The NALCN channel regulates metastasis and nonmalignant cell dissemination

Rahrmann, Eric P.; Shorthouse, David; Jassim, Amir; Hu, Linda P; Ortiz, Mariaestela; Mahler–Araujo, Betania; Vogel, Peter; Páez-Ribes, Marta; Fatemi, Atefeh; Hannon, Gregory J.; Iyer, Radhika; Blundon, Jay A.; Lourenço, Filipe C.; Kay, Jonathan; Nazarian, Rosalynn M.; Hall, Benjamin A.; Zakharenko, Stanislav S.; Winton, Douglas J.; Zhu, Linghui; Gilbertson, Richard J.

doi:10.1038/s41588-022-01182-0

Cited by 41 publications

(33 citation statements)

References 59 publications

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“…Loss of NALCN promotes cancer metastasis. A dramatic increase in cancer metastasis with the deletion of NALCN in mice validates NALCN lossof-function is a significant cancer metastasis driver (Rahrmann et al, 2022). Deleting NALCN from normal gastric stem cells, upregulation of epithelial-mesenchymal transition and invasion genes were observed within 72 h (Rahrmann et al, 2022).…”

Section: Discussionmentioning

confidence: 93%

“…Mutations of NALCN in human cancer at a similar frequency of TP53, suggesting that NALCN could act as a tumor suppressor (Joerger and Fersht, 2016). Recently, Eric P. Rahrmann et al found that trafficking of epithelial cells to distant tissues is regulated by NALCN, and loss of NALCN promotes cancer metastasis (Rahrmann et al, 2022). However, no comprehensive pan-cancer analysis of NALCN has been conducted.…”

Section: Discussionmentioning

confidence: 99%

“…A genome-wide association study showed that SNPs located in the genomic regions of NALCN have prognostic implication in advanced NSCLC ( Lee et al, 2013 ). Circulating tumor cells (CTCs) and metastases are increased significantly through NALCN regulates malignant epithelial cells released into the blood from primary tumors ( Rahrmann et al, 2022 ). Here, survival association analysis was conducted for each type of cancer using Cox regression analysis and KM survival curves, to examine the relationship between NALCN expression level and cancer prognosis, including OS, PFI, and DSS.…”

Section: Discussionmentioning

confidence: 99%

“…For a long time, NALCN was identified as a single ion channel. However, lately study has revealed that NALCN is essential for the metastasis of cancer and the transmission of normal cells ( Rahrmann et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

“…In gastric and colorectal cancers, there was an enriched presence of loss-of-function mutations of NALCN. Tumor incidence was unaffected by deletion of NALCN in mouse model, but tumor cell metastasis was markedly increased ( Rahrmann et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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NALCN is a potential biomarker and therapeutic target in human cancers

Chang

et al. 2023

Front. Genet.

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Background: Sodium leak channel non-selective (NALCN), known as a voltage-independent Na+ channel, is increasingly considered to play vital roles in tumorigenesis and metastasis of human cancers. However, no comprehensive pan-cancer analysis of NALCN has been conducted. Our study aims to explore the potential diagnostic, prognostic and therapeutic value of NALCN in human cancers.Methods: Through comprehensive application of datasets from Human Protein Atlas (HPA), The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), Enhanced Version of Tumor Immune Estimation Resource (TIMER2.0), Tumor and Immune System Interaction Database (TISIDB), The University of Alabama at Birmingham Cancer data analysis Portal (UALCAN), cBioPortal, GeneMANIA and Search Tool for the Retrieval of Interaction Gene/Proteins (STRING) databases, we explored the potential roles of NALCN in different cancers. The differential expression, prognostic implications, pathological stages and grades, molecular and immune subtypes, diagnostic accuracy, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, immune checkpoint genes, chemokine genes, major histocompatibility complex (MHC)-related genes, tumor-infiltrating immune cells (TIICs), promoter methylation, mutations, copy number alteration (CNA), and functional enrichment related to NALCN were analyzed.Results: Most cancers lowly expressed NALCN. Upregulated NALCN expression was associated with poor or better prognosis in different cancers. Moreover, NALCN was correlated with clinicopathological features in multiple cancers. NALCN showed high diagnostic accuracy in 5 caner types. NALCN is highly linked with immune-related biomarkers, immune-related genes and TIICs. Significant methylation changes and genetic alteration of NALCN can be observed in many cancers. Enrichment analysis showed that NALCN is closely related to multiple tumor-related signaling pathways.Conclusion: Our study revealed the vital involvement of NALCN in cancer. NALCN can be used as a prognostic biomarker for immune infiltration and clinical outcomes, and has potential diagnostic and therapeutic implications.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NALCN is a potential biomarker and therapeutic target in human cancers

Chang

et al. 2023

Front. Genet.

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Neuron-Cancer Synaptic and Other Electrical Signaling

Venkatesh¹

2023

Cancer Neuroscience

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How much do we know about the metastatic process?

Rodriguez-Tirado,

Sosa

2024

Clin Exp Metastasis

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Cancer cells can leave their primary sites and travel through the circulation to distant sites, where they lodge as disseminated cancer cells (DCCs), even during the early and asymptomatic stages of tumor progression. In experimental models and clinical samples, DCCs can be detected in a non-proliferative state, defined as cellular dormancy. This state can persist for extended periods until DCCs reawaken, usually in response to niche-derived reactivation signals. Therefore, their clinical detection in sites like lymph nodes and bone marrow is linked to poor survival. Current cancer therapy designs are based on the biology of the primary tumor and do not target the biology of the dormant DCC population and thus fail to eradicate the initial or subsequent waves of metastasis. In this brief review, we discuss the current methods for detecting DCCs and highlight new strategies that aim to target DCCs that constitute minimal residual disease to reduce or prevent metastasis formation. Furthermore, we present current evidence on the relevance of DCCs derived from early stages of tumor progression in metastatic disease and describe the animal models available for their study. We also discuss our current understanding of the dissemination mechanisms utilized by genetically less- and more-advanced cancer cells, which include the functional analysis of intermediate or hybrid states of epithelial–mesenchymal transition (EMT). Finally, we raise some intriguing questions regarding the clinical impact of studying the crosstalk between evolutionary waves of DCCs and the initiation of metastatic disease.

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The NALCN channel regulates metastasis and nonmalignant cell dissemination

Cited by 41 publications

References 59 publications

NALCN is a potential biomarker and therapeutic target in human cancers

NALCN is a potential biomarker and therapeutic target in human cancers

Neuron-Cancer Synaptic and Other Electrical Signaling

How much do we know about the metastatic process?

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