2. Academic Validation
  3. Distinct tumor architectures and microenvironments for the initiation of breast cancer metastasis in the brain

Distinct tumor architectures and microenvironments for the initiation of breast cancer metastasis in the brain

  • Cancer Cell. 2024 Sep 12:S1535-6108(24)00314-3. doi: 10.1016/j.ccell.2024.08.015.
Siting Gan 1,  Danilo G Macalinao 2,  Sayyed Hamed Shahoei 2,  Lin Tian 2,  Xin Jin 3,  Harihar Basnet 2,  Catherine Bibby 2,  James T Muller 4,  Pranita Atri 5,  Evan Seffar 5,  Walid Chatila 5,  Ali Karacay 6,  Pharto Chanda 6,  Anna-Katerina Hadjantonakis 4,  Nikolaus Schultz 5,  Edi Brogi 6,  Tejus A Bale 6,  Nelson S Moss 7,  Rajmohan Murali 6,  Dana Pe'er 8,  Joan Massagué 9
Affiliations

Affiliations

  • 1 Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2 Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang Province 310024, China; Research Center for Industries of the Future, School of Life Sciences, Westlake University, Hangzhou, Zhejiang Province 310024, China.
  • 4 Developmental Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5 Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 6 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 7 Department of Neurological Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 8 Computational and Systems Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA.
  • 9 Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: massaguj@mskcc.org.
PMID: 39270646 DOI: 10.1016/j.ccell.2024.08.015
Abstract

Brain metastasis, a serious complication of Cancer, hinges on the initial survival, microenvironment adaptation, and outgrowth of disseminated Cancer cells. To understand the early stages of brain colonization, we investigated two prevalent sources of cerebral relapse, triple-negative (TNBC) and HER2+ (HER2BC) breast cancers. Using mouse models and human tissue samples, we found that these tumor types colonize the brain, with a preference for distinctive tumor architectures, stromal interfaces, and autocrine programs. TNBC models tend to form perivascular sheaths with diffusive contact with astrocytes and microglia. In contrast, HER2BC models tend to form compact spheroids driven by autonomous tenascin C production, segregating stromal cells to the periphery. Single-cell transcriptomics of the tumor microenvironment revealed that these architectures evoke differential Alzheimer's disease-associated microglia (DAM) responses and engagement of the GAS6 receptor Axl. The spatial features of the two modes of brain colonization have relevance for leveraging the stroma to treat brain metastasis.

Keywords

brain metastasis; breast cancer; extracellular matrix; microglia; tumor architecture; tumor microenvironment.

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