A new study reveals that HMGA1 promotes cancer stem-like traits and increases sensitivity to monensin in gastric cancer cells

Researchers from the "Differentiation and Cancer" group at i3S, in collaboration with António Pombinho, from the "BioSciences Screening" platform, and Filipe Pereira, from Lund University, elucidated the role of the transcription factor HMGA1 in gastric cancer stem cells. The study, entitled "HMGA1 stimulates cancer stem-like features and sensitivity to monensin in gastric cancer," was recently published in the journal "Experimental Cell Research."

Gastric cancer remains a global health concern, often diagnosed at advanced stages with poor prognosis. Cancer stem cells (CSCs) drive tumor growth, metastasis, and treatment resistance. This study identifies HMGA1 as a key regulator of stem-like traits in gastric CSCs, enriched in SOX2, C-MYC, and other stemness markers. We show that monensin selectively targets HMGA1-expressing CSCs, offering a potential therapeutic strategy.

Authors and Affiliations:

Diana Pádua^1,2,3, Paula Figueira^1,2, António Pombinho^1,4, Inês Monteiro^1,2, Carlos Filipe Pereira^5,6,7, Raquel Almeida^1,2 and Patrícia Mesquita^1,2*

¹ i3S-Institute for Research and Innovation in Health, University of Porto, 4200-135 Porto, Portugal.

² IPATIMUP-Institute of Molecular Pathology and Immunology, University of Porto, 4200-465 Porto, Portugal.

³ ICBAS-School of Medicine and Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal.

⁴ IBMC-Institute of Molecular and Cell Biology, University of Porto, 4200-135 Porto, Portugal.

⁵ CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.

⁶ Cell Reprogramming in Hematopoiesis and Immunity Laboratory, Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, BMC A12, 221 84 Lund, Sweden.

⁷ Wallenberg Center for Molecular Medicine, Lund University, 221 84 Lund, Sweden.

Abstract:

Gastric cancer represents a serious health problem worldwide, with insufficient molecular biomarkers and therapeutic options. Consequently, several efforts have been directed towards finding specific disease markers in order to develop new therapies capable of defeating gastric cancer. Attention has been pointed to cancer stem cells (CSCs) as they are primarily responsible for tumor initiation and recurrence, making them essential therapeutic targets. Using the SORE6-GFP reporter system, based on the expression of SOX2 and/or OCT4 to drive GFP expression, we isolated gastric cancer stem-like cells (SORE6+ cells) enriched in several molecules, including SOX2, C-MYC, KLF4, HIF-1α, NOTCH1 and HMGA1. Here, we explored the previously undisclosed link of HMGA1 with gastric CSCs. Our results indicated that HMGA1 can activate a transcriptional program that includes SOX2, C-MYC, and KLF4 and endows cells with CSC features. We further showed that chemical induction of gastric CSCs using ciclopirox (CPX) can be mediated by HMGA1. Finally, we showed that HMGA1 GFP+ cells were sensitive to monensin confirming the selective activity of this drug over CSCs. Thus, HMGA1 is a key player in the cellular reprogramming of gastric non-CSCs to cancer stem-like cells.

Journal: Experimental Cell Research

Link: https://www.sciencedirect.com/science/article/pii/S0014482724003483?via%3Dihub