The Emerging Portrait of Glial Cell Line-derived Neurotrophic Factor Family Receptor Alpha (GFRα) in Cancers

Li, Qingshang; Cao, Zhijun; Zhao, Shuliang

doi:10.7150/ijms.64133

Cited by 3 publications

(8 citation statements)

References 67 publications

(76 reference statements)

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“…The copyright holder for this preprint this version posted June 14, 2024. ; https://doi.org/10.1101/2024.06.14.598770 doi: bioRxiv preprint members of the glial cell line-derived neurotrophic factor (GDNF) family within the TGF-β superfamily with roles in neuronal survival, growth, and differentiation [84]. The GDNF family exhibits diverse roles in cancer [85] [86], including an association with therapy resistance in ERpositive BC, highlighting GFRA1 as a potential target [87][88][89] [90]. Additionally, the wellstudied chemokine interaction between 'CX3CL1' (C-X3-C chemokine ligand 1) and 'CX3CR1' (C-X3-C chemokine receptor 1) [91] is prominent in BrighTNess (Figure 4F; see PPI network in Supplementary Figure 6G), which is known to be involved in progression and metastasis across multiple cancers including BC, presenting a promising pan-cancer target [92] (which was not certified by peer review) is the author/funder.…”

Section: Identifying Key Cell-cell Interactions Associated With Chemo...mentioning

confidence: 99%

The expression patterns of different cell types and their interactions in the tumor microenvironment are predictive of breast cancer patient response to neoadjuvant chemotherapy

Dhruba,

Sahni,

Wang

et al. 2024

Preprint

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The tumor microenvironment (TME) is a complex ecosystem of diverse cell types whose interactions govern tumor growth and clinical outcome. While the TME’s impact on immunotherapy has been extensively studied, its role in chemotherapy response remains less explored. To address this, we developed DECODEM (DEcouplingCell-type-specificOutcomes usingDEconvolution andMachine learning), a generic computational framework leveraging cellular deconvolution ofbulk transcriptomicsto associate the gene expression of individual cell types in the TME with clinical response. Employing DECODEM to analyze the gene expression of breast cancer (BC) patients treated with neoadjuvant chemotherapy, we find that the gene expression of specific immune cells (myeloid,plasmablasts,B-cells) and stromal cells (endothelial,normal epithelial,CAFs) are highly predictive of chemotherapy response, going beyond that of the malignant cells. These findings are further tested and validated in a single-cell cohort of triple negative breast cancer. To investigate the possible role of immune cell-cell interactions (CCIs) in mediating chemotherapy response, we extended DECODEM to DECODEMi to identify such CCIs, validated in single-cell data. Our findings highlight the importance of active pre-treatment immune infiltration for chemotherapy success. The tools developed here are made publicly available and are applicable for studying the role of the TME in mediating response from readily available bulk tumor expression in a wide range of cancer treatments and indications.

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Section: Identifying Key Cell-cell Interactions Associated With Chemo...mentioning

confidence: 99%

The expression patterns of different cell types and their interactions in the tumor microenvironment are predictive of breast cancer patient response to neoadjuvant chemotherapy

Dhruba,

Sahni,

Wang

et al. 2024

Preprint

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“…The GFRα family, consisting of GFRα1, GFRα2, GFRα3, and GFRα4, is anchored to the plasma membrane via Glycosylphosphatidylinositols (GPIs). GPIs serve as membrane anchors for numerous eukaryotic cell surface proteins, including members of the GFRα family [97]. Although GFRα1, GFRα2, GFRα3, and GFRα4 are structurally similar, they determine specificity for four ligands called glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN), and persephin (PSPN), respectively [98].…”

Section: Nerve Growth Factor Receptor (Ngfr)mentioning

confidence: 99%

“…Although GFRα1, GFRα2, GFRα3, and GFRα4 are structurally similar, they determine specificity for four ligands called glial cell line-derived neurotrophic factor (GDNF), neurturin (NRTN), artemin (ARTN), and persephin (PSPN), respectively [98]. GFRα receptors, which are associated with cell growth, differentiation, cell migration and tissue maturation, have been extensively linked to various cancers [97]. GFRα1 expression is significantly upregulated in human breast cancers [99].…”

Section: Nerve Growth Factor Receptor (Ngfr)mentioning

confidence: 99%

“…GFRα [97] ARTN [97] Sympathetic innervation [19] Cholinergic innervation [121] NTRK inhibitor [89] mAChRs [117] ACh [120] NMDARs [130] NA DRD2 [146] NA…”

