bims-meluca 2023-07-09 papers

Funct Integr Genomics. 2023 Jul 04. 23(3): 221

Glycolysis induces Th2 cell infiltration and significantly affects prognosis and immunotherapy response to lung adenocarcinoma.

Liping Zeng, Lu Liang, Xianlei Fang, Sha Xiang, Chenglong Dai, Tao Zheng, Tian Li, Zhenbo Feng.

Glycolysis has a major role in cancer progression and can affect the tumor immune microenvironment, while its specific role in lung adenocarcinoma (LUAD) remains poorly studied. We obtained publicly available data from The Cancer Genome Atlas and Gene Expression Omnibus databases and used R software to analyze the specific role of glycolysis in LUAD. The Single Sample Gene Set Enrichment Analysis (ssGSEA) indicated a correlation between glycolysis and unfavorable clinical outcome, as well as a repression effect on the immunotherapy response of LUAD patients. Pathway enrichment analysis revealed a significant enrichment of MYC targets, epithelial-mesenchymal transition (EMT), hypoxia, G2M checkpoint, and mTORC1 signaling pathways in patients with higher activity of glycolysis. Immune infiltration analysis showed a higher infiltration of M0 and M1 macrophages in patients with elevated activity of glycolysis. Moreover, we developed a prognosis model based on six glycolysis-related genes, including DLGAP5, TOP2A, KIF20A, OIP5, HJURP, and ANLN. Both the training and validation cohorts demonstrated the high efficiency of prognostic prediction in this model, which identified that patients with high risk may have a poorer prognosis and lower sensitivity to immunotherapy. Additionally, we also found that Th2 cell infiltration may predict poorer survival and resistance to immunotherapy. The study indicated that glycolysis is significantly associated with poor prognosis in patients with LUAD and immunotherapy resistance, which might be partly dependent on the Th2 cell infiltration. Additionally, the signature comprised of six genes related to glycolysis showed promising predictive value for LUAD prognosis.

Keywords: Glycolysis; Immunotherapy; Model; Prognosis; Th2 cell

DOI: https://doi.org/10.1007/s10142-023-01155-4

bioRxiv. 2023 Jun 14. pii: 2023.06.14.544941. [Epub ahead of print]

Live-cell invasive phenotyping uncovers the ALK2/BMP6 iron homeostasis pathway as a therapeutic vulnerability in LKB1-mutant lung cancer.

Junghui Koo, Chang-Soo Seong, Rebecca E Parker, Bhakti Dwivedi, Robert A Arthur, Ashok Reddy Dinasarapu, H Richard Johnston, Henry Claussen, Carol Tucker-Burden, Suresh S Ramalingam, Haian Fu, Wei Zhou, Adam I Marcus, Melissa Gilbert-Ross.

The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that likely contribute to unique growth properties and therapeutic susceptibilities. Despite this, pre-clinical discovery strategies designed to exploit invasive phenotypes are lacking. To address this, we designed an experimental system to screen for targetable signaling pathways linked to active early invasion phenotypes in the two most prominent molecular subtypes, TP53 and LKB1, of KRAS-driven lung adenocarcinoma (LUAD). By combining live-cell imaging of human bronchial epithelial cells in a 3D invasion matrix with RNA transcriptome profiling, we identified the LKB1-specific upregulation of bone morphogenetic protein 6 (BMP6). Examination of early-stage lung cancer patients confirmed upregulation of BMP6 in LKB1-mutant lung tumors. At the molecular level, we find that the canonical iron regulatory hormone Hepcidin is induced via BMP6 signaling upon LKB1 loss, where intact LKB1 kinase activity is necessary to maintain signaling homeostasis. Furthermore, pre-clinical studies in a novel Kras/Lkb1-mutant syngeneic mouse model show that potent growth suppression was achieved by inhibiting the ALK2/BMP6 signaling axis with single agents that are currently in clinical trials. We show that alterations in the iron homeostasis pathway are accompanied by simultaneous upregulation of ferroptosis protection proteins. Thus, LKB1 is sufficient to regulate both the 'gas' and 'breaks' to finely tune iron-regulated tumor progression.

DOI: https://doi.org/10.1101/2023.06.14.544941

Aging (Albany NY). 2023 Jul 03. 15

PRMT5 facilitates angiogenesis and EMT via HIF-1α/VEGFR/Akt signaling axis in lung cancer.

Yonghua Zheng, Huaxia Ji, Wulin Yi, Zhanjun Chen, Xiaobiao Hu, Jie Zhou, Yang Wang, Xiao Zheng.

Abnormal angiogenesis is a critical factor in tumor growth and metastasis, and protein arginine methyltransferase 5 (PRMT5), a prominent type II enzyme, is implicated in various human cancers. However, the precise role of PRMT5 in regulating angiogenesis to promote lung cancer cell metastasis and the underlying molecular mechanisms are not fully understood. Here, we show that PRMT5 is overexpressed in lung cancer cells and tissues, and its expression is triggered by hypoxia. Moreover, inhibiting or silencing PRMT5 disrupts the phosphorylation of the VEGFR/Akt/eNOS angiogenic signaling pathway, NOS activity, and NO production. Additionally, inhibiting PRMT5 activity reduces HIF-1α expression and stability, resulting in the down-regulation of the VEGF/VEGFR signaling pathway. Our findings indicate that PRMT5 promotes lung cancer epithelial-mesenchymal transition (EMT), which might be possibly through controlling the HIF-1α/VEGFR/Akt/eNOS signaling axis. Our study provides compelling evidence of the close association between PRMT5 and angiogenesis/EMT and highlights the potential of targeting PRMT5 activity as a promising therapeutic approach for treating lung cancer with abnormal angiogenesis.

