Activin receptor-like kinase 1 is associated with immune cell infiltration and regulates CLEC14A transcription in cancer

• Published in: Angiogenesis (London) Vol. 22; no. 1; pp. 117 - 131
• Main Authors: Bocci, Matteo, Sjölund, Jonas, Kurzejamska, Ewa, Lindgren, David, Marzouka, Nour-Al-Dain, Bartoschek, Michael, Höglund, Mattias, Pietras, Kristian
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.02.2019; Springer Nature B.V
• Subjects: Activin; Activin Receptors, Type II - genetics; Activin Receptors, Type II - immunology; ALK1; Angiogenesis; Animals; Biological activity; Biomarkers; Biomarkers, Tumor - genetics; Biomarkers, Tumor - immunology; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer and Oncology; Cancer och onkologi; Cancer Research; Cardiology; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - immunology; Cell Biology; Cell signaling; Clinical Medicine; Computer applications; Endothelial cell; Endothelial cells; Female; Gene expression; Gene Expression Regulation, Neoplastic - immunology; Genes; Growth factors; Humans; Immune system; Infiltration; Kinases; Klinisk medicin; Lectins, C-Type - genetics; Lectins, C-Type - immunology; Male; Medical and Health Sciences; Medicin och hälsovetenskap; Metastases; Mice; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - pathology; Nutrients; Oncology; Ophthalmology; Original Paper; Pathophysiology; Precision medicine; Proteins; Reagents; Receptors; Tissue analysis; Transcription; Transcription, Genetic - immunology; Transforming growth factor-b; Tumor biology; Tumors; Vascular endothelial growth factor; Tumor biology; Angiogenesis; Endothelial cell; Pathophysiology; Cell signaling; ALK1
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-018-9642-5

Cancer cells sustain their metabolic needs through nutrients and oxygen supplied by the bloodstream. The requirement for tumor angiogenesis has been therapeutically exploited in the clinical setting mainly by means of inhibition of the vascular endothelial growth factor family of ligands and receptors. Despite promising results in preclinical models, the benefits for patients proved to be limited. Inadequate efficacy similarly halted the development of agents impinging on the activity of the activin receptor-like kinase (ALK)1, a member of the transforming growth factor-β superfamily. Notwithstanding its characterization as an endothelial cell marker, the full spectrum of biological processes associated with ALK1 is essentially unexplored. Here, we present data revealing the genetic network associated with ACVRL1 (the gene encoding for ALK1) expression in human cancer tissues. Computational analysis unveiled a hitherto unknown role for ACVRL1 in relation to genes modulating the functionality of the immune cell compartment. Moreover, we generated a signature of 8 genes co-expressed with ACVRL1 across different tumor types and characterized the c-type lectin domain containing protein ( CLEC ) 14A as a potential downstream target of ACVRL1 . Considering the lack of reagents for ALK1 detection that has hampered the field to date, our work provides the opportunity to validate the 8-gene signature and CLEC14A as biomarkers for ALK1 activity. Ultimately, this may help revisit the clinical development of already existing ALK1-blocking compounds as precision medicines for cancer.