Lung-resident alveolar macrophages regulate the timing of breast cancer metastasis

Erica Dalla ¹, Michael Papanicolaou ², Matthew D Park ³

¹Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
³Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Cancer Research UK Edinburgh Centre, University of Edinburgh, Edinburgh, UK.
⁵Harry Perkins Institute of Medical Research, QEII Medical Centre and Centre for Medical Research, The University of Western Australia, Nedlands, WA 6009, Australia.
⁶Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
⁷Cancer Immunity Laboratory, Molecular Oncology Program, Spanish National Cancer Centre, Madrid, Spain.
⁸Cancer Dormancy Institute, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA; Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
⁹Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

⁰Division of Hematology and Oncology, Department of Medicine and Department of Otolaryngology, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Cell +

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October 8, 2024

View abstract on PubMed

Summary

Tissue-resident alveolar macrophages induce dormancy in breast cancer cells through transforming growth factor-beta 2 (TGF-β2) signaling, preventing lung metastasis. Downregulation of this TGF-β2 pathway allows cancer cells to awaken and proliferate.

Area Of Science

Oncology
Immunology
Cell Biology

Background

Breast cancer cells can disseminate to the lungs and remain dormant.
Mechanisms controlling breast cancer cell dormancy in the lungs are not fully understood.
Tissue-resident alveolar macrophages are implicated in suppressing metastasis.

Purpose Of The Study

To investigate the role of alveolar macrophages in maintaining breast cancer cell dormancy in the lungs.
To elucidate the molecular mechanisms by which alveolar macrophages suppress cancer cell proliferation.
To identify signaling pathways involved in the transition from dormancy to active metastasis.

Main Methods

Ligand-receptor mapping to identify molecular interactions.
Intravital imaging to visualize macrophage-cancer cell dynamics in vivo.
Experimental depletion of alveolar macrophages.
Genetic manipulation of TGF-β2 receptor expression in cancer cells.

Main Results

Alveolar macrophages express transforming growth factor-beta 2 (TGF-β2).
TGF-β2 signaling, mediated by the TGF-βRIII receptor on cancer cells, maintains cancer cell dormancy.
Depletion of alveolar macrophages or loss of TGF-βRIII in cancer cells leads to metastatic awakening.
Aggressive breast cancer cells evade dormancy by downregulating TGF-βRIII or avoiding macrophage interaction.

Conclusions

Alveolar macrophages function as a critical immune barrier against breast cancer lung metastasis.
TGF-β2 signaling is essential for macrophage-mediated suppression of cancer cell growth.
Downregulation of the TGF-β2 pathway enables breast cancer cells to overcome dormancy and proliferate, leading to overt metastasis.

Keywords:

TGFβ2 TGFβR3 alveolar macrophage breast cancer dormancy homeostasis intravital imaging lung metastasis reawakening

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