Unraveling molecular characteristics and functional exploration of panoptosis for prognosis stratification in lung adenocarcinoma: a tumor marker prognostic study.

BACKGROUND

As a unique cell death modality mediated by multifaceted PANoptosome complexes, PANoptosis plays a crucial role in the development, invasion, and drug resistance of cancers. However, there is a lack of mechanisms for the PANoptosis in lung adenocarcinoma (LUAD).

METHODS

More than 1500 biopsy samples of LUAD and other cancers were collected from diversified cohorts in various databases. 10 machine-learning methodologies were combined into 101 algorithm combinations to establish the prognostic model. The landscape of tumor immune microenvironment (TIME) and response to immunotherapy were assessed across the bulk-transcriptome profile utilizing different algorithms. Single-cell RNA sequencing (scRNA-seq) unveiled one crucial gene as the risk factor of LUAD, which was verified and explored the potential biological mechanisms in vitro and in vivo.

RESULTS

In our research, the PANoptosis Score (PAN Score) can be regarded as an independent prognostic factor for LUAD, which outperformed other clinical features and previously published literatures. Integrating PAN Score with other clinical features into a nomogram enhanced the predictive accuracy. Meanwhile, patients with high PAN Score exhibited a suppressed TIME, less tumor-infiltrated lymphocytes, and resistance to immunotherapy and chemotherapy. As the crucial contributor of PAN Score, deficiency of 14-3-3γ (YWHAG) impaired LUAD progression significantly in vitro and in vivo, enhanced the sensitivity to chemotherapy, as well as activated the PANoptosis via decreasing the concentration of vasopressin.

CONCLUSIONS

Briefly, PAN Score is a robust biomarker for the prediction of prognosis and therapy response in LUAD patients. The YWHAG-vasopressin-PANoptosis axis may become the potential therapeutic target for LUAD.