Abstract:KRAS mutations are causally linked to pro-tumor inflammation and identified as driving factors in tumorigenesis. Here, using multi-omics data gathered from a large set of patients, we showed that KRAS mutation was associated with a specific landscape of alternative mRNA splicing that connected to myeloid inflammation in intrahepatic cholangiocarcinoma (iCCA). Then, we identified a negative feedback mechanism in which the upregulation of interleukin 1 receptor antagonist (IL1RN)-201/203 due to alternative splic… Show more
“…Due to the limitations of prior 10 × single-cell techniques, neutrophils in TIME were not included in this dataset. Intriguingly, prior studies have unveiled that neutrophils are enriched in KRAS -mutated iCCA samples, consistent with our results that KRAS mutations were obviously enriched in the high LMRG score group (Lin et al 2022a ; Zhang et al 2023 ). Fig.…”
Section: Resultssupporting
confidence: 93%
“…Due to the limited sensitivity of scRNA-seq to neutrophils, neutrophil variations in scRNA-seq datasets were not analyzed. Given previous findings that neutrophils were enriched in tumors with KARS mutations (Lin et al 2022a ; Zhang et al 2023 ), neutrophils were included in further experimental verification.…”
Purpose
Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant and fatal liver tumor with increasing incidence worldwide. Lactate metabolism has been recently reported as a crucial contributor to tumor progression and immune regulation in the tumor microenvironment. However, it remains poorly identified about the biological functions of lactate metabolism in iCCA, which hinders the development of prognostic tools and therapeutic interventions.
Methods
The univariate Cox regression analysis and Boruta algorithm were utilized to identify key lactate metabolism-related genes (LMRGs), and a prognostic signature was constructed based on LMRG scores. Genomic variations and immune cell infiltration were evaluated in the high and low LMRG score groups. Finally, the biological functions of key LMRGs were verified with in vitro and in vivo experiments.
Results
Patients in the high LMRG score group exhibit a poor prognosis compared to those in the low LMRG score group, with a high frequency of TP53 and KRAS mutations. Moreover, the infiltration and function of NK cells were compromised in the high LMRG score group, consistent with the results from two independent single-cell RNA sequencing datasets and immunohistochemistry of tissue microarrays. Experimental data revealed that lactate dehydrogenase A (LDHA) knockdown inhibited proliferation and migration in iCCA cell lines and tumor growth in immunocompetent mice.
Conclusion
Our study revealed the biological roles of LDHA in iCCA and developed a reliable lactate metabolism-related prognostic signature for iCCA, offering promising therapeutic targets for iCCA in the clinic.
“…Due to the limitations of prior 10 × single-cell techniques, neutrophils in TIME were not included in this dataset. Intriguingly, prior studies have unveiled that neutrophils are enriched in KRAS -mutated iCCA samples, consistent with our results that KRAS mutations were obviously enriched in the high LMRG score group (Lin et al 2022a ; Zhang et al 2023 ). Fig.…”
Section: Resultssupporting
confidence: 93%
“…Due to the limited sensitivity of scRNA-seq to neutrophils, neutrophil variations in scRNA-seq datasets were not analyzed. Given previous findings that neutrophils were enriched in tumors with KARS mutations (Lin et al 2022a ; Zhang et al 2023 ), neutrophils were included in further experimental verification.…”
Purpose
Intrahepatic cholangiocarcinoma (iCCA) is a highly malignant and fatal liver tumor with increasing incidence worldwide. Lactate metabolism has been recently reported as a crucial contributor to tumor progression and immune regulation in the tumor microenvironment. However, it remains poorly identified about the biological functions of lactate metabolism in iCCA, which hinders the development of prognostic tools and therapeutic interventions.
Methods
The univariate Cox regression analysis and Boruta algorithm were utilized to identify key lactate metabolism-related genes (LMRGs), and a prognostic signature was constructed based on LMRG scores. Genomic variations and immune cell infiltration were evaluated in the high and low LMRG score groups. Finally, the biological functions of key LMRGs were verified with in vitro and in vivo experiments.
Results
Patients in the high LMRG score group exhibit a poor prognosis compared to those in the low LMRG score group, with a high frequency of TP53 and KRAS mutations. Moreover, the infiltration and function of NK cells were compromised in the high LMRG score group, consistent with the results from two independent single-cell RNA sequencing datasets and immunohistochemistry of tissue microarrays. Experimental data revealed that lactate dehydrogenase A (LDHA) knockdown inhibited proliferation and migration in iCCA cell lines and tumor growth in immunocompetent mice.
Conclusion
Our study revealed the biological roles of LDHA in iCCA and developed a reliable lactate metabolism-related prognostic signature for iCCA, offering promising therapeutic targets for iCCA in the clinic.
