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Tackling Stem-Like Cells in Tobacco Smoke-Mediated Cancer Ma

Institution: University of California, Davis
Investigator(s): Ching-Hsien Chen,
Award Cycle: 2018 (Cycle 27) Grant #: 27KT-0004 Award: $750,000
Subject Area: Cancer
Award Type: New Investigator Awards

Initial Award Abstract

Lung cancer remains the leading cause of cancer mortality worldwide and approximately 85% of lung cancers result from smoking. Exposure to tobacco smoke has recently been reported to increase the proportion of cancer stem-like cells (CSCs) in certain cancers. CSCs, also known as tumor-initiating cells, refer to a side population of cancer cells that can drive cancer malignancy, resistance to chemotherapy and relapse after treatment. Targeting the CSCs subpopulation directly among a mixed cancer population by identifying specific markers and signaling pathways has been considered as a promising strategy for lung cancer treatment. However, how tobacco-smoke induces the acquisition of stem cell-like properties in lung cancer remains poorly understood. In particular, the mechanism underlying cancer stemness is not completely understood, which limits identification of biomarkers and therapeutic targets. Through integration and analysis of multi-omics data, we have identified the membrane-associated protein, myristoylated alanine-rich C kinase substrates (MARCKS), as a putative smoke-responsive molecule involved in cancer stemness signatures. Previously, we identified up-regulation of phospho-MARCKS as a novel predictor of lung cancer malignancy but the link between MARCKS activation and lung cancer stemness has not been established. Our preliminary data have shown that smoke-enhanced phospho-MARCKS promotes malignant progression of lung cancer cells. Surprisingly, downregulation of phospho-MARCKS in smoke-mediated lung cancer spheres acts in parallel with decreased stemness genes. Given these observations, we hypothesize that smoke-triggered elevation of phospho-MARCKS may participate in maintenance of cancer stemness and/or survival of CSCs, contributing to lung cancer malignancy. To study this hypothesis, three Specific Aims are proposed.  Aim 1 is to determine whether MARCKS is dysregulated in smoke-related CSCs and lung cancer patients. Aim 2 is to characterize the functional roles of MARCKS in smoke-mediated cancer stemness. Aim 3 is to elucidate the molecular basis of MARCKS in the maintenance of cancer stem-like properties. Achievement of these specific aims will characterize novel molecular mechanisms underlying smoke-mediated malignant progression, thereby providing novel therapeutic targets such as phospho-MARCKS for combating cancer stemness.