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Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis
Qi Sun, … , David A. Cheresh, Jay S. Desgrosellier
Qi Sun, … , David A. Cheresh, Jay S. Desgrosellier
Published December 11, 2017
Citation Information: J Clin Invest. 2018;128(1):531-544. https://doi.org/10.1172/JCI93707.
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Research Article Oncology Stem cells

Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis

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Abstract

Breast cancer cells with stem cell properties are key contributors to metastatic disease, and there remains a need to better understand and target these cells in human cancers. Here, we identified rare stem-like cells in patients’ tumors characterized by low levels of the proapoptotic molecule p53-upregulated modulator of apoptosis (PUMA) and showed that these cells play a critical role in tumor progression that is independent of clinical subtype. A signaling axis consisting of the integrin αvβ3, Src kinase, and the transcription factor Slug suppresses PUMA in these cells, promoting tumor stemness. We showed that genetic or pharmacological disruption of αvβ3/Src signaling drives PUMA expression, specifically depleting these stem-like tumor cells; increases their sensitivity to apoptosis; and reduces pulmonary metastasis, with no effect on primary tumor growth. Taken together, these findings point to PUMA as a key vulnerability of stem-like cells and suggest that pharmacological upregulation of PUMA via Src inhibition may represent a strategy to selectively target these cells in a wide spectrum of aggressive breast cancers.

Authors

Qi Sun, Jacqueline Lesperance, Hiromi Wettersten, Elaine Luterstein, Yoko S. DeRose, Alana Welm, David A. Cheresh, Jay S. Desgrosellier

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Figure 6

Src inhibition upregulates PUMA and depletes stem-like cells in distinct breast cancer subtypes.

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Src inhibition upregulates PUMA and depletes stem-like cells in distinct...
(A) Representative FACS density plots of the HCC38 and HCC1143 breast cancer cell lines showing the live, CD49f+ cells according to their cell-surface EpCAM and αvβ3 expression. (B) Immunoblot of the indicated FACS-sorted cell populations from HCC1143 cells. β-Actin was used as a loading control. (C) Primary and secondary tumorsphere assays in methylcellulose for the indicated sorted cell populations. Shown are the total number of colonies per well. Primary tumorspheres, HCC38; P < 0.0001 for EpCAMloαvβ3+ versus all other cell types, HCC1143; P < 0.0001 for EpCAMhiαvβ3– versus EpCAMhiαvβ3+ and EpCAMloαvβ3– versus EpCAMloαvβ3+. Secondary tumorspheres, HCC38; P < 0.0001 for EpCAMloαvβ3+ versus all other cell types, HCC1143 (EpCAMloαvβ3+); P = 0.0037 (vs. EpCAMhiαvβ3–), P = 0.0094 (vs. EpCAMhiαvβ3+), P = 0.0059 (vs. EpCAMloαvβ3–). Statistical analysis was performed by 1-way ANOVA with Tukey’s multiple comparisons test. n = 3 independent experiments. (D) Western blot analysis of the indicated HCC1143 sorted cells treated with DMSO vehicle or 100 nM dasatinib for 24 hours. β-Actin was used as a loading control. Data shown in A, B, and D are representative of 3 independent experiments. (E) Bar graphs show the number of tumorspheres per field formed in the indicated HCC38 and HCC1143 cell populations after treatment with vehicle (DMSO) or 500 nM dasatinib. The P values for vehicle versus dasatinib are as follows: P = 0.0208 (HCC38; EpCAMloαvβ3+); P = 0.0384 (HCC1143; EpCAMloαvβ3+); P = 0.4060 (HCC1143; EpCAMhiαvβ3+). Statistical analysis was performed by Student’s t test (E). n = 3 independent experiments performed in triplicate. Data in C and E represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001. See also Supplemental Figure 6.
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