Wednesday, April 2, 2025
4/2/2025
Deciphering the Role of Mycobiome (Fungus) in Lung Carcinogenesis - The role of 'polymorphic microbes' in cancer development and progression has been extensively studied, but research on the role of fungi (mycobiomes) is surprisingly limited. To address this gap, we have developed an innovative 3D-organotypic lung (iLung) model derived from human pluripotent stem cells (hPSCs). This model in combination with live spore-based exposure/infection methods, allows for the study of direct contact between epithelial cells and pathogens in the culture media, providing more accurate representation of real-life exposure, infection, and intratumoral colonization. Using this model, the team has demonstrated extensive DNA damage and identified specific DNA breakage motifs and mutational signatures in lung cells infected with spores of Aspergillus fumigatus (Asp), a common fungal pathogen found in human airways and lung cancer samples. Notably, significant mutations were observed in important cancer genes, and lung cancer lines treated with Asp showed more advanced and aggressive tumor phenotypes. The team also noticed increased levels of IL-33 and other type 2 cytokines, IL-4, IL-5 and IL-13, known regulators of Th2-type immune responses, in treated cells. These preliminary studies led to the hypothesis that mycobiomes can promote malignancy either directly, by inducing mutations, or indirectly, by reshaping host immune responses. The team proposes to test this hypothesis using the hPSC-derived iLung system, live spore- based infection models, and advanced technologies such as identification of mutational signature, single-cell transcriptomics, and molecular modeling using quantum mechanics calculation. The research project is centered on three aims. The first aim is to establish the carcinogenic effect of fungi on lung cancer, particularly focusing on Asp and other common fungal species (e.g. Alternaria) in lung cancer. The second aim is to understand the mechanism of fungal mutagenesis, examining both direct and indirect routes, such as the role of mycotoxins and the increase of reactive oxygen species (ROS). The third aim is to determine the effect of fungus-induced remodeling of host immunity in lung cancer. The research's expected outcome is to illuminate the mechanisms by which fungi contribute to cancer development and progression. This could pave the way for the development of novel diagnostic, preventive, and therapeutic strategies against cancer influenced by mycobiomes.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).