Section: Lung Cancermentioning

confidence: 99%

“…GFRα [97] ARTN [97,178], GDNF [97,105,168] NRTN [97] Sensory innervation [23,24] Beta blocker [2,39] NGF knockdown [23,88] Anti-NT3 [88] DRD2 blocker [221] DRD2 [221] NA Trks [88,90] BDNF, NT-3, NT-4/5 [88] AMPARs [126], NMDARs [132] Glutamate [126] Prostate cancer GFRα1 [97,102] GDNF [97] Sympathetic innervation [18] parasympathetic innervation [18] Beta blocker [54,207] β2 and β3 receptor deletion [18] DRD2 blocker [186] NMDAR [129,183] Glutamate [183] Trks [88] NT-3, BDNF, NGF [88] Breast cancer DRD2 [146] NA Sympathetic innervation [38,79] Sensory innervation [91] Surgical denervation [17] Beta blockers [31,53] NMDA [131] Glutamate [182,183] Trks [89] BDNF [159], NT-3 …”

Section: Lung Cancermentioning

confidence: 99%

See 2 more Smart Citations

Unveiling the Neural Environment in Cancer: Exploring the Role of Neural Circuit Players and Potential Therapeutic Strategies

Nguyen,

Ngoc,

Choi

et al. 2023

Cells

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The regulation of the immune environment within the tumor microenvironment has provided new opportunities for cancer treatment. However, an important microenvironment surrounding cancer that is often overlooked despite its significance in cancer progression is the neural environment surrounding the tumor. The release of neurotrophic factors from cancer cells is implicated in cancer growth and metastasis by facilitating the infiltration of nerve cells into the tumor microenvironment. This nerve–tumor interplay can elicit cancer cell proliferation, migration, and invasion in response to neurotransmitters. Moreover, it is possible that cancer cells could establish a network resembling that of neurons, allowing them to communicate with one another through neurotransmitters. The expression levels of players in the neural circuits of cancers could serve as potential biomarkers for cancer aggressiveness. Notably, the upregulation of certain players in the neural circuit has been linked to poor prognosis in specific cancer types such as breast cancer, pancreatic cancer, basal cell carcinoma, and stomach cancer. Targeting these players with inhibitors holds great potential for reducing the morbidity and mortality of these carcinomas. However, the efficacy of anti-neurogenic agents in cancer therapy remains underexplored, and further research is necessary to evaluate their effectiveness as a novel approach for cancer treatment. This review summarizes the current knowledge on the role of players in the neural circuits of cancers and the potential of anti-neurogenic agents for cancer therapy.

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Assessment of CRISPRa-mediated gdnf overexpression in an In vitro Parkinson’s disease model

Guzmán-Sastoque,

Sotelo,

Esmeral

et al. 2024

Front. Bioeng. Biotechnol.

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IntroductionParkinson’s disease (PD) presents a significant challenge in medical science, as current treatments are limited to symptom management and often carry significant side effects. Our study introduces an innovative approach to evaluate the effects of gdnf overexpression mediated by CRISPRa in an in vitro model of Parkinson’s disease. The expression of gdnf can have neuroprotective effects, being related to the modulation of neuroinflammation and pathways associated with cell survival, differentiation, and growth.MethodsWe have developed a targeted delivery system using a magnetite nanostructured vehicle for the efficient transport of genetic material. This system has resulted in a substantial increase, up to 200-fold) in gdnf expression in an In vitro model of Parkinson’s disease using a mixed primary culture of astrocytes, neurons, and microglia.Results and DiscussionThe delivery system exhibits significant endosomal escape of more than 56%, crucial for the effective delivery and activation of the genetic material within cells. The increased gdnf expression correlates with a notable reduction in MAO-B complex activity, reaching basal values of 14.8 μU/μg of protein, and a reduction in reactive oxygen species. Additionally, there is up to a 34.6% increase in cell viability in an In vitro Parkinson’s disease model treated with the neurotoxin MPTP. Our study shows that increasing gdnf expression can remediate some of the cellular symptoms associated with Parkinson’s disease in an in vitro model of the disease using a novel nanostructured delivery system.

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The Emerging Portrait of Glial Cell Line-derived Neurotrophic Factor Family Receptor Alpha (GFRα) in Cancers

Cited by 3 publications

References 67 publications

The expression patterns of different cell types and their interactions in the tumor microenvironment are predictive of breast cancer patient response to neoadjuvant chemotherapy

The expression patterns of different cell types and their interactions in the tumor microenvironment are predictive of breast cancer patient response to neoadjuvant chemotherapy

Unveiling the Neural Environment in Cancer: Exploring the Role of Neural Circuit Players and Potential Therapeutic Strategies

Assessment of CRISPRa-mediated gdnf overexpression in an In vitro Parkinson’s disease model

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