title: Endothelial ALK1 Is a Therapeutic Target to Block Metastatic Dissemination of Breast Cancer.
abstract: Exploration of new strategies for the prevention of breast cancer metastasis is justifiably at the center of clinical attention. In this study, we combined a computational biology approach with mechanism-based preclinical trials to identify inhibitors of activin-like receptor kinase (ALK) 1 as effective agents for blocking angiogenesis and metastasis in breast cancer. Pharmacologic targeting of ALK1 provided long-term therapeutic benefit in mouse models of mammary carcinoma, accompanied by strikingly reduced metastatic colonization as a monotherapy or part of combinations with chemotherapy. Gene-expression analysis of breast cancer specimens from a population-based nested case-control study encompassing 768 subjects defined endothelial expression of ALK1 as an independent and highly specific prognostic factor for metastatic manifestation, a finding that was corroborated in an independent clinical cohort. Overall, our results suggest that pharmacologic inhibition of endothelial ALK1 constitutes a tractable strategy for interfering with metastatic dissemination of breast cancer.
authors.affiliation: Ludwig Institute for Cancer Research, Uppsala, Sweden. Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sara I
authors.initials: SI
authors.lastname: Cunha
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Lund University, Lund, Sweden.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bocci
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: John
authors.initials: J
authors.lastname: Lövrot
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Lund University, Lund, Sweden.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Eleftheriou
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Pernilla
authors.initials: P
authors.lastname: Roswall
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Lund University, Lund, Sweden.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Cordero
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Lindström
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Lund University, Lund, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Bartoschek
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: B Kristian
authors.initials: BK
authors.lastname: Haller
authors.affiliation: Acceleron Pharma, Cambridge, Massachusetts.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Pearsall
authors.affiliation: Acceleron Pharma, Cambridge, Massachusetts.
authors.forename: Aaron W
authors.initials: AW
authors.lastname: Mulivor
authors.affiliation: Acceleron Pharma, Cambridge, Massachusetts.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Lund University, Lund, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Larsson
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergh
authors.affiliation: Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. Division of Translational Cancer Research, Department of Laboratory Medicine, Medicon Village, Lund University, Lund, Sweden. Kristian.Pietras@med.lu.se.
authors.forename: Kristian
authors.initials: K
authors.lastname: Pietras
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D004727:Endothelium / Q000201:enzymology; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II