Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma

Department of Drug Design and Pharmacology

Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma. / Lewinska, Monika; Zhuravleva, Ekaterina; Satriano, Letizia; Martinez, Marta B; Bhatt, Deepak K; Oliveira, Douglas V N P; Antoku, Yasuko; Keggenhoff, Friederike L; Castven, Darko; Marquardt, Jens U; Matter, Matthias S; Erler, Janine T; Oliveira, Rui C; Aldana, Blanca I; Al-Abdulla, Ruba; Perugorria, Maria J; Calvisi, Diego F; Perez, Luis Arnes; Rodrigues, Pedro M; Labiano, Ibone; Banales, Jesus M; Andersen, Jesper B.

In: Gastroenterology, Vol. 166, No. 5, 2023, p. 886-901.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Lewinska, M, Zhuravleva, E, Satriano, L, Martinez, MB, Bhatt, DK, Oliveira, DVNP, Antoku, Y, Keggenhoff, FL, Castven, D, Marquardt, JU, Matter, MS, Erler, JT, Oliveira, RC, Aldana, BI, Al-Abdulla, R, Perugorria, MJ, Calvisi, DF, Perez, LA, Rodrigues, PM, Labiano, I, Banales, JM & Andersen, JB 2023, 'Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma', Gastroenterology, vol. 166, no. 5, pp. 886-901. https://doi.org/10.1053/j.gastro.2023.11.302

APA

Lewinska, M., Zhuravleva, E., Satriano, L., Martinez, M. B., Bhatt, D. K., Oliveira, D. V. N. P., Antoku, Y., Keggenhoff, F. L., Castven, D., Marquardt, J. U., Matter, M. S., Erler, J. T., Oliveira, R. C., Aldana, B. I., Al-Abdulla, R., Perugorria, M. J., Calvisi, D. F., Perez, L. A., Rodrigues, P. M., ... Andersen, J. B. (2023). Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma. Gastroenterology, 166(5), 886-901. https://doi.org/10.1053/j.gastro.2023.11.302

Vancouver

Lewinska M, Zhuravleva E, Satriano L, Martinez MB, Bhatt DK, Oliveira DVNP et al. Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma. Gastroenterology. 2023;166(5):886-901. https://doi.org/10.1053/j.gastro.2023.11.302

Author

Lewinska, Monika ; Zhuravleva, Ekaterina ; Satriano, Letizia ; Martinez, Marta B ; Bhatt, Deepak K ; Oliveira, Douglas V N P ; Antoku, Yasuko ; Keggenhoff, Friederike L ; Castven, Darko ; Marquardt, Jens U ; Matter, Matthias S ; Erler, Janine T ; Oliveira, Rui C ; Aldana, Blanca I ; Al-Abdulla, Ruba ; Perugorria, Maria J ; Calvisi, Diego F ; Perez, Luis Arnes ; Rodrigues, Pedro M ; Labiano, Ibone ; Banales, Jesus M ; Andersen, Jesper B. / Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma. In: Gastroenterology. 2023 ; Vol. 166, No. 5. pp. 886-901.

Bibtex

@article{c4ec63bfcfd4404f8d25fe99386e76e3,

title = "Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma",

abstract = "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.",

author = "Monika Lewinska and Ekaterina Zhuravleva and Letizia Satriano and Martinez, {Marta B} and Bhatt, {Deepak K} and Oliveira, {Douglas V N P} and Yasuko Antoku and Keggenhoff, {Friederike L} and Darko Castven and Marquardt, {Jens U} and Matter, {Matthias S} and Erler, {Janine T} and Oliveira, {Rui C} and Aldana, {Blanca I} and Ruba Al-Abdulla and Perugorria, {Maria J} and Calvisi, {Diego F} and Perez, {Luis Arnes} and Rodrigues, {Pedro M} and Ibone Labiano and Banales, {Jesus M} and Andersen, {Jesper B}",

year = "2023",

doi = "10.1053/j.gastro.2023.11.302",

language = "English",

volume = "166",

pages = "886--901",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "Elsevier",

number = "5",

}

RIS

TY - JOUR

T1 - Fibroblast-Derived Lysyl Oxidase Increases Oxidative Phosphorylation and Stemness in Cholangiocarcinoma

AU - Lewinska, Monika

AU - Zhuravleva, Ekaterina

AU - Satriano, Letizia

AU - Martinez, Marta B

AU - Bhatt, Deepak K

AU - Oliveira, Douglas V N P

AU - Antoku, Yasuko

AU - Keggenhoff, Friederike L

AU - Castven, Darko

AU - Marquardt, Jens U

AU - Matter, Matthias S

AU - Erler, Janine T

AU - Oliveira, Rui C

AU - Aldana, Blanca I

AU - Al-Abdulla, Ruba

AU - Perugorria, Maria J

AU - Calvisi, Diego F

AU - Perez, Luis Arnes

AU - Rodrigues, Pedro M

AU - Labiano, Ibone

AU - Banales, Jesus M

AU - Andersen, Jesper B

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

U2 - 10.1053/j.gastro.2023.11.302

DO - 10.1053/j.gastro.2023.11.302

M3 - Journal article

C2 - 38096955

VL - 166

SP - 886

EP - 901

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 5

ER -

ID: 381218725