Outcome In Lung Adenocarcinoma Research Articles

Investigating the role of disulfidptosis related genes in radiotherapy resistance of lung adenocarcinoma

BackgroundRadiotherapy resistance is an important reason for high mortality in lung cancer patients, but the mechanism is still unclear. Dysregulation of cell proliferation and death plays a crucial role in the onset and progression of lung adenocarcinoma (LUAD). In recent times, a novel form of cellular demise called disulfidptosis, has attracted increasing attention. However, it is unclear whether the radiation-related disulfidptosis genes have prognostic role in LUAD.MethodsA complete suite of bioinformatics tools was used to analyze the expression and prognostic significance of radiation-related disulfidptosis genes. Afterward, we investigated the predictive significance of the risk signature in tumor microenvironments (TME), somatic mutations, and immunotherapies. In addition, we conducted a series of experiments to verify the expression of differentially expressed radiotherapy related disulfidptosis genes (DERRDGs) in vitro.ResultsA total of 88 DERRDGs were found. We constructed and validated a novel prognostic model based on PRELP, FGFBP1, CIITA and COL5A1. The enrichment analysis showed the DERRDG affected tumor prognosis by influencing tumor microenvironments (TME) and immunotherapy. And we constructed nomogram to promote clinical application. In addition, q-PCR confirmed the significant differences in the expression of prognostic genes between A549 irradiation-resistance cell and A549. Finally, western-blot, IHC staining, and small interference experiment suggested that PRELP may be a potential biomarker for radiotherapy resistance, whose low expression was associated with poor outcomes in LUAD patients.ConclusionThis study reveals the signature and possible underlying mechanisms of DERRDGs in LUAD and discovered the key gene PRELP, which helps to identify new prognostic biomarkers and provides a basis for future research.

Prognostic heterogeneity of Ki67 in non-small cell lung cancer: A comprehensive reappraisal on immunohistochemistry and transcriptional data.

In the present study, the debatable prognostic value of Ki67 in patients with non-small cell lung cancer (NSCLC) was attributed to the heterogeneity between lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC). Based on meta-analyses of 29 studies, a retrospective immunohistochemical cohort of 1479 patients from our center, eight transcriptional datasets and a single-cell datasets with 40 patients, we found that high Ki67 expression suggests a poor outcome in LUAD, but conversely, low Ki67 expression indicates worse prognosis in LUSC. Furthermore, low proliferation in LUSC is associated with higher metastatic capacity, which is related to the stronger epithelial-mesenchymal transition potential, immunosuppressive microenvironment and angiogenesis. Finally, nomogram model incorporating clinical risk factors and Ki67 expression outperformed the basic clinical model for the accurate prognostic prediction of LUSC. With the largest prognostic assessment of Ki67 from protein to mRNA level, our study highlights that Ki67 also has an important prognostic value in NSCLC, but separate evaluation of LUAD and LUSC is necessary to provide more valuable information for clinical decision-making in NSCLC.

Harnessing lipid metabolism modulation for improved immunotherapy outcomes in lung adenocarcinoma

BackgroundWhile anti-programmed cell death protein-1 (PD-1) monotherapy has shown effectiveness in treating lung cancer, its response rate is limited to approximately 20%. Recent research suggests that abnormal lipid metabolism in...

SIRT2 as a Potential Biomarker in Lung Adenocarcinoma: Implications for Immune Infiltration.

