The Expanding Role of Cancer Stem Cell Marker ALDH1A3 in Cancer and Beyond

McLean, Meghan E.; MacLean, Maya R.; Cahill, Hannah F.; Arun, Raj Pranap; Walker, Olivia L.; Wasson, Marie-Claire D.; Fernando, Wasundara; Venkatesh, Jaganathan; Marcato, Paola

doi:10.3390/cancers15020492

Cited by 17 publications

(10 citation statements)

References 118 publications

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“…It is well appreciated that ALDH1A3 is an important driver of stemness in multiple cancer types, including breast, melanoma, glioblastoma, prostate, non-small cell lung cancer (NSCLC), head and neck cancer, and colon cancer [47]. Indeed, ALDH1A3 has been shown to enhance metastasis, clonogenicity, and chemoresistance [48,49].…”

Section: Aldh1a3mentioning

confidence: 99%

Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways

MacLean,

Walker,

Arun

et al. 2024

IJMS

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Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients.

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Section: Aldh1a3mentioning

confidence: 99%

Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways

MacLean,

Walker,

Arun

et al. 2024

IJMS

Self Cite

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“…Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) is one of 19 ALDH isoforms that convert aldehydes to carboxylates. ALDH1A3 is overexpressed in various cancers and is a marker of cancer stem cells, which contributes to cancer initiation, metastasis, therapeutic resistance, and relapse ( 15–17 ). ALDH1A3 mediates diverse intracellular events, such as retinoic acid biosynthesis and mitochondrial metabolism ( 18 ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacologic Targeting of Histone H3K27 Acetylation/BRD4-dependent Induction of ALDH1A3 for Early-phase Drug Tolerance of Gastric Cancer

Lee,

Mashima,

Kawata

et al. 2024

Cancer Research Communications

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Anticancer drug-tolerant persister (DTP) cells at an early phase of chemotherapy reshape refractory tumors. Aldehyde dehydrogenase 1 family member A3 (ALDH1A3) is commonly upregulated by various anticancer drugs in gastric cancer patient-derived cells (PDCs) and promotes tumor growth. However, the mechanism underlying the generation of ALDH1A3-positive DTP cells remains elusive. Here, we investigated the mechanism of ALDH1A3 expression and a combination therapy targeting gastric cancer DTP cells. We found that gastric cancer tissues treated with neoadjuvant chemotherapy (NAC) showed high ALDH1A3 expression. ChIP-PCR and ChIP-seq analyses revealed that histone H3 lysine 27 acetylation was enriched in the ALDH1A3 promoter in 5-Fluorouracil (5-FU)-tolerant persister PDCs. By chemical library screening, we found that the BET inhibitors OTX015/birabresib and I-BET-762/molibresib suppressed DTP-related ALDH1A3 expression and preferentially inhibited DTP cell growth. In DTP cells, BRD4, but not BRD2/3, was recruited to the ALDH1A3 promoter and BRD4 knockdown decreased drug-induced ALDH1A3 upregulation. Combination therapy with 5-FU and OTX015 significantly suppressed in vivo tumor growth. These observations suggest that BET inhibitors are efficient DTP cell-targeting agents for gastric cancer treatment.

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“…Among the three isoforms, ALDH1A3 has been described to be overexpressed in different neoplasms, including pancreatic cancer, high-grade gliomas, and ovarian cancer, but is not expressed in the non-neoplastic cells. Specifically, ALDH1A3 is highly expressed in drug resistant cancer stem cells (CSCs), characterized by the capability to promote self-renewal, clonogenic growth and metastases [ 16 , 17 ]. Recently, an analysis of 84 MPM patients from the TGCA database revealed that high ALDH1A3 expression is significantly associated with worse prognosis [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment

Boumya

Fallarini

Siragusa

et al. 2023

IJMS

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Aldehyde dehydrogenase 1A3 (ALDH1A3), one of the three members of the aldehyde dehydrogenase 1A subfamily, has been associated with increased progression and drug resistance in various types of solid tumours. Recently, it has been reported that high ALDH1A3 expression is prognostic of poor survival in patients with malignant pleural mesothelioma (MPM), an asbestos-associated chemoresistant cancer. We treated MPM cells, cultured as multicellular spheroids, with NR6, a potent and highly selective ALDH1A3 inhibitor. Here we report that NR6 treatment caused the accumulation of toxic aldehydes, induced DNA damage, CDKN2A expression and cell growth arrest. We observed that, in CDKN2A proficient cells, NR6 treatment induced IL6 expression, but abolished CXCL8 expression and IL-8 release, preventing both neutrophil recruitment and generation of neutrophil extracellular traps (NETs). Furthermore, we demonstrate that in response to ALDH1A3 inhibition, CDKN2A loss skewed cell fate from senescence to apoptosis. Dissecting the role of ALDH1A3 isoform in MPM cells and tumour microenvironment can open new fronts in the treatment of this cancer.

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The Expanding Role of Cancer Stem Cell Marker ALDH1A3 in Cancer and Beyond

Cited by 17 publications

References 118 publications

Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways

Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways

Pharmacologic Targeting of Histone H3K27 Acetylation/BRD4-dependent Induction of ALDH1A3 for Early-phase Drug Tolerance of Gastric Cancer

A Selective ALDH1A3 Inhibitor Impairs Mesothelioma 3-D Multicellular Spheroid Growth and Neutrophil Recruitment

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