RESUMO
BACKGROUND & AIMS: Metabolic and transcriptional programs respond to extracellular matrix-derived cues in complex environments, such as the tumor microenvironment. Here, we demonstrate how lysyl oxidase (LOX), a known factor in collagen crosslinking, contributes to the development and progression of cholangiocarcinoma (CCA). METHODS: Transcriptomes of 209 human CCA tumors, 143 surrounding tissues, and single-cell data from 30 patients were analyzed. The recombinant protein and a small molecule inhibitor of the LOX activity were used on primary patient-derived CCA cultures to establish the role of LOX in migration, proliferation, colony formation, metabolic fitness, and the LOX interactome. The oncogenic role of LOX was further investigated by RNAscope and in vivo using the AKT/NICD genetically engineered murine CCA model. RESULTS: We traced LOX expression to hepatic stellate cells and specifically hepatic stellate cell-derived inflammatory cancer-associated fibroblasts and found that cancer-associated fibroblast-driven LOX increases oxidative phosphorylation and metabolic fitness of CCA, and regulates mitochondrial function through transcription factor A, mitochondrial. Inhibiting LOX activity in vivo impedes CCA development and progression. Our work highlights that LOX alters tumor microenvironment-directed transcriptional reprogramming of CCA cells by facilitating the expression of the oxidative phosphorylation pathway and by increasing stemness and mobility. CONCLUSIONS: Increased LOX is driven by stromal inflammatory cancer-associated fibroblasts and correlates with diminished survival of patients with CCA. Modulating the LOX activity can serve as a novel tumor microenvironment-directed therapeutic strategy in bile duct pathologies.
Assuntos
Neoplasias dos Ductos Biliares , Fibroblastos Associados a Câncer , Colangiocarcinoma , Células Estreladas do Fígado , Proteína-Lisina 6-Oxidase , Microambiente Tumoral , Humanos , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/enzimologia , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Fibroblastos Associados a Câncer/enzimologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Colangiocarcinoma/patologia , Colangiocarcinoma/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/enzimologia , Regulação Neoplásica da Expressão Gênica , Células Estreladas do Fígado/metabolismo , Células Estreladas do Fígado/patologia , Células Estreladas do Fígado/enzimologia , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/enzimologia , Fosforilação Oxidativa , Proteína-Lisina 6-Oxidase/metabolismo , Proteína-Lisina 6-Oxidase/genética , Transdução de SinaisRESUMO
Desmoplasia is a common feature of aggressive cancers, driven by a complex interplay of protein production and degradation. Basigin is a type 1 integral membrane receptor secreted in exosomes or released by ectodomain shedding from the cell surface. Given that soluble basigin is increased in the circulation of patients with a poor cancer prognosis, we explored the putative role of the ADAM12-generated basigin ectodomain in cancer progression. We show that recombinant basigin ectodomain binds ß1 integrin and stimulates gelatin degradation and the migration of cancer cells in a matrix metalloproteinase (MMP)- and ß1-integrin-dependent manner. Subsequent in vitro and in vivo experiments demonstrated the altered expression of extracellular matrix proteins, including fibronectin and collagen type 5. Thus, we found increased deposits of collagen type 5 in the stroma of nude mice tumors of the human tumor cell line MCF7 expressing ADAM12-mimicking the desmoplastic response seen in human cancer. Our findings indicate a feedback loop between ADAM12 expression, basigin shedding, TGFß signaling, and extracellular matrix (ECM) remodeling, which could be a mechanism by which ADAM12-generated basigin ectodomain contributes to the regulation of desmoplasia, a key feature in human cancer progression.
Assuntos
Proteína ADAM12 , Basigina , Proteínas da Matriz Extracelular , Animais , Feminino , Humanos , Camundongos , Proteína ADAM12/metabolismo , Proteína ADAM12/genética , Basigina/metabolismo , Basigina/genética , Linhagem Celular Tumoral , Movimento Celular , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Regulação Neoplásica da Expressão Gênica , Células MCF-7 , Camundongos Nus , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/genética , Ligação Proteica , Domínios Proteicos , Integrina beta1/metabolismoRESUMO
Neurodegenerative diseases constitute a global health issue and a major economic burden. They significantly impair both cognitive and motor functions, and their prevalence is expected to rise due to ageing societies and continuous population growth. Conventional therapies provide symptomatic relief, nevertheless, disease-modifying treatments that reduce or halt neuron death and malfunction are still largely unavailable. Amongst the common hallmarks of neurodegenerative diseases are protein aggregation, oxidative stress, neuroinflammation and mitochondrial dysfunction. Transcription factor nuclear factor-erythroid 2-related factor 2 (NRF2) constitutes a central regulator of cellular defense mechanisms, including the regulation of antioxidant, anti-inflammatory and mitochondrial pathways, making it a highly attractive therapeutic target for disease modification in neurodegenerative disorders. Here, we describe the role of NRF2 in the common hallmarks of neurodegeneration, review the current pharmacological interventions and their challenges in activating the NRF2 pathway, and present alternative therapeutic approaches for disease modification.