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Updated: Dec 12, 2025
Isolation and Functional Assessment of Human Breast Cancer Stem Cells from Cell and Tissue Samples
Published on: October 2, 2020
Stromal cell diversity associated with immune evasion in human triple-negative breast cancer
Sunny Z Wu1,2, Daniel L Roden1,2, Chenfei Wang3
1The Kinghorn Cancer Centre and Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
Abstract:
The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple-negative breast cancers (TNBCs) remains poorly understood, limiting the development of stromal-targeted therapies. Single-cell RNA sequencing of five TNBCs revealed two cancer-associated fibroblast (CAF) and two perivascular-like (PVL) subpopulations. CAFs clustered into two states: the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell signalling predictions, we provide evidence that stromal-immune crosstalk acts via a diverse array of immunoregulatory molecules. Importantly, the investigation of gene signatures from inflammatory-CAFs and differentiated-PVL cells in independent TNBC patient cohorts revealed strong associations with cytotoxic T-cell dysfunction and exclusion, respectively. Such insights present promising candidates to further investigate for new therapeutic strategies in the treatment of TNBCs.
Insights
Researchers identified distinct cancer-associated fibroblast (CAF) and perivascular-like (PVL) cell states in triple-negative breast cancer (TNBC). These stromal subpopulations influence tumor progression and immune response, offering new therapeutic targets for TNBC treatment.
Area of Science:
- Oncology
- Immunology
- Cell Biology
Background:
- The tumor stroma plays a critical role in regulating cancer development.
- Stromal heterogeneity in triple-negative breast cancer (TNBC) is not well understood, hindering the development of targeted therapies.
- Identifying distinct stromal cell populations is crucial for understanding TNBC progression and treatment.
Purpose of the Study:
- To investigate the heterogeneity of stromal cells in human triple-negative breast cancers.
- To characterize different subpopulations of cancer-associated fibroblasts (CAFs) and perivascular-like (PVL) cells.
- To explore the functional roles and therapeutic potential of identified stromal states in TNBC.
Main Methods:
- Single-cell RNA sequencing was performed on five TNBC tumors.
- Bioinformatic analysis was used to identify and cluster distinct CAF and PVL subpopulations.
- Cell signaling pathway predictions were employed to understand stromal-immune crosstalk.
- Gene signatures from identified stromal states were analyzed in independent TNBC patient cohorts.
Main Results:
- Two distinct CAF subpopulations (myofibroblast-like and immunomodulatory) and two PVL subpopulations (differentiated and immature) were identified.
- These stromal states exhibited unique morphologies, spatial distributions, and extracellular matrix regulatory functions.
- Stromal-immune crosstalk involves a wide range of immunoregulatory molecules.
- Inflammatory-CAF and differentiated-PVL signatures correlated with cytotoxic T-cell dysfunction and exclusion in TNBC patients, respectively.
Conclusions:
- Stromal heterogeneity in TNBC comprises distinct CAF and PVL subpopulations with unique functional properties.
- Specific stromal states are associated with immune dysfunction in TNBC, highlighting their role in treatment resistance.
- These findings provide novel insights into stromal-immune interactions and identify potential therapeutic targets for TNBC.
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