FOXD1–ALDH1A3 Signaling Is a Determinant for the Self-Renewal and Tumorigenicity of Mesenchymal Glioma Stem Cells

Abstract

Glioma stem-like cells (GSC) with tumor initiating activity orchestrate the cellular hierarchy in glioblastoma (GBM) and engender therapeutic resistance. Recent work has divided GSC into two subtypes with a mesenchymal (MES) GSC population as the more malignant subtype. In this study, we identify the FOXD1-ALDH1A3 signaling axis as a determinant of the MES GSC phenotype. The transcription factor FOXD1 is expressed predominantly in patient-derived cultures enriched with MES, but not with the proneural (PN) GSC subtype. shRNA-mediated attenuation of FOXD1 in MES GSC ablates their clonogenicity in vitro and in vivo. Mechanistically, FOXD1 regulates the transcriptional activity of ALDH1A3, an established functional marker for MES GSC. Indeed, the functional roles of FOXD1 and ALDH1A3 are likely evolutionally conserved, insofar as RNAi-mediated attenuation of their orthologous genes in Drosophila blocks formation of brain tumors engineered in that species. In clinical specimens of high-grade glioma, the levels of expression of both FOXD1 and ALDH1A3 are inversely correlated with patient prognosis. Lastly, a novel small molecule inhibitor of ALDH we developed, termed GA11, displays potent in vivo efficacy when administered systemically in a murine GSC-derived xenograft model of GBM. Collectively, our findings define a FOXD1-ALDH1A3 pathway in controlling the clonogenic and tumorigenic potential of MES GSC in GBM tumors.

FOXD1 Promotes Cell Growth and Metastasis by Activation of Vimentin in NSCLC

“…Furthermore, we revealed that a higher expression level of FOXD1 was associated with malignant behavior and poorer prognosis of NSCLC patients. It is worth mentioning that FOXD1 is after all a transcription factor so nuclear localization would be expected, but FOXD1 was mainly in cytoplasm, which was previously reported [8]. However, we don't found that high levels of FOXD1 expression were significantly associated with these clinicopathological findings, including the presence of squamous cell carcinoma, male gender and history of heavy smoking.…”

“…Thus, the dysregulation of FOX genes is also observed in a variety of cancerspage5. The FOXD1 gene is located on chromosome 5q12 and is involved in a wide array of biological processes, including proliferation, invasion and tumorigenesis [5,7,8]. A previous study used microarray datasets from 90 lung cancer specimens to analyze the levels of FOXD1 mRNA and found that the aberrant FOXD1 mRNA was correlated with NSCLC patient survival.…”

“…Another study has shown that FOXD1 promoted cell proliferation and chemotherapy resistance by inducing the G1 to S phase transition in breast cancer [10]. FOXD1 was reported to be significantly upregulated in glioma samples, and further investigations suggested that FOXD1 directly regulated ALDH1A3 transcription to activate clonogenic and tumorigenic potential of mesenchymal stem-like cells of glioma [8]. These findings strongly indicated that FOXD1 enrichment in tumor cells might affect biological functions, including cell proliferation, apoptosis, invasion, and metastasis.…”

“…Furthermore, FOXD1 was found to be a mediator and indicator of cell reprogramming by mediating self-renewal and differentiation [6,7]. Increasing evidence has indicated that cell reprogramming is associated with tumor initiation and progress [8]. For example, FOXD1 was found to be increased in prostate cancer tissues and associated with lymph node metastasis [9].…”

Multiplexed RNAi therapy against brain tumor-initiating cells via lipopolymeric nanoparticle infusion delays glioblastoma progression

“…To evaluate the feasibility of local delivery to BTICs directly in the core of xenografts in mice, we opted to encapsulate combinations of siRNAs in 7C1 LPNPs targeting the four TFs concurrently. Because other circuits are responsible for maintaining the stem celllike phenotypes in other GBM subgroups listed in The Cancer Gene Atlas (TCGA), and because additional genetic/epigenetic circuits are being identified (25)(26)(27)(28), the current choice of RNAi therapeutic targets is not expected to apply to all GBM subtypes. The primary purpose of our work was to establish a proof-ofprinciple approach and to demonstrate that tumorigenesis can be antagonized using this vehicle and delivery strategy.…”