Unknown,Transcriptomics,Genomics,Proteomics

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MiR-203, a microRNA of multilayered epithelia, inhibits metastatic fitness in human squamous cell carcinoma

ABSTRACT: The colonization of distant organs by metastatic carcinoma cells underpins most human cancer-related deaths, including those from head and neck squamous cell carcinoma (HNSCC). We report that miR-203, a miRNA that promotes keratinocyte differentiation, is necessary and sufficient to inhibit multiple post-extravasation events during HNSCC lung metastasis, including initial survival/engraftment, escape from metastatic dormancy, and overt colonization in vivo. Restoration of miR-203 expression in established lung metastases reduces overall metastatic burden. Instead of promoting differentiation, miR-203 controls lung metastasis through direct targeting of genes involved in cytoskeletal dynamics (LASP1), ECM remodeling (SPARC), and cell metabolism (NUAK1). Expression of miR-203 and its downstream targets correlates with HNSCC overall survival outcomes, suggesting the therapeutic potential of targeting this signaling axis. Total RNA (including small RNAs) was isolated from cultured cells stably infected in biological duplicate with either a scrambled control hairpin or miR-203. Samples were harvested in technical duplicate.

ORGANISM(S): Homo sapiens

SUBMITTER: Nathan Benaich

PROVIDER: E-GEOD-47028 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Project 1: The deregulation of the actin cytoskeleton has been extensively studied in metastatic dissemination. However, the post-dissemination role of the actin cytoskeleton dysregulation is poorly understood. Here we report that fascin, an actin-bundling protein, promotes lung cancer metastatic colonization by augmenting metabolic stress resistance and mitochondrial OXPHOS. Fascin is directly recruited to mitochondria under metabolic stress to stabilize mitochondrial actin filaments (mtF-actin). Using unbiased metabolomics and proteomics approaches, we discovered that fascin-mediated mtF-actin remodeling promotes mitochondrial OXPHOS by increasing the biogenesis of respiratory Complex I. Mechanistically, fascin and mtF-actin controls the homeostasis of mtDNA to promote mitochondrial OXPHOS. The disruption of mtFactin abrogates fascin-mediated lung cancer metastasis. Conversely, restoration of mitochondrial respiration using yeast NDI1 in fascin depleted cancer cells is able to rescue lung metastasis. Our findings indicate that the dysregulated actin cytoskeleton in metastatic lung cancer could be targeted to rewire mitochondrial metabolism and to prevent metastatic recurrence. Project 2: There is a pool of mitochondrial dNTP in the cell maintained by the mitochondrial deoxynucleoside salvage pathway and dedicated for the mtDNA homeostasis in slow-cycling and post-mitotic cells. The role of the mitochondrial deoxynucleoside salvage pathway in tumor initiation and progression is poorly understood. Here, we investigated the role of the mitochondrial deoxyguanosine kinase (DGUOK), a rate-limiting enzyme in the mitochondrial deoxynucleoside salvage pathway, in the self-renewal of lung adenocarcinoma cancer stem-like cells (CSC). Our data support that DGUOK overexpression strongly correlates with cancer progression and patient survival. The depletion of DGUOK robustly inhibited lung adenocarcinoma tumor growth, metastasis and CSC self-renewal. Mechanistically, DGUOK is required for the biogenesis of respiratory Complex I and mitochondrial OXPHOS, which in turn regulates CSC self-renewal through AMPK-YAP1 signaling. The restoration of mitochondrial OXPHOS in DGUOK depleted lung cancer cells using NDI1, a single subunit yeast NADH : ubiquinone oxidoreductase, was able to rescue AMPK-YAP1 signaling and CSC stemness. Genetic targeting of DGUOK using doxycycline-inducible CRISPR/Cas9 was able to markedly induce tumor regression. Our findings reveal a novel role for mitochondrial dNTP metabolism in lung cancer tumor growth and progression, and implicate that the mitochondrial deoxynucleotide salvage pathway could be potentially targeted to prevent CSC-mediated therapy resistance and metastatic recurrence.

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MiR-203, a microRNA of multilayered epithelia, inhibits metastatic fitness in human squamous cell carcinoma

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