bims-meluca 2023-08-13 papers

Mol Oncol. 2023 Aug 11.

Soluble galectin-3 as a microenvironment-relevant immunoregulator with prognostic and predictive value in lung adenocarcinoma.

Susana Torres-Martínez, Silvia Calabuig-Fariñas, Andrea Moreno-Manuel, Giulia Bertolini, Alejandro Herreros-Pomares, Eva Escorihuela, Elena Duréndez-Saéz, Ricardo Guijarro, Ana Blasco, Luca Roz, Carlos Camps, Eloisa Jantus-Lewintre.

Despite the success of therapies in lung cancer, more studies of new biomarkers for patient selection are urgently needed. The present study aims to analyze the role of galectin-3 (GAL-3) in the lung tumor microenvironment (TME) using tumorspheres as a model and explore its potential role as a predictive and prognostic biomarker in non-small cell lung cancer (NSCLC) patients. For in vitro studies, lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) primary cultures from early-stage patients and commercial cell lines were cultured, using tumorsphere-forming assays and adherent conditions for the control counterparts. We analyzed the pattern of secretion and expression of GAL-3 using reverse transcription-quantitative real-time PCR (RTqPCR), immunoblot, immunofluorescence, flow cytometry and immunoassay analysis. Our results using three-dimensional (3D) models of lung tumor cells revealed that soluble GAL-3 (sGAL-3) is highly expressed and secreted. To more accurately mimic the TME, a co-culture of tumorspheres and fibroblasts was used, revealing that GAL-3 could be important as an immunomodulatory molecule expressed and secreted in the TME, modulating immunosuppression through regulatory T cells (TREGS ). In the translational phase, we confirmed that patients with high expression levels of GAL-3 had more TREGS , which suggests that tumors may be recruiting this population through GAL-3. Next, we evaluated levels of sGAL-3 before surgery in LUAD and LUSC patients, hypothesizing that sGAL-3 could be used as an independent prognostic biomarker for overall survival and relapse-free survival in early-stage LUAD patients. Additionally, levels of sGAL-3 at pretreatment and first response assessment from plasma to predict clinical outcomes in advanced LUAD and LUSC patients treated with first-line pembrolizumab were evaluated, further supporting that sGAL-3 has a high efficiency in predicting durable clinical response to pembrolizumab with an area under curve (AUC) of 0.801 (p=0.011). Moreover, high levels might predict decreased progression-free survival and overall survival to anti-PD-1 therapy, with sGAL-3 being a prognosis-independent biomarker for advanced LUAD.

Keywords: TREG; biomarker; lung adenocarcinoma; sGAL-3; tumorspheres

DOI: https://doi.org/10.1002/1878-0261.13505

Front Oncol. 2023 ;13 1209299

Extracellular circulating miRNAs as potential non-invasive biomarkers in non-small cell lung cancer patients.

Justyna Raczkowska, Agnieszka Bielska, Adam Krętowski, Magdalena Niemira.

Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancers and is a malignant condition resistant to advanced-stage treatment. Despite the advancement in detection and treatment techniques, the disease is taking a deadly toll worldwide, being the leading cause of cancer death every year. Current diagnostic methods do not ensure the detection of the disease at an early stage, nor can they predict the risk of its development. There is an urgent need to identify biomarkers that can help predict an individual's risk of developing NSCLC, distinguish NSCLC subtype, allow monitor disease and treatment progression which can improve patient survival. Micro RNAs (miRNAs) represent the class of small and non-coding RNAs involved in gene expression regulation, influencing many biological processes such as proliferation, differentiation, and carcinogenesis. Research reports significant differences in miRNA profiles between healthy and neoplastic tissues in NSCLC. Its abundant presence in biofluids, such as serum, blood, urine, and saliva, makes them easily detectable and does not require invasive collection techniques. Many studies support miRNAs' importance in detecting, predicting, and prognosis of NSCLC, indicating their utility as a promising biomarker. In this work, we reviewed up-to-date research focusing on biofluid miRNAs' role as a diagnostic tool in NSCLC cases. We also discussed the limitations of applying miRNAs as biomarkers and highlighted future areas of interest.

Keywords: NSCLC; biofluids; biomarker; miRNA; microRNA; non-small cell lung cancer; plasma; serum

DOI: https://doi.org/10.3389/fonc.2023.1209299

Cell Rep. 2023 Aug 04. pii: S2211-1247(23)00956-7. [Epub ahead of print]42(8): 112945

HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1.

Zhou Yang, Wei Su, Xiyi Wei, Shuang Qu, Dan Zhao, Jingwan Zhou, Yunjun Wang, Qing Guan, Chao Qin, Jun Xiang, Ke Zen, Bing Yao.

Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes ferroptosis resistance in solid tumors in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which promotes tumor ferroptosis under hypoxia, HIF-1α is the main driver of hypoxia-induced ferroptosis resistance. Mechanistically, HIF-1α-induced lactate contributes to ferroptosis resistance in a pH-dependent manner that is parallel to the classical SLC7A11 and FSP1 systems. In addition, HIF-1α also enhances transcription of SLC1A1, an important glutamate transporter, and promotes cystine uptake to promote ferroptosis resistance. In support of the role of hypoxia in ferroptosis resistance, silencing HIF-1α sensitizes mouse solid tumors to ferroptosis inducers. In conclusion, our results reveal a mechanism by which hypoxia drives ferroptosis resistance and identify the combination of hypoxia alleviation and ferroptosis induction as a promising therapeutic strategy for solid tumors.

Keywords: CP: Cancer; CP: Metabolism; SLC1A1; ferroptosis; hypoxia; hypoxia-inducible factor 1α; lactate

DOI: https://doi.org/10.1016/j.celrep.2023.112945

Oncol Lett. 2023 Sep;26(3): 381

Monocyte subsets associated with the efficacy of anti‑PD‑1 antibody monotherapy.

Immune checkpoint inhibitors (ICIs) are among the most notable advances in cancer immunotherapy; however, reliable biomarkers for the efficacy of ICIs are yet to be reported. Programmed death (PD)-ligand 1 (L1)-expressing CD14+ monocytes are associated with shorter overall survival (OS) time in patients with cancer treated with anti-PD-1 antibodies. The present study focused on the classification of monocytes into three subsets: Classical, intermediate and non-classical. A total of 44 patients with different types of cancer treated with anti-PD-1 monotherapy (pembrolizumab or nivolumab) were enrolled in the present study. The percentage of each monocyte subset was investigated, and the percentage of cells expressing PD-L1 or PD-1 within each of the three subsets was further analyzed. Higher pretreatment classical monocyte percentages were correlated with shorter OS (r=-0.32; P=0.032), whereas higher non-classical monocyte percentages were correlated with a favorable OS (r=0.39; P=0.0083). PD-L1-expressing classical monocytes accounted for a higher percentage of the total monocytes than non-classical monocytes with PD-L1 expression. In patients with non-small cell lung cancer (NSCLC), a higher percentage of PD-L1-expressing classical monocytes was correlated with shorter OS (r=-0.60; P=0.012), which is similar to the observation for the whole patient cohort. Comparatively, higher percentages of non-classical monocytes expressing PD-L1 were significantly associated with better OS, especially in patients with NSCLC (r=0.60; P=0.010). Moreover, a higher percentage of non-classical monocytes contributed to prolonged progression-free survival in patients with NSCLC (r=0.50; P=0.042), with similar results for PD-L1-expressing non-classical monocytes. The results suggested that the percentage of monocyte subsets in patients with cancer before anti-PD-1 monotherapy may predict the treatment efficacy and prognosis. Furthermore, more classical monocytes and fewer non-classical monocytes, especially those expressing PD-L1, are involved in shortening OS time, which may indicate the poor efficiency of anti-PD-1 treatment approaches.

Keywords: anti-programmed death-1 antibody; biomarker; cancer immunotherapy; classical monocytes; immune checkpoint inhibitors; monocyte subsets; non-classical monocytes; programmed death-ligand 1

DOI: https://doi.org/10.3892/ol.2023.13967

bioRxiv. 2023 Jul 24. pii: 2023.07.23.550157. [Epub ahead of print]

A genome-wide single-cell 3D genome atlas of lung cancer progression.

Miao Liu, Shengyan Jin, Sherry S Agabiti, Tyler B Jensen, Tianqi Yang, Jonathan S D Radda, Christian F Ruiz, Gabriel Baldissera, Mandar Deepak Muzumdar, Siyuan Wang.

Alterations in three-dimensional (3D) genome structures are associated with cancer 1-5 . However, how genome folding evolves and diversifies during subclonal cancer progression in the native tissue environment remains unknown. Here, we leveraged a genome-wide chromatin tracing technology to directly visualize 3D genome folding in situ in a faithful Kras -driven mouse model of lung adenocarcinoma (LUAD) 6 , generating the first single-cell 3D genome atlas of any cancer. We discovered stereotypical 3D genome alterations during cancer development, including a striking structural bottleneck in preinvasive adenomas prior to progression to LUAD, indicating a stringent selection on the 3D genome early in cancer progression. We further showed that the 3D genome precisely encodes cancer states in single cells, despite considerable cell-to-cell heterogeneity. Finally, evolutionary changes in 3D genome compartmentalization - partially regulated by polycomb group protein Rnf2 through its ubiquitin ligase-independent activity - reveal novel genetic drivers and suppressors of LUAD progression. Our results demonstrate the importance of mapping the single-cell cancer 3D genome and the potential to identify new diagnostic and therapeutic biomarkers from 3D genomic architectures.

DOI: https://doi.org/10.1101/2023.07.23.550157