Selective inhibition of ALDH1A3 impedes breast cancer growth and metastasis by blocking ALDH1A3-driven transcriptional programs
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE293106 | GEO | 2026/01/28
REPOSITORIES: GEO
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Project description:The development of efficacious therapies targeting metastatic spread of breast cancer to the brain represents an unmet clinical need. Accordingly, an improved understanding of the molecular underpinnings of central nervous system spread and progression of breast cancer brain metastases (BCBM) is required. In this study, the clinical burden of disease in BCBM was investigated, as well as the role of aldehyde dehydrogenase 1A3 (ALDH1A3) in the metastatic cascade leading to BCBM development. Initial analysis of clinical survival trends for breast cancer and BCBM determined improvement of breast cancer survival rates, however this has failed to positively impact the prognostic milestones of triple-negative breast cancer (TNBC) brain metastases (BM). ALDH1A3 and a representative epithelial-mesenchymal transition (EMT) gene signature (mesenchymal markers CD44, Vimentin) were compared in tumors derived from BM, lung metastases (LM) or bone metastases (BoM) of patients as well as mice post-injection of TNBC cells. Selective elevation of the EMT signature and ALDH1A3 were observed in BM, unlike LM and BoM, especially in the tumor edge. Furthermore, ALDH1A3 was determined to play a role in BCBM establishment via regulation of circulating tumor cell (CTC) adhesion and migration phases in the BCBM cascade. Validation through genetic and pharmacologic inhibition of ALDH1A3 via lentiviral shRNA knockdown and a novel small molecule inhibitor demonstrated selective inhibition of BCBM formation with prolonged survival of tumor-bearing mice. Given the survival benefits via targeting ALDH1A3, it may prove an effective therapeutic strategy for BCBM prevention and/or treatment.
2020-01-01 | GSE138361 | GEO
Project description:Cancer progression and therapy resistance arise from metabolic and transcriptional adaptations, but how these are interconnected is less well understood. We propose that in melanoma, the pan-cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) couples TFAP2B-neural crest stem cell gene transcription with a distinct acetyl-histone H3 landscape via its substrate acetaldehyde. Mechanistically, nuclear acetyl-CoA synthetase 2 (ACSS2) colocalises with ALDH1A3 to bind glucose metabolic and neural crest stem cell gene loci and promote local acetyl-histone H3 modification dependent on ALDH1A3. Consistent with clinical observations that dedifferentiation into stem cell states confer poor prognosis in melanoma patients and mediate drug resistance, we found in a zebrafish melanoma model that targeting the ALDH1A3-high subpopulation with an ALDH1 suicide inhibitor delayed BRAF inhibitor drug-resistant relapse. Our work identifies ALDH1A3 as a master coordinator of acetaldehyde metabolites that directly regulates chromatin-based gene regulation, and which can be pharmacologically targeted to improve therapeutic outcomes.
2024-06-29 | GSE243834 | GEO
Project description:Cancer progression and therapy resistance arise from metabolic and transcriptional adaptations, but how these are interconnected is less well understood. We propose that in melanoma, the pan-cancer stem cell marker aldehyde dehydrogenase 1A3 (ALDH1A3) couples TFAP2B-neural crest stem cell gene transcription with a distinct acetyl-histone H3 landscape via its substrate acetaldehyde. Mechanistically, nuclear acetyl-CoA synthetase 2 (ACSS2) colocalises with ALDH1A3 to bind glucose metabolic and neural crest stem cell gene loci and promote local acetyl-histone H3 modification dependent on ALDH1A3. Consistent with clinical observations that dedifferentiation into stem cell states confer poor prognosis in melanoma patients and mediate drug resistance, we found in a zebrafish melanoma model that targeting the ALDH1A3-high subpopulation with an ALDH1 suicide inhibitor delayed BRAF inhibitor drug-resistant relapse. Our work identifies ALDH1A3 as a master coordinator of acetaldehyde metabolites that directly regulates chromatin-based gene regulation, and which can be pharmacologically targeted to improve therapeutic outcomes.