SIRT2 play important roles in cell cycle and cellular metabolism in the development of non-small cell lung cancer (NSCLC), and SIRT2 exhibits its therapeutic effect on NSCLC tumors with high expression of SIRT2. Nevertheless, the clinical relevance of SIRT2 in lung adenocarcinoma (LUAD), particularly its impact on tumor growth and prognostic implications, remains obscure. This investigation entailed a comprehensive analysis of SIRT2 mRNA and protein expression levels in diverse tumor and corresponding healthy tissues, utilizing databases such as TIMER 2.0, UALCAN, and HPA. Prognostic correlations of SIRT2 expression in LUAD patients, stratified by distinct clinicopathological characteristics, were evaluated using the KM Plotter database. Additionally, the TCGA and TIMER 2.0 databases were employed to assess the relationship between SIRT2 and immune infiltration, as well as to calculate immunity, stromal, and estimation scores, thus elucidating the role of SIRT2 in modulating tumor immunotherapy responses. Furthermore, Gene Set Enrichment Analysis (GSEA) was utilized to elucidate SIRT2's biological functions in pan-cancer cells. Our findings revealed a marked reduction in both mRNA and protein levels of SIRT2 in LUAD tumors relative to healthy tissue. Survival analysis indicated that diminished SIRT2 expression correlates with adverse prognostic outcomes in LUAD. Furthermore, SIRT2 expression demonstrated a significant association with various clinicopathologic attributes of LUAD patients, influencing survival outcomes across different clinicopathologic states. Functional enrichment analyses highlighted SIRT2's involvement in cell cycle regulation and immune response. Notably, SIRT2 exhibited a positive correlation with immune cell infiltration, including natural killer (NK) cells, macrophages, and dendritic cells (DCs). In summary, SIRT2 was a potential prognostic biomarker for LUAD and and a new immunotherapy target.

Expression of Pluripotency Factors OCT4 and LIN28 Correlates with Survival Outcome in Lung Adenocarcinoma.

Background and Objectives: Lung adenocarcinoma is a leading cause of cancer-related mortality despite recent therapeutic advances. Cancer stem cells have gained increasing attention due to their ability to induce cancer cell proliferation through self-renewal and differentiation into multiple cell lineages. OCT4 and LIN28 (and their homologs A and B) have been identified as key regulators of pluripotency in mammalian embryonic (ES) and induced stem (IS) cells, and they are the crucial regulators of cancer progression. However, their exact role in lung adenocarcinoma has not yet been clarified. Materials and Methods: The aim of this study was to explore the role of the pluripotency factors OCT4 and LIN28 in a cohort of surgically resected human lung adenocarcinomas to reveal possible biomarkers for lung adenocarcinoma prognosis and potential therapeutic targets. The expressions of OCT4, LIN28A and LIN28B were analyzed in formalin-fixed, paraffin-embedded tissue samples from 96 patients with lung adenocarcinoma by immunohistochemistry. The results were analyzed with clinicopathologic parameters and were related to the prognosis of patients. Results: Higher OCT4 expression was related to an improved 5-year overall survival (OS) rate (p < 0.001). Nuclear LIN28B expression was lower in stage I and II tumors (p < 0.05) compared to advanced stage tumors. LIN28B cytoplasmic expression was associated with 5-year OS rates not only in univariate (p < 0.005), but also in multivariate analysis (where age, gender, histopathological subtype and stage were used as cofactors, p < 0.01 HR = 2.592). Patients with lower LIN28B expression showed improved 5-year OS rates compared to patients with increased LIN28B expression. Conclusions: Our findings indicate that OCT4 and LIN28B are implicated in lung adenocarcinoma progression and prognosis outcome; thus, they serve as promising prognostic biomarkers and putative therapeutic targets in lung adenocarcinomas.

PCDH11X mutation as a potential biomarker for immune checkpoint therapies in lung adenocarcinoma.

Immune checkpoint inhibitors (ICIs) have achieved impressive success in lung adenocarcinoma (LUAD). However, the response to ICIs varies among patients, and predictive biomarkers are urgently needed. PCDH11X is frequently mutated in LUAD, while its role in ICI treatment is unclear. In this study, we curated genomic and clinical data of 151 LUAD patients receiving ICIs from three independent cohorts. Relations between PCDH11X and treatment outcomes of ICIs were examined. A melanoma cohort collected from five published studies, a pan-cancer cohort, and non-ICI-treated TCGA-LUAD cohort were also examined to investigate whether PCDH11X mutation is a specific predictive biomarker for LUAD ICI treatment. Among the three ICI-treated LUAD cohorts, PCDH11X mutation (PCDH11X-MUT) was associated with better clinical response compared to wild-type PCDH11X (PCDH11X-WT). While in ICI-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and the non-ICI-treated TCGA-LUAD cohort, no significant differences in overall survival (OS) were observed between the PCDH11X-MUT and PCDH11X-WT groups. PCDH11X mutation was associated with increased PD-L1 expression, tumor mutation burden (TMB), neoantigen load, DNA damage repair (DDR) mutations, and hot tumor microenvironment in TCGA-LUAD cohort. Our findings suggested that the PCDH11X mutation might serve as a specific biomarker to predict the efficacy of ICIs for LUAD patients. Considering the relatively small sample size of ICI-treated cohorts, future research with larger cohorts and prospective clinical trials will be essential for validating and further exploring the role of PCDH11X mutation in the context of immunotherapy outcomes in LUAD. KEY MESSAGES: PCDH11X mutation is associated with better clinical response compared to wild type PCDH11X in three ICIs-treated LUAD cohorts. In ICIs-treated melanoma cohort, the pan-cancer cohort excluding LUAD, and non-ICIs-treated TCGA-LUAD cohortsPCDH11X mutation is not associated with better clinical response, suggesting PCDH11X mutation might be a specific biomarker to predict the efficacy of ICIs treatment for LUAD patients. PCDH11X mutation is associated with increased PD-L1 expression, tumor mutation burden, and neoantigen load in TCGA-LUAD cohort. PCDH11X mutation is associated with hot tumor microenvironment in TCGA-LUAD cohort.

