VSTM2L Human

What is VSTM2L and what are its primary biological functions?

VSTM2L, previously known as C20orf102, is a secreted protein that regulates the interleukin (IL)-4 signaling pathway and functions as an antagonist of humanin, a neuroprotective peptide . The protein was identified through interaction studies with humanin and has been shown to modulate neuronal viability .

Methodological approaches for studying VSTM2L function include:

• Protein-protein interaction assays (yeast two-hybrid, co-immunoprecipitation)

• Secretion assays in cultured cells

• Functional antagonism studies against humanin activity

• Expression analysis across tissues and disease states

VSTM2L's dual involvement in immune pathways and neuroprotection suggests it may serve as a bridge between immune function and neurological processes, making it particularly interesting for researchers in neuroinflammation and neuroimmunology.

What is the expression profile of VSTM2L across normal human tissues?

VSTM2L demonstrates a tissue-specific expression pattern that provides insights into its potential biological roles. Based on GTEx data analysis, VSTM2L mRNA shows widespread but variable expression across normal human tissues .

Methodological approaches for expression profiling:

• RNA sequencing from GTEx database for transcriptome analysis

• Immunohistochemistry from Human Protein Atlas for protein validation

• Comparative expression analysis across multiple databases (GTEx, TCGA)

• qPCR validation in tissue panels

The high expression in brain and pituitary aligns with findings that VSTM2L antagonizes humanin, a neuroprotective peptide, suggesting specialized functions in the central nervous system .

How does VSTM2L expression vary across different cancer types?

VSTM2L expression shows remarkable heterogeneity across cancer types, with significant implications for its potential role in cancer biology .

Research methodologies for cancer expression analysis:

• Integrated analysis of TCGA and GTEx databases

• Cancer cell line expression from CCLE database

• Protein validation through immunohistochemistry

• Correlation with clinical parameters (stage, grade)

These contrasting expression patterns suggest context-dependent roles of VSTM2L in different tumor types, possibly related to tissue-specific signaling pathways or tumor microenvironment interactions .

Which databases and tools are most valuable for VSTM2L research?

Researchers investigating VSTM2L can leverage multiple complementary databases to gain comprehensive insights :

Methodological considerations:

• Data normalization approaches (e.g., log2 conversion for RNA-seq)

• Integration of multiple data sources for comprehensive analysis

• Validation across independent cohorts

• Statistical methods for correlation analysis

This multi-database approach enables robust analysis of VSTM2L across various biological and clinical contexts .

What is known about the interaction between VSTM2L and humanin?

VSTM2L was identified as a novel secreted antagonist of humanin (HN), a 24-residue peptide with protective activity against cytotoxic and neurotoxic insults .

Key experimental findings:

• VSTM2L interacts with humanin in both yeast and mammalian cell systems

• VSTM2L is secreted in cultured cells and present in serum

• VSTM2L colocalizes with humanin in specific brain regions

• VSTM2L colocalizes with humanin in primary cultured neurons

• VSTM2L modulates neuronal viability

Methodological approaches for studying this interaction:

• Protein interaction screening (yeast two-hybrid)

• Co-immunoprecipitation for validation in mammalian systems

• Secretion assays to confirm extracellular function

• Immunofluorescence for colocalization studies

• Neuronal viability assays to assess functional antagonism

This interaction suggests VSTM2L may play a role in regulating neuroprotective pathways, with potential implications for neurodegenerative conditions like Alzheimer's disease .

How does VSTM2L expression correlate with patient prognosis across different cancer types?

VSTM2L demonstrates remarkable cancer-specific prognostic significance, serving as either a favorable or unfavorable indicator depending on cancer type :

Advanced methodological approaches:

• Multivariate Cox regression analysis to control for clinical covariates

• Time-dependent ROC curve analysis for predictive performance (AUC = 0.692 for VSTM2L in STAD)

• Kaplan-Meier survival analysis stratified by expression levels

• Validation in independent GEO cohorts (GSE84437 for STAD, GSE2748 for KIRP)

The contrasting prognostic value of VSTM2L in different cancers suggests distinct biological roles that researchers should consider when designing targeted studies or therapeutic approaches .

