Scholar - SciOpen

Protein lactylation is a new way for the “metabolic waste” lactic acid to perform novel functions. Nevertheless, our understanding of the contribution of protein lactylation to both tumor progression and therapeutic interventions remains imited. The construction of a scoring system for lactylation to predict the prognosis of pan-cancer patients and to evaluate the tumor immune microenvironment (TIME) would improve our understanding of the clinical significance of lactylation.

Methods

Consensus clustering analysis of lactylation-related genes was used to cluster 177 pancreatic adenocarcinoma (PAAD) patients. Subsequently, a scoring system was developed using the least absolute shrinkage and selection operator (LASSO) regression. Internal validation and external validation were both conducted to assess and confirm the predictive accuracy of the scoring system. Finally, leucine rich repeat containing 1 (LRRC1), a newly discovered lactylation-related gene, was analyzed in PAAD in vitro.

Results

Utilizing the profiles of 332 lactylation-related genes, a total of 177 patients with PAAD were segregated into two distinct groups. LacCluster^high patients had a poorer prognosis than LacCluster^low patients. Through the differential analysis between the LacCluster^high and LacCluster^low groups, we identified additional genes associated with lactylation. These genes were then integrated to construct the LacCluster-enhanced system, which enabled more accurate prognosis prediction for patients with PAAD. Then, a lactylation index containing three genes (LacI-3) was constructed using LASSO regression. This was done to enhance the usability of the LacCluster-enhanced system in the clinic. Compared to those in the LacI-3^high subgroup, patients in the LacI-3^low subgroup exhibited increased expression of immune checkpoint-related genes, more immune cell infiltration, lower tumor mutation burdens, and better prognoses, indicating a “hot tumor” phenotype. Moreover, knocking down the expression of LRRC1, the hub gene in the LacI-3 scoring system, inhibited PAAD cell invasion, migration, and proliferation in vitro. Ultimately, the significance of LacI-3 across cancers was confirmed.

Conclusion

Our findings strongly imply that protein lactylation may represent a new approach to diagnosing and treating malignant tumors.

Open Access Full Length Article Issue

Cancer-associated fibroblasts derived fibronectin extra domain A promotes sorafenib resistance in hepatocellular carcinoma cells by activating SHMT1

Yan Dong, Yanrong Chen, Yijie Wang, Xiang Zhao, Ruiyang Zi, Jie Hao, Qiong Ding, Haoran Jiang, Xuesong Wang, Fanghao Lu, Houjie Liang, Zhihao Wei, Jianjun Li

Genes & Diseases 2024, 11(6): 101330

Published: 20 May 2024

Abstract

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Resistance to sorafenib, an effective first-line treatment for advanced hepatocellular carcinoma (HCC), greatly compromised the prognosis of patients. The extracellular matrix is one of the most abundant components of the tumor microenvironment. Beyond acting as a physical barrier, it remains unclear whether cell interactions and signal transduction mediated by the extracellular matrix contribute to sorafenib resistance. With the analysis of primary HCC organoid RNA-seq data combined with in vivo and in vitro experiments validation, we discovered that fibronectin extra domain A (FN-EDA) derived from cancer-associated fibroblasts played a critical role in sorafenib resistance. Mechanistically, FN-EDA stimulates the up-regulation of the key one-carbon metabolism enzyme SHMT1 in HCC cells via the TLR4/NF-κB signaling pathway, thereby countering the oxidative stress induced by sorafenib. Moreover, we reinforced the clinical significance of our discoveries by conducting in vivo assays with an immunodeficiency subcutaneous xenograft tumor model, which was established using primary cancer-associated fibroblasts derived from clinical HCC tissues, and through the analysis of HCC samples obtained from The Cancer Genome Atlas (TCGA) database. Our findings suggest that targeting the FN-EDA/SHMT1 pathway could be a potential strategy to improve sorafenib responsiveness in HCC patients.

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