“…We detected the phosphorylation level of ERK after co-culture, but we found that after about 12 h–24 h, the phosphorylation level of ERK became irregular, and even at 48h, the phosphorylation level of SIRPB1 KO could be higher than that of SIRPB1 WT in some repeated experiments, possibly due to the activation of some feedback mechanism. For example, Zhang et al [ 70 ] found that two transcripts of IL1RN (ENST00000259206.9 and ENST00000361779.7) were generated by mutually exclusive exons, which could inhibit ERK through some negative feedback mechanism. Between macrophages and microglia in vivo and the THP-1 model in vitro, there were variations in their expression profiles.…”
Background
SIRPB1 expression is upregulated in various tumor types, including gliomas, and is known to contribute to tumor progression; nevertheless, its function in the immune milieu of gliomas is still mainly unknown.
Methods
This study, we analyzed 1152 normal samples from the GTEx database and 670 glioma samples from the TCGA database to investigate the relationship between the expression of SIRPB1 and clinicopathological features. Moreover, SIRPB1 gene knockout THP-1 cell lines were constructed using CRISPR/Cas9 and were induced into a co-culture of macrophages and glioma cells in vitro to learn more about the role of SIRPB1 in the glioma immune milieu. Lastly, we established a prognostic model to predict the effect of SIRPB1 on prognosis.
Results
Significantly higher levels of SIRPB1 expression were found in gliomas, which had an adverse effect on the immune milieu and correlated poorly with patient survival. SIRPB1 activation with certain antibodies results in SYK phosphorylation and the subsequent activation of calcium, MAPK, and NF-κB signaling pathways. This phenomenon is primarily observed in myeloid-derived cells as opposed to glioma cells. In vitro co-culture demonstrated that macrophages with SIRPB1 knockout showed decreased IL1RA, CCL2, and IL-8, which were recovered upon ectopic expression of SIRPB1 but reduced again following treatment with SYK inhibitor GS9973. Critically, a lower overall survival rate was linked to increased SIRPB1 expression. Making use of SIRPB1 expression along with additional clinicopathological variables, we established a nomogram that showed a high degree of prediction accuracy.
Conclusions
Our study demonstrates that glioma cells can be activated by macrophages via SIRPB1, subsequently reprogramming the TME, suggesting that SIRPB1 could serve as a promising therapeutic target for gliomas.
“…iCCA S2 is characterized by the lowest methylation level and the highest mutation burden among the four subtypes, and a gene-expression pattern associated with cell cycle/DNA replication, whereas iCCA S3 is characterized by considerably high interpatient heterogeneity of tumor immunity, a gene-expression pattern associated with carbohydrate metabolism and a preference for KRAS alterations, which closely associates with the response of anti–PD-1 therapy synergistically enhanced by interleukin-1 receptor antagonist (IL1 Ra; ref. 63 ). Based on the results from in vitro function analyses, the high frequency of GBP4 demethylation in S2 and S3 also highlights the urgent need for future anti-GBP4 treatment, and the poor survival of S2 and S3 also raises the necessity of combined surgical-adjuvant therapies for these two subtypes.…”
Intrahepatic cholangiocarcinoma (iCCA) is the second most prevalent primary liver cancer. While the genetic characterization of iCCA has led to targeted therapies for treating tumors with FGFR2 alterations and IDH1/2 mutations, only a limited number of patients can benefit from these strategies. Epigenomic profiles have emerged as potential diagnostic and prognostic biomarkers for improving treatment of cancers. In this study, we conducted whole-genome bisulfite sequencing on 331 iCCAs integrated with genetic, transcriptomic, and proteomic analyses, demonstrating the existence of four DNA methylation subtypes of iCCAs (S1-S4) that exhibited unique post-operative clinical outcomes. The S1 group was an IDH1/2-mutation-specific subtype with moderate survival. The S2 subtype was characterized by the lowest methylation level and the highest mutational burden among the four subtypes and displayed upregulation of a gene expression pattern associated with cell cycle/DNA replication. The S3 group was distinguished by high inter-patient heterogeneity of tumor immunity, a gene expression pattern associated with carbohydrate metabolism, and an enrichment of KRAS alterations. Patients with the S2 and S3 subtypes had the shortest survival among the four subtypes. Tumors in the S4 subtype, which had the best prognosis, showed global methylation levels comparable to normal controls, increased FGFR2 fusions/BAP1 mutations, and the highest copy number variant burdens. Further integrative and functional analyses identified GBP4 demethylation, which is highly prevalent in the S2 and S3 groups, as an epigenetic oncogenic factor that regulates iCCA proliferation, migration, and invasion. Together, this study identifies prognostic methylome alterations and epigenetic drivers in iCCA.
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