Friday, May 9, 2025
5/9/2025
Metabolic control of malignant fates in lung cancer - PROJECT SUMMARY Lung adenocarcinoma (LUAD) is a significant public health burden in the United States, causing an estimated 55,000 deaths annually. Despite advances in immunotherapies, chemotherapies, and oncoprotein-targeted therapies, most patients ultimately relapse and cures remain elusive. Within a tumor, LUAD cancer cells adopt a spectrum of cell states endowed with variable potential for malignant progression and treatment resistance. Whether these different cell states have different metabolic preferences, and whether targeting these preferences can eliminate specific cell states, remains poorly understood. Using cell lines derived from mouse and human LUAD tumors, we discovered that a central metabolic pathway, the tricarboxylic acid (TCA) cycle, adopts a non-canonical configuration in de-differentiated LUAD states. Manipulating non-canonical or canonical TCA cycle configurations induced differentiation or de-differentiation, respectively. Our findings raise the possibility that metabolic remodeling is required for the emergence and maintenance of cell states that drive LUAD progression and treatment resistance. The goal of the proposed work is to determine how specific TCA configurations support malignant LUAD states. We hypothesize that differentiated LUAD cell states require the canonical TCA cycle whereas de-differentiated LUAD states require the non- canonical TCA cycle. To test this hypothesis, we will manipulate components of each TCA cycle in autochthonous mouse models and human patient-derived xenograft models and monitor tumor burden, progression, and emergence of specific cell states (Aim 1); determine the TCA cycle outputs that support malignant states (Aim 2), and assess the impact of TCA cycle manipulation on resistance to targeted therapy and chemotherapies (Aim 3). The proposed experiments will reveal how central metabolic networks contribute to LUAD heterogeneity and identify pathways that can be targeted to eliminate treatment-resistant cells and improve LUAD therapy.
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