ALDH1A1 as a marker for metastasis initiating cells: A mechanistic insight

• Published in: Experimental cell research 2024-09, Vol.442 (1), p.114213, Article 114213
• Main Authors: Datta, Nandini, VP, Snijesh, Parvathy, K., A S, Sneha, Maliekal, Tessy Thomas
• Format: Article
• Language: English
• Subjects: Aldehyde Dehydrogenase - genetics; Aldehyde Dehydrogenase - metabolism; Aldehyde Dehydrogenase 1 Family - genetics; Aldehyde Dehydrogenase 1 Family - metabolism; ALDH1A1; Animals; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Epithelial-Mesenchymal Transition - genetics; Humans; Metastasis; Metastasis initiating cells (MICs); Neoplasm Metastasis; Neoplasms - genetics; Neoplasms - metabolism; Neoplasms - pathology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Retinal Dehydrogenase - genetics; Retinal Dehydrogenase - metabolism; Retinoic acid signaling; Tumor Microenvironment
• ISSN: 0014-4827; 1090-2422; 1090-2422
• DOI: 10.1016/j.yexcr.2024.114213

Since metastasis accounts for the majority of cancer morbidity and mortality, attempts are focused to block metastasis and metastasis initiating cellular programs. It is generally believed that hypoxia, reactive oxygen species (ROS) and the dysregulated redox pathways regulate metastasis. Although induction of epithelial to mesenchymal transition (EMT) can initiate cell motility to different sites other than the primary site, the initiation of a secondary tumor at a distant site depends on self-renewal property of cancer stem cell (CSC) property. That subset of metastatic cells possessing CSC property are referred to as metastasis initiating cells (MICs). Among the different cellular intermediates regulating metastasis in response to hypoxia by inducing EMT and self-renewal property, ALDH1A1 is a critical molecule, which can be used as a marker for MICs in a wide variety of malignancies. The cytosolic ALDHs can irreversibly convert retinal to retinoic acid (RA), which initiates RA signaling, important for self-renewal and EMT. The metastasis permissive tumor microenvironment increases the expression of ALDH1A1, primarily through HIF1α, and leads to metabolic reprograming through OXPHOS regulation. The ALDH1A1 expression and its high activity can reprogram the cancer cells with the transcriptional upregulation of several genes, involved in EMT through RA signaling to manifest hybrid EMT or Hybrid E/M phenotype, which is important for acquiring the characteristics of MICs. Thus, the review on this topic highlights the use of ALDH1A1 as a marker for MICs, and reporters for the marker can be effectively used to trace the population in mouse models, and to screen drugs that target MICs. •Metastasis initiating cells can self-renew and undergo epithelial to mesenchymal transition.•ALDH1A1 can be used as a metastasis initiating cell marker.•ALDH1A1 is involved in retinoic acid signaling and metabolic reprogramming in cells.•Retinoic acid signaling can help acquire metastasis initiating cell properties.