2024-06-29 | GSE243840 | GEO
Project description:Selective inhibition of ALDH1A3 impedes breast cancer growth and metastasis by blocking ALDH1A3-driven transcriptional programs
| PRJNA1242824 | ENA
Project description:Drug-tolerant persister (DTP) cells arise in the early phase of chemotherapy and contribute to tumor relapse. In gastric cancer, we previously identified aldehyde dehydrogenase 1 family member A3 (ALDH1A3) as a DTP signature gene that contributes to survival after chemotherapy, while it remains elusive how the ALDH1A3-overexpressing DTP cells are enriched after chemotherapy and contribute to tumor promotion. Here, we demonstrated that ALDH1A3 was frequently overexpressed in clinical gastric cancer specimen after neoadjuvant chemotherapy and ALDH1A3 overexpression in gastric cancer patient-derived cells (PDCs) promoted tumor growth in vivo. Live imaging revealed that the ALDH1A3-overexpressing DTP cells were induced rather than selected after 5-fluorouracil (5-FU) treatment. We identified global elevation of histone H3 lysine 27 acetylation (H3K27ac) in the promoter regions of DTP cells including ALDH1A3 gene locus. Chemical screening further revealed bromodomain and extra-terminal motif (BET) protein inhibitors as efficient perturbators of the DTP phenotype. The BET inhibitors suppressed 5-FU-induced ADLH1A3 expression and selectively prevented the DTP cell proliferation. Importantly, ALDH1A3 downregulation and growth inhibition by BET inhibitors was rescued by exogenous ALDH1A3 expression. Among BET proteins, BRD4 was preferentially recruited to the ALDH1A3 promoter and promoted its expression in DTP cells. The BET inhibitor, Birabresib/OTX015, significantly suppressed ALDH1A3 expression and potentiated antitumor effect of 5-FU in gastric PDC xenograft model. These data indicate that the global H3K27ac induction and the BRD4-dependent ALDH1A3 induction is essential for gastric cancer drug tolerance.
2023-10-24 | GSE245888 | GEO
Project description:Drug-tolerant persister (DTP) cells arise in the early phase of chemotherapy and contribute to tumor relapse. In gastric cancer, we previously identified aldehyde dehydrogenase 1 family member A3 (ALDH1A3) as a DTP signature gene that contributes to survival after chemotherapy, while it remains elusive how the ALDH1A3-overexpressing DTP cells are enriched after chemotherapy and contribute to tumor promotion. Here, we demonstrated that ALDH1A3 was frequently overexpressed in clinical gastric cancer specimen after neoadjuvant chemotherapy and ALDH1A3 overexpression in gastric cancer patient-derived cells (PDCs) promoted tumor growth in vivo. Live imaging revealed that the ALDH1A3-overexpressing DTP cells were induced rather than selected after 5-fluorouracil (5-FU) treatment. We identified global elevation of histone H3 lysine 27 acetylation (H3K27ac) in the promoter regions of DTP cells including ALDH1A3 gene locus. Chemical screening further revealed bromodomain and extra-terminal motif (BET) protein inhibitors as efficient perturbators of the DTP phenotype. The BET inhibitors suppressed 5-FU-induced ADLH1A3 expression and selectively prevented the DTP cell proliferation. Importantly, ALDH1A3 downregulation and growth inhibition by BET inhibitors was rescued by exogenous ALDH1A3 expression. Among BET proteins, BRD4 was preferentially recruited to the ALDH1A3 promoter and promoted its expression in DTP cells. The BET inhibitor, Birabresib/OTX015, significantly suppressed ALDH1A3 expression and potentiated antitumor effect of 5-FU in gastric PDC xenograft model. These data indicate that the global H3K27ac induction and the BRD4-dependent ALDH1A3 induction is essential for gastric cancer drug tolerance.
2023-10-24 | GSE245887 | GEO
Project description:Aldehyde dehydrogenase (ALDH1) activity has long been established as a pro-tumorigenic feature of many cancers, yet the identification of specific isoforms that are enriched in cancer, the mechanism of action of this isoform(s), and viable therapeutic strategies to target this pathway have long remained absent. Whereas one of the well-established functions of the ALDH1a family is the conversion of retinaldehyde into retinoic acid to activate nuclear retinoid signaling, the retinoid pathway is paradoxically hypothesized as a cell-intrinsic tumor suppressor pathway. Here we resolve this long-standing conflict by showing that while ALDH1a3 is broadly overexpressed across diverse cancer types, ALDH1a3 expressing tumor cells often lose the sensitivity to retinoid signaling. Instead, all-trans retinoic acid produced by ALDH1a3 acts in a paracrine fashion to suppress anti-tumor immunity and promote tumor growth. We further used structure-based high throughput screening to develop a series of first-in-class, therapeutically viable antagonists of ALDH1a3 with potent anti-tumor immunotherapeutic activity, an excellent pharmacological profile and no evidence of toxicity. Findings of this study resolve prior contradictions in the retinoid pathway through the development of highly specific and potent ALDH1a3 inhibitors.
