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Breast cancer stem cells: mechanobiology reveals highly invasive cancer cell subpopulations

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Abstract

Cancer stem-like cells (CSCs) are a typically small subpopulation of highly tumorigenic cells that can self-renew, differentiate, drive tumor progression, and may mediate drug resistance and metastasis. Metastasis driving CSCs are expected to be highly invasive. To determine the relative invasiveness of CSCs, we isolate distinct subpopulations in the metastatic, MDA-MB-231 breast-cancer cell line, identified by the stem-cell markers aldehyde dehydrogenase (ALDH) and CD44. We determine CSC-subpopulation invasiveness levels using our rapid (2 h) mechanobiology-based assay. Specifically, invasive cells forcefully push and indent the surface of physiological–stiffness synthetic gels to cell-scale depths, where the percentage of indenting cells and their attained depths have previously provided clinically relevant predictions of the metastatic risk in different cancer types. We observe that the small (3.2%) CD44+ALDH+ cell-subpopulation indents more and attains significantly deeper depths (65% indenting to 6 ± 0.3 µm) relative to CD44+ALDH−, CD44−ALDH−, CD44−ALDH+ cells, and the whole-sample control (with 18–44% indenting cells reaching average depths of 4.4–5 µm). The CD44+ALDH+ similarly demonstrates twofold higher migratory capacity in Boyden chambers. The higher invasiveness of CD44+ALDH+ cells reveals their likely role in facilitating disease progression, providing prognostic markers for increased risk of recurrence and metastasis.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

CSCs:

Cancer stem-like cells

ALDH:

Aldehyde dehydrogenase

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

APS:

Ammonium persulfate

TEMED:

Tetramethylethylenediamine

ANOVA:

Analysis of variance

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Acknowledgements

The work was partially supported by the Israeli Ministry of Science and Technology (MOST) Medical Devices Program (Grant no. 3-17427), by the Samuel H. Born Fund for Biomedical Research, and by the Russel Berrie Nano Institute at the Technion-IIT.

Funding

The work was partially supported by the Israeli Ministry of Science and Technology (MOST) Medical Devices Program (Grant no. 3–17427), the Samuel H. Born Fund for Biomedical Research, and by the Russel Berrie Nano Institute at the Technion-IIT.

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  1. Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, 3200003, Haifa, Israel

    Martha B. Alvarez-Elizondo & Daphne Weihs

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  1. Martha B. Alvarez-Elizondo
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  2. Daphne Weihs
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MBA-E and DW contributed to the study conception and design, material preparation, data collection and analysis. The first draft of the manuscript was written by MBA-E and DW.

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Correspondence to Daphne Weihs.

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Alvarez-Elizondo, M.B., Weihs, D. Breast cancer stem cells: mechanobiology reveals highly invasive cancer cell subpopulations. Cell. Mol. Life Sci. 79, 134 (2022). https://doi.org/10.1007/s00018-022-04181-w

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