What is the relationship between VSTM2L and tumor-infiltrating immune cells?

VSTM2L expression shows significant correlations with tumor-infiltrating immune cells (TIICs) across multiple cancer types, suggesting a role in immune regulation within the tumor microenvironment :

Methodological considerations:

• Computational deconvolution of bulk RNA-seq to estimate immune cell fractions

• Correlation analysis with adjustment for tumor purity

• Validation using immunohistochemistry or flow cytometry

• Integration with other immune parameters (checkpoint molecules, cytokines)

These correlations vary substantially across cancer types, suggesting tissue-specific or context-dependent immune regulatory functions of VSTM2L .

How does VSTM2L correlate with immunomodulatory factors across cancer types?

VSTM2L shows significant associations with various immunomodulatory factors, including immunostimulatory and immunoinhibitory molecules :

Methodological approaches:

• Comprehensive correlation analysis with established immunomodulators

• Pathway enrichment analysis to identify relevant immune signaling networks

• Analysis of ImmuneScore and StromalScore correlations

• Integration with clinical response data where available

The strongest correlations with ImmuneScore were observed in CHOL (r=0.44), LGG (r=-0.4), and LUSC (r=0.39), while StromalScore showed strongest correlations in TGCT (r=0.55), CHOL (r=0.4), and BLCA (r=0.36) .

These patterns suggest VSTM2L may influence the tumor microenvironment through complex interactions with multiple immune regulatory pathways .

What methodological approaches are optimal for investigating VSTM2L as a prognostic biomarker?

Based on the established prognostic value of VSTM2L in multiple cancers, researchers should consider these methodological approaches :

Advanced considerations:

• Integration with established prognostic factors (TNM staging, molecular subtypes)

• Development of composite prognostic models incorporating VSTM2L

• Sensitivity analysis for expression cutoff determination

• Correction for multiple testing when assessing multiple cancer types

For STAD specifically, multivariate Cox regression demonstrated VSTM2L as an independent prognostic marker when compared to clinical characteristics such as primary tumor and lymph node status, with an AUC of 0.692 in ROC analysis .

How can researchers investigate potential mechanisms behind VSTM2L's dual role in cancer prognosis?

VSTM2L's contrasting prognostic associations across cancer types present an intriguing research opportunity :

Comprehensive investigative framework:

• Comparative transcriptomic analysis between cancers with opposing prognostic associations

• Protein interaction network analysis to identify tissue-specific binding partners

• Functional studies with tissue-specific cellular models

• CRISPR/Cas9 knockout followed by phenotype characterization

• Patient-derived xenograft models with varying VSTM2L expression levels

Understanding these mechanistic differences could potentially resolve the apparent contradiction in VSTM2L's prognostic role and suggest targeted therapeutic approaches for specific cancer contexts .

What are the optimal experimental methods for studying VSTM2L protein interactions?

Investigating VSTM2L's interactions with humanin and other potential binding partners requires sophisticated protein interaction methodologies :

Secretion analysis approaches:

• Conditioned media analysis with western blotting

• ELISA development for quantitative measurement

• Mass spectrometry for secretome profiling

• Signal peptide analysis and mutation studies

These methodologies have successfully identified VSTM2L as an interactor with humanin and could reveal additional binding partners that might explain its diverse biological functions .

How can researchers effectively analyze VSTM2L's relationship with tumor mutation burden and microsatellite instability?

The relationship between VSTM2L expression and genomic instability markers provides insight into potential mechanisms of action :

Technical considerations:

• Normalization of TMB scores across cancer types

• Standardization of MSI calculation methods

• Multiple testing correction for pan-cancer analysis

• Integration with other genomic instability markers

What bioinformatic pipelines are most appropriate for analyzing VSTM2L expression across multi-institutional datasets?

