In vivo turnover and biodistribution of soluble AXL: implications for biomarker development.
Biodistribution
Biomarker
Clearance
sAXL
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
12 Jul 2024
12 Jul 2024
Historique:
received:
13
03
2024
accepted:
03
07
2024
medline:
13
7
2024
pubmed:
13
7
2024
entrez:
12
7
2024
Statut:
epublish
Résumé
Soluble biomarkers are paramount to personalized medicine. However, the in vivo turnover and biodistribution of soluble proteins is seldom characterized. The cleaved extracellular domain of the AXL receptor (sAXL) is a prognostic biomarker in several diseases and a predictive marker of AXL targeting agents. Plasma sAXL reflects a balance between production in tissues with lymphatic transport into the circulation and removal from blood by degradation or excretion. It is unclear how this transport cycle affects plasma sAXL levels that are the metric for biomarker development. Radiolabeled mouse sAxl was monitored after intravenous injection to measure degradation and urinary excretion of sAxl, and after intradermal injection to mimic tissue or tumor production. sAxl was rapidly taken-up and degraded by the liver and kidney cortex. Surprisingly, intact sAxl was detectable in urine, indicating passage through the glomerular filter and a unique sampling opportunity. The structure of sAxl showed an elongated, flexible molecule with a length of 18 nm and a thickness of only 3 nm, allowing passage through the glomerulus and excretion into the urine. Intradermally injected sAxl passed through local and distant lymph nodes, followed by uptake in liver and kidney cortex. Low levels of sAxl were seen in the plasma, consistent with an extended transit time from local tissue to circulation. The rapid plasma clearance of sAxl suggests that steady-state levels in blood will sensitively and dynamically reflect the rate of production of sAxl in the tissues but will be influenced by perturbations of liver and kidney function.
Identifiants
pubmed: 38997436
doi: 10.1038/s41598-024-66665-y
pii: 10.1038/s41598-024-66665-y
doi:
Substances chimiques
Axl Receptor Tyrosine Kinase
0
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Biomarkers
0
Proto-Oncogene Proteins
0
AXL receptor tyrosine kinase, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
16141Informations de copyright
© 2024. The Author(s).
Références
Dengler, M. et al. Soluble Axl is an accurate biomarker of cirrhosis and hepatocellular carcinoma development: Results from a large scale multicenter analysis. Oncotarget 8, 46234–46248. https://doi.org/10.18632/oncotarget.17598 (2017).
doi: 10.18632/oncotarget.17598
pubmed: 28526812
pmcid: 5542263
Staufer, K. et al. The non-invasive serum biomarker soluble Axl accurately detects advanced liver fibrosis and cirrhosis. Cell Death Dis. 8, e3135. https://doi.org/10.1038/cddis.2017.554 (2017).
doi: 10.1038/cddis.2017.554
pubmed: 29072690
pmcid: 5680921
Gustafsson, A. et al. Differential expression of Axl and Gas6 in renal cell carcinoma reflecting tumor advancement and survival. Clin. Cancer Res. 15, 4742–4749. https://doi.org/10.1158/1078-0432.CCR-08-2514 (2009).
doi: 10.1158/1078-0432.CCR-08-2514
pubmed: 19567592
Johansson, G. et al. Soluble AXL: A possible circulating biomarker for neurofibromatosis type 1 related tumor burden. PLoS ONE 9, e115916. https://doi.org/10.1371/journal.pone.0115916 (2014).
doi: 10.1371/journal.pone.0115916
pubmed: 25551830
pmcid: 4281253
Flem-Karlsen, K. et al. Soluble AXL as a marker of disease progression and survival in melanoma. PLoS ONE 15, e0227187. https://doi.org/10.1371/journal.pone.0227187 (2020).
doi: 10.1371/journal.pone.0227187
pubmed: 31917795
pmcid: 6952099
Ekman, C., Linder, A., Akesson, P. & Dahlback, B. Plasma concentrations of Gas6 (growth arrest specific protein 6) and its soluble tyrosine kinase receptor sAxl in sepsis and systemic inflammatory response syndromes. Crit. Care 14, R158. https://doi.org/10.1186/cc9233 (2010).
doi: 10.1186/cc9233
pubmed: 20731857
pmcid: 2945142
Loges, S. et al. Bemcentinib (oral AXL inhibitor) in combination with low-dose cytarabine is well tolerated and efficacious in older relapsed AML patients. Updates from the ongoing phase II trial (NCT02488408) and preliminary translational results indicating bemcentinib elicits anti-AML immune responses. Blood 138, 3410. https://doi.org/10.1182/blood-2021-147225 (2021).
doi: 10.1182/blood-2021-147225
Aukland, K. & Reed, R. K. Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol. Rev. 73, 1–78. https://doi.org/10.1152/physrev.1993.73.1.1 (1993).
doi: 10.1152/physrev.1993.73.1.1
pubmed: 8419962
Muslimovic, A. et al. Novel clearance of muscle proteins by muscle cells. Eur. J. Cell Biol. 99, 151127. https://doi.org/10.1016/j.ejcb.2020.151127 (2020).
doi: 10.1016/j.ejcb.2020.151127
pubmed: 33162173
Muslimovic, A. et al. The liver and kidneys mediate clearance of cardiac troponin in the rat. Sci. Rep. 10, 6791. https://doi.org/10.1038/s41598-020-63744-8 (2020).
doi: 10.1038/s41598-020-63744-8
pubmed: 32322013
pmcid: 7176693
Jumper, J. et al. Highly accurate protein structure prediction with AlphaFold. Nature 596, 583–589. https://doi.org/10.1038/s41586-021-03819-2 (2021).
doi: 10.1038/s41586-021-03819-2
pubmed: 34265844
pmcid: 8371605
Mirdita, M. et al. ColabFold: Making protein folding accessible to all. Nat. Methods 19, 679–682. https://doi.org/10.1038/s41592-022-01488-1 (2022).
doi: 10.1038/s41592-022-01488-1
pubmed: 35637307
pmcid: 9184281
Ohlson, M. et al. Effects of filtration rate on the glomerular barrier and clearance of four differently shaped molecules. Am. J. Physiol. Renal Physiol. 281, F103–F113. https://doi.org/10.1152/ajprenal.2001.281.1.F103 (2001).
doi: 10.1152/ajprenal.2001.281.1.F103
pubmed: 11399651
Nielsen, R., Christensen, E. I. & Birn, H. Megalin and cubilin in proximal tubule protein reabsorption: From experimental models to human disease. Kidney Int. 89, 58–67. https://doi.org/10.1016/j.kint.2015.11.007 (2016).
doi: 10.1016/j.kint.2015.11.007
pubmed: 26759048
Rygh, C. B. et al. Longitudinal investigation of permeability and distribution of macromolecules in mouse malignant transformation using PET. Clin. Cancer Res. 17, 550–559. https://doi.org/10.1158/1078-0432.CCR-10-2049 (2011).
doi: 10.1158/1078-0432.CCR-10-2049
pubmed: 21106723