SACM - United States of America
Permanent URI for this collectionhttps://drepo.sdl.edu.sa/handle/20.500.14154/9668
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Item Restricted Field Cancerization and Microbiome Effects on Lung Cancer: A Source of Early Detection Biomarkers to Improve Patients’ Outcome(George Mason University, 2024-08-16) Alhammad, Rayan; Luchini, AlessandraLung cancer results in more deaths than any other cancer in the United States and worldwide, with non-small cell lung cancer (NSCLC) accounting for most cases. Diagnosis typically involves chest imaging, molecular testing, and biopsy. However, most patients are diagnosed at advanced stages, with only a 6% chance of a 5-year survival rate. In contrast, early-stage diagnosis and treatment can result in a favorable prognosis, with a high 5-year survival rate of 70-90%. The concept of tumor field cancerization describes a phenomenon where exposure to carcinogens can cause histologic changes in large areas of tissue, creating a field of pre-malignant cells that can eventually develop into tumors. Additionally, microbiota dysbiosis might influence tumor development. Studies have identified several commensal bacteria present in the lower airway tracts, such as Streptococcus, Prevotella, and Veillonella. The high mortality rate of lung cancer is often attributed to i) its late-stage diagnosis, ii) aggressive nature given its ability to metastasize early in the disease process complicating treatment and reducing survival rates, and iii) significant therapeutic challenges despite current treatments such as surgery, chemotherapy, radiation therapy, targeted therapy and immunotherapy. Despite advancements, the survival rate for advanced lung cancer remains low. To address this challenge, our research focuses on identifying risk protein biomarkers that are associated with the earliest molecular changes indicative of an ongoing tumorigenic process, thus offering significant potential for early intervention. Our study investigates the phenotypic molecular changes in the bronchial tree of NSCLC patients in light of the field cancerization theory and correlates these findings with blood biomarkers to support the future development of a non-invasive risk assessment test. Using enhanced liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomic analysis and two independent cohorts of lung cancer patients (N=18, and N=263) with matched plasma and bronchial tree tissue specimens, we identified a set of 6 and 13 candidate risk plasma biomarkers with tissue origin. Additionally, we explored the microbiome proteome composition in NSCLC patient tissue and plasma to support future characterization of its potential role in cancer development. Risk biomarkers will enable the evaluation of individuals at high risk, guiding necessary lifestyle adjustments and facilitating the development of personalized prevention plans and therapies.52 0Item Restricted Dissecting the Role of Enhancer of Zeste Homolog 2 (EZH2) in Neuroendocrine Transdifferentiation (NE-TD) in Non-Small Cell Lung Cancer (NSCLC) of Epithelial Origin.(Geogre Mason University, 2024-08-12) Alsubaie, Abduljalil Mohammed M; Pierobon, MariaelenaLung cancer Lung cancer is a highly prevalent and lethal disease that is responsible for a significant number of cancer-related deaths worldwide. The introduction of targeted treatments in lung cancer, like EGFR inhibitors and immunotherapies, has profoundly affected survival of NSCLC patients. Even so, the therapeutic effects of these compounds are often temporary, and resistance is regularly acquired by tumor cells to adapt to unfavorable and harmful conditions. Lineage plasticity, or the ability of cancer cells to change their physical characteristics and functions, and histological shift is emerging as important defense mechanism tumors utilize to survive treatment. For example, in response to treatment, Non-Small Cell Lung Cancers (NSCLCs) can acquire neuroendocrine (NE) characteristics and transform into Small Cell Lung Cancers (SCLCs). Conventional chemotherapy can achieve short-term response in these transformed tumors, but this mechanism of resistance remains largely untreatable and results in high levels of mortality. That is why identifying molecular drivers of NE transdifferentiation (TD) is of primary importance for devising effective therapeutic interventions and reducing lung cancer associated mortality. Overexpression of the epigenetic regulator histone-lysine N-methyltransferase Enhancer of Zeste Homolog (EZH2) has been associated with the development of SCLCs and NE-TD in prostate cancer, however, EZH2 functions has not been explored in NE transdifferentiated NSCLCs. In this study, we demonstrated that overexpression of EZH2 is associated with the acquisition of NE traits in NSCLCs and other cancers of epithelial origine. We have also demonstrated that inhibition of EZH2 in NE-TD NSCLCs reverses cancer cells to a non-NE state. Lastly, we showed that EZH2 inhibition in RB proficient tumors expressing NE markers reinstates Rb function and sensitivity to CDK4/6 inhibition. Our data provide novel understanding on the role of EZH2 in NE-TD of NSCLCs. If validated in more complex model systems, these data may provide a foundation for future clinical investigations specifically targeting patients affected by tumors for which effective therapeutic options are limited.28 0