Robust bioinformatic approaches are essential for comprehensive VSTM2L analysis :

Specific pipeline components used in VSTM2L research:

• Merger of GTEx and TCGA data for comprehensive normal vs. tumor comparison

• Log2 normalization of RNA-seq data

• Kaplan-Meier analysis with median expression cutoff

• Cox regression with clinical covariate adjustment

• Spearman correlation for immune parameter associations

These approaches have successfully identified the pan-cancer expression patterns and prognostic significance of VSTM2L across multiple independent datasets .

How should researchers design functional studies to investigate VSTM2L's role in neuronal viability?

Based on VSTM2L's identified interaction with the neuroprotective peptide humanin, functional studies should address :

Critical methodological considerations:

• Selection of appropriate neuronal culture systems (primary neurons, neuronal cell lines)

• Development of quantitative viability and stress response assays

• Dosage titration to identify physiologically relevant concentrations

• Temporal analysis to distinguish immediate vs. delayed effects

• Integration with AD-relevant stressors (Aβ, tau, oxidative stress)

These approaches can help elucidate VSTM2L's potential role in neurodegenerative conditions like Alzheimer's disease through its antagonism of humanin's neuroprotective functions .

What are the best approaches for developing VSTM2L-targeted therapeutics based on current knowledge?

The dual role of VSTM2L in cancer prognosis and neuronal regulation suggests multiple therapeutic strategies :

Critical development steps:

• High-throughput screening for small molecule modulators

• Structure-based design targeting protein-protein interfaces

• Antibody development with functional validation

• Cancer-type specific preclinical models

• Patient stratification biomarkers

Given VSTM2L's context-dependent roles, therapeutic development requires careful consideration of tissue specificity and potential off-target effects across different biological systems .

How might VSTM2L's dual role in cancer and neuroprotection be integrated into a unified biological model?

The seemingly disparate functions of VSTM2L in cancer biology and neuronal regulation present an intriguing research opportunity :

This integrative approach may uncover shared molecular mechanisms that explain VSTM2L's diverse biological roles and potentially identify novel therapeutic opportunities targeting both cancer and neurological conditions .

What is the current state of research on VSTM2L genetic variants and their clinical significance?

While the search results don't specifically address VSTM2L genetic variants, this represents an important research direction:

This research area could provide insights into individual variability in VSTM2L expression and function, potentially explaining differential disease susceptibility or treatment response across patient populations.

How can single-cell transcriptomics advance our understanding of VSTM2L's role in the tumor microenvironment?

Single-cell approaches offer unprecedented resolution for investigating VSTM2L in complex tissues:

This high-resolution analysis could resolve apparent contradictions in VSTM2L's roles by identifying specific cellular contexts where it promotes or inhibits tumor progression, potentially leading to more precise therapeutic targeting strategies.

What is the potential role of VSTM2L in response to cancer immunotherapy?

Given VSTM2L's correlations with immune parameters, investigating its role in immunotherapy response represents a promising research direction :

The association between VSTM2L and immunomodulatory factors suggests it may influence treatment response through modulation of the tumor immune microenvironment, potentially serving as both a predictive biomarker and therapeutic target in the immunotherapy context .

How might VSTM2L research inform precision medicine approaches across cancer types?

The cancer-specific prognostic patterns of VSTM2L suggest opportunities for precision oncology applications :

Development considerations:

• Clinical assay development and validation

• Integration with existing molecular testing platforms

• Prospective validation in clinical trials

• Regulatory pathway for biomarker approval

The dual prognostic nature of VSTM2L emphasizes the importance of cancer-specific approaches in precision medicine, potentially improving patient selection for aggressive treatment regimens or clinical trials .

What are the most critical unresolved questions about VSTM2L that researchers should prioritize?

Despite significant progress in understanding VSTM2L, several fundamental questions remain:

• What is the molecular mechanism explaining VSTM2L's opposite prognostic roles in different cancers?

• How does VSTM2L regulate both immune function and neuronal viability?

• What are the downstream signaling pathways of VSTM2L in different cellular contexts?

• How does VSTM2L expression change during disease progression?

• What is the three-dimensional structure of VSTM2L and its complexes with binding partners?

Addressing these questions will require interdisciplinary approaches combining cancer biology, immunology, neuroscience, and structural biology to fully elucidate VSTM2L's complex biological roles .