Identification and validation of a novel cuproptosis signature for stratifying different prognostic, immune,...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Pancreatic adenocarcinoma (PAAD) is a lethal malignancy with limited effective treatments.
• Cuproptosis, a novel cell death pathway, presents new opportunities for cancer therapy and assessment.

Purpose of the Study:

• To develop and validate a cuproptosis-related (CR) risk signature for prognostic assessment in PAAD.
• To investigate the association of the CR risk signature with the tumor immune microenvironment (TIM), programmed cell death (PCD) patterns, metabolic processes, and therapeutic efficacy.
• To explore the functional role of Lipoyltransferase 1 (LIPT1) in pancreatic cancer.

Main Methods:

• Constructed a CR risk signature using Lasso regression and validated it in multiple cohorts.
• Analyzed TIM, PCD, and metabolic associations using CIBERSORT, ESTIMATE, ssGSEA, and GESA.
• Evaluated therapeutic correlations using tumor mutation burden, immune checkpoint expression, TIDE, and GDSC.
• Assessed LIPT1 function in PAAD cells via in vitro assays and clinical sample analysis.

Main Results:

• A four-gene CR risk signature (LIPT1, LIAS, PDP1, GCSH) demonstrated significant prognostic value.
• The CR risk score correlated with CD8+ T cell and macrophage infiltration but not with PCD or metabolic patterns.
• The CR risk score predicted immunotherapy efficacy but not response to targeted or chemotherapeutic agents.
• LIPT1 was downregulated in PAAD, and its silencing promoted cancer cell proliferation, migration, and invasion.

Conclusions:

• The novel CR risk signature effectively stratifies PAAD patients.
• Cuproptosis regulatory genes, exemplified by LIPT1, offer promising avenues for PAAD treatment and clinical assessment.