Keywords: EMT; HIF-1α; PRMT5; angiogenesis; lung cancer

DOI: https://doi.org/10.18632/aging.204826

J Comput Assist Tomogr. 2023 Jul 07.

Body Composition and Radiomics From 18F-FDG PET/CT Together Help Predict Prognosis for Patients With Stage IV Non-Small Cell Lung Cancer.

Yi Zhang, Weiyue Tan, Zhonghang Zheng, Jie Wang, Ligang Xing, Xiaorong Sun.

PURPOSE: To determine whether integration of data on body composition and radiomic features obtained using baseline 18F-FDG positron emission tomography/computed tomography (PET/CT) images can be used to predict the prognosis of patients with stage IV non-small cell lung cancer (NSCLC).METHODS: A total of 107 patients with stage IV NSCLC were retrospectively enrolled in this study. We used the 3D Slicer (The National Institutes of Health, Bethesda, Maryland) software to extract the features of PET and CT images. Body composition measurements were taken at the L3 level using the Fiji (Curtis Rueden, Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison) software. Independent prognostic factors were defined by performing univariate and multivariate analyses for clinical factors, body composition features, and metabolic parameters. Data on body composition and radiomic features were used to build body composition, radiomics, and integrated (combination of body composition and radiomic features) nomograms. The models were evaluated to determine their prognostic prediction capabilities, calibration, discriminatory abilities, and clinical applicability.
RESULTS: Eight radiomic features relevant to progression-free survival (PFS) were selected. Multivariate analysis showed that the visceral fat area/subcutaneous fat area ratio independently predicted PFS (P = 0.040). Using the data for body composition, radiomic features, and integrated features, nomograms were established for the training (areas under the curve = 0.647, 0.736, and 0.803, respectively) and the validation sets (areas under the receiver operating characteristic = 0.625, 0.723, and 0.866, respectively); the integrated model showed better prediction ability than that of the other 2 models. The calibration curves revealed that the integrated nomogram exhibited a better agreement between the estimation and the actual observation in terms of prediction of the probability of PFS than that of the other 2 models. Decision curve analysis revealed that the integrated nomogram was superior to the body composition and radiomics nomograms for predicting clinical benefit.
CONCLUSION: Integration of data on body composition and PET/CT radiomic features can help in prediction of outcomes in patients with stage IV NSCLC.

DOI: https://doi.org/10.1097/RCT.0000000000001496

Transl Oncol. 2023 Jul 04. pii: S1936-5233(23)00121-3. [Epub ahead of print]35 101735

Matched tissue and liquid biopsies for advanced non-small cell lung cancer patients A potentially indispensable complementary approach.

Paul Hofman.

The introduction of liquid biopsies (LB) has brought forth a number of therapeutic opportunities into the domain of thoracic oncology. Many of which have been adopted for care of patients presenting with advanced non-squamous non-small cell lung cancer (aNS-NSCLC). For example, one of the most frequent indications to perform a LB in these patients, at least in Europe, is for patients treated with tyrosine kinase inhibitors (TKIs) targeting EGFR and ALK genomic alterations when the tumor progresses. A tissue biopsy (TB) must then be taken, ideally from a site of a tumor that progresses, in particular if the LB does not permit detection of a mechanism of resistance to TKI. A LB from a patient with aNS-NSCLC is recommended before first-line therapy if no tissue and/or cytological material is accessible or if the extracted nucleic acid is insufficient in amount and/or of poor quality. At present a LB and a TB are rarely performed simultaneously before treatment and/or on tumor progression. This complementary/matched testing approach is still controversial but needs to be better evaluated to determine the true benefit to care of patients. This review provides an update on the complementarity of the LB and TB method for care of patients presenting with aNS-NSCLC.

Keywords: Liquid biopsy; Lung cancer; NGS; Precision medicine; RT-PCR; Tissue biopsy

DOI: https://doi.org/10.1016/j.tranon.2023.101735

bioRxiv. 2023 Jun 23. pii: 2023.06.15.545165. [Epub ahead of print]

Characterization of genetic and molecular tools for studying the endogenous expression of Lactate dehydrogenase in Drosophila melanogaster.

Madhulika Rai, Sarah M Carter, Shefali A Shefali, Geetanjali Chawla, Jason M Tennessen.

Drosophila melanogaster larval development relies on a specialized metabolic state that utilizes carbohydrates and other dietary nutrients to promote rapid growth. One unique feature of the larval metabolic program is that Lactate Dehydrogenase (Ldh) activity is highly elevated during this growth phase when compared to other stages of the fly life cycle, indicating that Ldh serves a key role in promoting juvenile development. Previous studies of larval Ldh activity have largely focused on the function of this enzyme at the whole animal level, however, Ldh expression varies significantly among larval tissues, raising the question of how this enzyme promotes tissue-specific growth programs. Here we characterize two transgene reporters and an antibody that can be used to study Ldh expression in vivo . We find that all three tools produce similar Ldh expression patterns. Moreover, these reagents demonstrate that the larval Ldh expression pattern is complex, suggesting the purpose of this enzyme varies across cell types. Overall, our studies validate a series of genetic and molecular reagents that can be used to study glycolytic metabolism in the fly.

DOI: https://doi.org/10.1101/2023.06.15.545165