Hitting the bull’s eye: targeting HMGA1 in cancer stem cells

Abstract

Emerging evidence suggests that when cancer cells hijack normal stem cell properties, they acquire the ability to invade, metastasize to distant sites and evade therapy. Thus, eliminating cancer cells with stem cell properties, or cancer stem cells, is of prime importance for the successful treatment of cancer, regardless of the tissue of origin. Previous efforts to target cancer stem cells (CSCs), however, have been largely unsuccessful. Recent studies led to the discovery of a novel role for the high mobility group A1 (HMGA1) protein as a master regulator in both CSCs and normal embryonic stem cells. Here, we present exciting new work unveiling HMGA1 as a promising target for therapies directed at eradicating CSCs.

Keywords::

• cancer stem cells
• embryonic stem cells
• epithelial–mesenchymal transition
• high mobility group A1 protein
• HMGA1

Financial & competing interests disclosure

The authors wish to thank the following funding sources for supporting this work: The NIH (R21 CA2149550, R03 CA164677, R03 CA164677), the Sol Goldman Cancer Center, AVON foundation, Safeway, Alex's Lemonade Stand Foundation, St. Baldrick's Foundation for Childhood Cancer Research, Association for Research on Childhood Cancer, Children's Leukemia Research Association, Maryland Stem Cell Research Fund (all to LMSR). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• High mobility group A1 (HMGA1) encodes the HMGA1a and HMGA1b chromatin remodeling proteins, which alter chromatin structure and modulate gene expression.

• HMGA1 is highly expressed in all aggressive, poorly differentiated tumors studied and high levels portend a poor prognosis in diverse tumors.

• HMGA1 is enriched in normal embryonic stem cells, adult stem cells and cancer stem cells.

• HMGA1 induces oncogenic transformation in cultured cells and aggressive tumors in transgenic mice.

• Silencing HMGA1 results in a dramatic reprogramming of proliferative, invasive, spindle-shaped, mesenchymal cancer cells into non-invasive cells with slow proliferation rates and a more differentiated, cuboidal-shaped, epithelial appearance.

• Switching off HMGA1 also blocks tumor progression and depletes cancer stem cells/tumor-initiator cells in murine models.

• HMGA1 is required for cellular reprogramming of somatic cells into induced pluripotent stem cells by the Yamanaka factors.

• HMGA1 induces stem cell transcriptional networks during normal development in pluripotent stem cells and during tumor progression in cancer cells.

• Recent work suggests that targeting HMGA1 will eliminate cancer stem cells in diverse tumors.

Notes