Friday, May 9, 2025
5/9/2025
Imaging mitochondrial heterogeneity in LKB1 mutant lung cancer - Abstract (30 line): The overarching goal of this R01 renewal is to advance our understanding of the impact that LKB1 inactivation has on mitochondrial bioenergetics, metabolism and therapy response in lung cancer. To accomplish this we will perform a structural and functional study of mitochondrial heterogeneity following LKB1 inactivation in lung adenocarcinomas (LUADs). Inactivating mutations of the LKB1 tumor suppressor gene frequently occur in LUADs. LKB1 functions as a master kinase that regulates cellular energetics and mitochondrial function through activation of adenosine monophosphate activated kinase (AMPK). As such, LKB1 mutations (LKB1-/-) result in severe defects in the cellular energetics and mitochondrial homeostasis of lung tumors, characterized by atypical mitochondria of varying size, morphology, and function. However, there remains a gap in our knowledge at a physiological and mechanistic level of how LKB1 inactivation disregulates mitochondrial structure and function in LUAD. To address this gap, we functionally imaged mitochondrial activity in LUADs utilizing the positron emission tomography (PET) imaging tracer 4-[18F]fluorobenzyl-triphenylphosphonium (18FBnTP) and found that 18FBnTP is an in vivo biomarker of mitochondrial bioenergetics. Expanding upon this, we performed 3-dimensional scanning blockface electron microscopy (3D SBEM) on lung tumors to map mitochondrial structure in vivo. As a direct result of our analysis of mitochondrial networks within LKB1+/+ and LKB1-/- mouse models of lung cancer we discovered the existence of distinct mitochondrial subpopulations. Each mitochondrial subpopulation carries with it a unique set of bioenergetic activities and sensitivities to apoptosis. Importantly, loss of LKB1 directly alters the structural landscape of mitochondrial subpopulations thus altering the functional, metabolic landscape of the tumor. We hypothesize that LKB1 loss induces remodeling and spatial reorganization of mitochondria subpopulations in lung tumors leading to disregulation of OXPHOS and cell survival pathways. To test this hypothesis we will utilize PET imaging in combination with 3- dimensional scanning blockface electron microscopy (3D SBEM) and respirometry to study mitochondrial heterogeneity LKB1 mutant LUADs. In Aim 1 we will investigate the mTORC1-Drp1 axis as a regulator of mitochondrial fission and cristae remodeling following inactivation of LKB1 in lung tumors. In Aim 2 we will investigate the LKB1/AMPK pathway as a novel regulator of peridroplet mitochondria and fatty acid oxidation in lung cancer. In Aim 3 we will test novel PTPMT1 inhibitors as chemosensitizing agents to overcome therapy resistant LKB1 mutant LUADs. The proposed studies hold promise to advance our fundamental understanding of mitochondrial biology and the impact that mitochondrial heterogeneity has on promoting lung tumorigenesis. The proposed work has relevance to human health in the areas of imaging based diagnosis and the development of new therapies to improve the treatment and outcomes of lung cancer patients.
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