFR-G719S and EGFR-A763_Y764insFQEA mutations. These findings are consistent with the proposed mechanism of activation of mutant EGFR by alteration of the proposed hydrophobic core. These data may help with the off-label selection of EGFR TKIs and clinical expectations of outcomes when targeted therapy is deployed for these rare EGFR mutated lung cancers. / 2026-03-08T00:00:00Z

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