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Anoikis patterns via machine learning strategy and experimental verification exhibit distinct prognostic and immune landscapes in melanoma

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Abstract

Background

Anoikis is a cell death programmed to eliminate dysfunctional or damaged cells induced by detachment from the extracellular matrix. Utilizing an anoikis-based risk stratification is anticipated to understand melanoma's prognostic and immune landscapes comprehensively.

Methods

Differential expression genes (DEGs) were analyzed between melanoma and normal skin tissues in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression data sets. Next, least absolute shrinkage and selection operator, support vector machine–recursive feature elimination algorithm, and univariate and multivariate Cox analyses on the 308 DEGs were performed to build the prognostic signature in the TCGA–melanoma data set. Finally, the signature was validated in GSE65904 and GSE22155 data sets. NOTCH3, PIK3R2, and SOD2 were validated in our clinical samples by immunohistochemistry.

Results

The prognostic model for melanoma patients was developed utilizing ten hub anoikis-related genes. The overall survival (OS) of patients in the high-risk subgroup, which was classified by the optimal cutoff value, was remarkably shorter in the TCGA–melanoma, GSE65904, and GSE22155 data sets. Low-risk patients exhibited low immune cell infiltration and high expression of immunophenoscores and immune checkpoints. They also demonstrated increased sensitivity to various drugs, including dasatinib and dabrafenib. NOTCH3, PIK3R2, and SOD2 were notably associated with OS by univariate Cox analysis in the GSE65904 data set. The clinical melanoma samples showed remarkably higher protein expressions of NOTCH3 (P = 0.003) and PIK3R2 (P = 0.009) than the para-melanoma samples, while the SOD2 protein expression remained unchanged.

Conclusions

In this study, we successfully established a prognostic anoikis-connected signature using machine learning. This model may aid in evaluating patient prognosis, clinical characteristics, and immune treatment modalities for melanoma.

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Data availability

This study's data generated or examined are comprehensively presented in this article or the supplementary materials. Without reservation, the author is committed to providing the raw data confirming the outcomes of this article to qualified researchers.

Abbreviations

ML:

Machine learning

GTEx:

Genotype-tissue expression

TCGA:

The cancer genome atlas

SVM–RFE:

Support vector machine–recursive feature elimination

ICPs:

Immune checkpoints

IPSs:

Immunophenoscores

LASSO:

Least absolute shrinkage and selection operator

DEGs:

Differentially expressed genes

DAVID:

Database for annotation, visualization and integrated discovery

TSG101:

Tumor susceptibility gene 101

NQO1:

NAD(P)H dehydrogenase (quinone 1)

EGFR:

Epidermal growth factor receptor

DAPK2:

Death-associated protein kinase 2

CEBPB:

CCAAT enhancer binding protein b

BNIP3:

Bcl-2/E1B 19 kDa interacting protein

ANXA5:

Annexin A5

PIK3R2:

Phosphatidylinositol 3-kinase p85beta

SOD2:

Superoxide dismutase 2

GO:

Gene Ontology

KEGG:

Kyoto encyclopedia of genes and genomes

AUC:

Area under the curve

AJCC:

American Joint Committee on Cancer

ROC:

Receiver operating characteristic

GDSC:

Genomics of drug sensitivity in cancer

IHC:

Immunohistochemistry

HR:

Hazard regression

TME:

Tumor microenvironment

IPSs:

Immunophenoscores

ICPs:

Immune checkpoints

CAF:

Cancer-associated fibroblast

MDSC:

Myeloid derived suppressive cell

M2 TAM:

M2 tumor-associated macrophages

PD-1:

Anti-programmed death 1

CTLA-4:

Anti-cytotoxic T lymphocyte-associated antigen 4

PD-L1:

Programmed death ligand 1

TIM3:

Mucin-domain containing-3

LAG3:

Lymphocyte-activation gene-3

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Funding

This research was supported by the National Science Foundation of China [grant number 31870974].

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Conceptualization, JL; data curation, JL, NN and RM; formal analysis, JL and SZ; funding acquisition, GL and YL; investigation, JL; methodology, JL and QD; software, JL; supervision, GL; validation, JL and SC; visualization, JL; writing—original draft, JL and GL; writing—review and editing, GL and YL.

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Correspondence to Yongxian Lai or Guangpeng Liu.

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12094_2023_3336_MOESM1_ESM.docx

Supplementary data to this article can be found online. Supplementary Table S1. The coefficients assessed by multivariate Cox regression. Supplementary Table S2. Correlations between the expression of NOTCH3 and PIK3R2 and clinical characteristics in melanoma patients. Supplementary Figure S1. Univariate Cox regression, OS, and ROC analysis of melanoma patients in the GSE65904 or GSE22155 datasets. (A)OS analysis of melanoma patients in the GSE22155 dataset. (B)ROC analysis of melanoma patients in the GSE22155 dataset. (C)Univariate Cox regression of melanoma patients in the GSE65904 dataset. (DOCX 266 KB)

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Liu, J., Ma, R., Chen, S. et al. Anoikis patterns via machine learning strategy and experimental verification exhibit distinct prognostic and immune landscapes in melanoma. Clin Transl Oncol 26, 1170–1186 (2024). https://doi.org/10.1007/s12094-023-03336-w

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