2025-08-25 | GSE260586 | GEO
Project description:Elevated aldehyde dehydrogenase (ALDH) activity correlates with poor outcome for many solid tumors as ALDHs potentially regulate cell proliferation and chemoresistance of cancer stem cells (CSCs). Accordingly, potent and selective inhibitors of key ALDHs may represent a novel CSC-directed treatment paradigm for ALDH+ cancer types. Of the many ALDH isoforms, we and others have implicated the elevated expression of ALDH1A3 in mesenchymal glioma stem cells (MES GSCs) as a target for the development of novel therapeutics. To this end, we used our structure of human ALDH1A3 combined with in silico modeling to identify a selective, active-site inhibitor of ALDH1A3. The lead compound, MCI-INI-3, is a selective competitive inhibitor of human ALDH1A3 and shows poor inhibitory effect on the structurally related isoform ALDH1A1. Mass spectrometry-based cellular thermal shift analysis revealed that ALDH1A3 is the primary binding protein for MCI-INI-3 in MES GSC lysates. The inhibitory effect of MCI-INI-3 on retinoic acid biosynthesis is comparable with that of ALDH1A3 knockout, suggesting that effective inhibition of ALDH1A3 is achieved with MCI-INI-3. Further development is warranted to characterize the role of ALDH1A3 and retinoic acid biosynthesis in glioma stem cell growth and differentiation.
2022-02-15 | PXD028125 | Pride
Project description:Aldehyde dehydrogenase (ALDH1) activity has long been established as a pro-tumorigenic feature of many cancers, yet the identification of specific isoforms that are enriched in cancer, the mechanism of action of this isoform(s), and viable therapeutic strategies to target this pathway have long remained absent. Whereas one of the well-established functions of the ALDH1a family is the conversion of retinaldehyde into retinoic acid to activate nuclear retinoid signaling, the retinoid pathway is paradoxically hypothesized as a cell-intrinsic tumor suppressor pathway. Here we resolve this long-standing conflict by showing that while ALDH1a3 is broadly overexpressed across diverse cancer types, ALDH1a3 expressing tumor cells often lose the sensitivity to retinoid signaling. Instead, all-trans retinoic acid produced by ALDH1a3 acts in a paracrine fashion to suppress anti-tumor immunity and promote tumor growth. We further used structure-based high throughput screening to develop a series of first-in-class, therapeutically viable antagonists of ALDH1a3 with potent anti-tumor immunotherapeutic activity, an excellent pharmacological profile and no evidence of toxicity. Findings of this study resolve prior contradictions in the retinoid pathway through the development of highly specific and potent ALDH1a3 inhibitors.
2025-08-26 | PXD052693 | Pride
Project description:Retinoids, derivatives of vitamin A, are key physiological molecules with regulatory effects on cell differentiation, proliferation and apoptosis. As a result, they are of interest for cancer therapy. Specifically, models of breast cancer have varied responses to manipulations of the retinoid signaling cascade. This study characterizes the transcriptional response of MDA-MB-231 and MDA-MB-468 breast cancer cells to retinaldehyde dehydrogenase 1A3 (ALDH1A3) and to all-trans retinoic acid (atRA). We demonstrate limited overlap between ALDH1A3-induced gene expression and atRA-induced gene expression in both cell lines, suggesting that the function of ALDH1A3 in breast cancer progression extends beyond its role as a retinaldehyde dehydrogenase. Our data reveals divergent transcriptional responses to atRA, which are largely independent of genomic retinoic acid response elements (RAREs) and consistent with the opposing responses of MDA-MB-231 and MDA-MB-468 to in vivo atRA treatment. We identify transcription factors associated with each gene set. Manipulation of one of the transcription factors (i.e. interferon regulatory factor 1; IRF1) demonstrates that it is the level of atRA-inducible and epigenetically regulated transcription factors that determine expression of target genes (e.g. CTSS, cathepsin S). This study provides a paradigm for complex, combinatorial responses of breast cancer models to atRA treatment, and illustrates the need to characterize RARE-independent responses to atRA in a variety of models.
2017-11-06 | GSE103426 | GEO