| Autor: |
Sun Q; Moores Cancer Center, and.; Department of Pathology, UCSD, La Jolla, California, USA., Lesperance J; Moores Cancer Center, and.; Department of Pathology, UCSD, La Jolla, California, USA., Wettersten H; Department of Pathology, UCSD, La Jolla, California, USA.; Sanford Consortium for Regenerative Medicine, La Jolla, California, USA., Luterstein E; Moores Cancer Center, and.; Department of Pathology, UCSD, La Jolla, California, USA., DeRose YS; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA., Welm A; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA., Cheresh DA; Department of Pathology, UCSD, La Jolla, California, USA.; Sanford Consortium for Regenerative Medicine, La Jolla, California, USA., Desgrosellier JS; Moores Cancer Center, and.; Department of Pathology, UCSD, La Jolla, California, USA. |
| Abstrakt: |
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. |
