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An Activin Receptor-Like Kinase 1-governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases

Safaee Talkhoncheh, Mehrnaz LU ; Sjölund, Jonas LU ; Bolivar, Paulina LU ; Kurzejamska, Ewa LU ; Cordero, Eugenia ; Vallès Pagès, Teia LU ; Larsson, Sara LU ; Lehn, Sophie LU ; Frimannsson, Gustav LU and Ingesson, Viktor , et al. (2025) In The Journal of clinical investigation
Abstract

The biology centered around the TGF-beta type I receptor Activin Receptor-Like Kinase (ALK)1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the... (More)

The biology centered around the TGF-beta type I receptor Activin Receptor-Like Kinase (ALK)1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation. Notably, ACVRL1+ TAMs coincided with an immunosuppressive phenotype, and were over-represented in human cancers progressing on therapy. Accordingly, breast cancer patients with a prominent ACVRL1hi TAM signature exhibited a significantly shorter survival. In conclusion, we shed light on an unexpected multimodal regulation of tumorigenic phenotypes by ALK1 and demonstrate its utility as a target for anti-angiogenic immunotherapy.

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publication status
epub
subject
in
The Journal of clinical investigation
publisher
The American Society for Clinical Investigation
external identifiers
  • pmid:39808498
ISSN
0021-9738
DOI
10.1172/JCI183086
language
English
LU publication?
yes
id
ff8c52ac-727d-4821-9420-17a9c693d76d
date added to LUP
2025-01-23 08:47:46
date last changed
2025-01-23 12:16:53
@article{ff8c52ac-727d-4821-9420-17a9c693d76d,
  abstract     = {{<p>The biology centered around the TGF-beta type I receptor Activin Receptor-Like Kinase (ALK)1 (encoded by ACVRL1) has been almost exclusively based on its reported endothelial expression pattern since its first functional characterization more than two decades ago. Here, in efforts to better define the therapeutic context in which to use ALK1 inhibitors, we uncover a population of tumor-associated macrophages (TAMs) that, by virtue of their unanticipated Acvrl1 expression, are effector targets for adjuvant anti-angiogenic immunotherapy in mouse models of metastatic breast cancer. The combinatorial benefit depended on ALK1-mediated modulation of the differentiation potential of bone marrow-derived granulocyte-macrophage progenitors, the release of CD14+ monocytes into circulation, and their eventual extravasation. Notably, ACVRL1+ TAMs coincided with an immunosuppressive phenotype, and were over-represented in human cancers progressing on therapy. Accordingly, breast cancer patients with a prominent ACVRL1hi TAM signature exhibited a significantly shorter survival. In conclusion, we shed light on an unexpected multimodal regulation of tumorigenic phenotypes by ALK1 and demonstrate its utility as a target for anti-angiogenic immunotherapy.</p>}},
  author       = {{Safaee Talkhoncheh, Mehrnaz and Sjölund, Jonas and Bolivar, Paulina and Kurzejamska, Ewa and Cordero, Eugenia and Vallès Pagès, Teia and Larsson, Sara and Lehn, Sophie and Frimannsson, Gustav and Ingesson, Viktor and Braun, Sebastian and Pantaleo, Jessica and Oudenaarden, Clara and Lauss, Martin and Pearsall, R Scott and Jönsson, Göran B and Rolny, Charlotte and Bocci, Matteo and Pietras, Kristian}},
  issn         = {{0021-9738}},
  language     = {{eng}},
  month        = {{01}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{The Journal of clinical investigation}},
  title        = {{An Activin Receptor-Like Kinase 1-governed monocytic lineage shapes an immunosuppressive landscape in breast cancer metastases}},
  url          = {{http://dx.doi.org/10.1172/JCI183086}},
  doi          = {{10.1172/JCI183086}},
  year         = {{2025}},
}