A Prognosis and Immunological Study of Cellular Aging Related lncRNAs in Lung Adenocarcinoma

Background: Recently, cellular senescence has been recognized as a novel hallmark of cancer. However, the mechanisms that control cellular senescence remain poorly understood. This study seeks to discover long non-coding RNAs (lncRNAs) that are linked to senescence and can predict outcomes in lung adenocarcinoma (LUAD) patients. Methods: Using RNA sequencing data from the Cancer Genome Atlas Lung Adenocarcinoma (TCGA-LUAD) and senescence genes from the CellAge database, a group of lncRNAs related to senescence was initially identified. Subsequently, through univariate and multivariate Cox regression analyses, a senescence-related lncRNA signature (SenLncSig) linked to the prognosis of LUAD was developed. LUAD patients were categorized into high-risk and low-risk groups based on the median risk score of SenLncSig. Kaplan-Meier analysis was employed to assess differences in overall survival (OS) between these subgroups. Additionally, disparities in Gene Set Enrichment Analysis (GSEA), immune infiltration, scores from the tumor immune dysfunction and exclusion (TIDE) module, and choices of chemotherapy and targeted therapy were also evaluated between the high-risk and low-risk groups. Results: Based on univariate and multivariate Cox regression analyses, we established a prognostic model composed of seven senescence-related lncRNAs, named SenLncSig, which includes AL031775.2, AC026355.1, AL365181.2, AC090559.1, AL606489.1, AL513550.1, and C20orf197. This model divides patients into high-risk and low-risk groups, with the high-risk group showing significantly shorter overall survival compared to the low-risk group, with a hazard ratio (HR) of 1.326. The predictive accuracy of SenLncSig was validated through ROC curves and principal component analysis (PCA). Additionally, we developed an intuitive survival prediction tool that combines SenLncSig with clinical pathological features to assess patients' overall survival (OS). Enrichment analysis (GSEA) revealed that SenLncSig is involved in multiple pathways related to tumor immune modulation. Risk model analysis indicated significant differences between the high and low-risk groups in terms of immune status and responses to immunotherapy, chemotherapy, and targeted therapy. Conclusion: In this study, a lncRNA signature named as SenLncSig was developed that not only identifies the senescence phenotype and predicts prognosis but also has the capability to forecast the response of LUAD to immunotherapy.

Abstract LB299: Dihydrouridine synthase 2 sustains levels of tRNACys and prevents ferroptosis in lung cancer

Abstract Dihydrouridine is a universally conserved tRNA modification installed by enzymes that are important for human health. High expression of dihydrouridine synthase 2 (DUS2) predicts poor patient outcomes in lung adenocarcinoma (LUAD) for reasons that are not yet clear. Here, we show in human cells and mouse xenografts that DUS2 suppresses ferroptosis, a metal-dependent non-apoptotic form of cell death that is emerging as a therapeutic target in lung cancer. Elevated DUS2 correlates with resistance to ferroptosis inducers and loss of DUS2 causes increased sensitivity with concomitant accumulation of toxic lipid peroxides. Mechanistically, DUS2 is required to maintain tRNA CysGCA levels, supporting translation of cysteine-rich proteins including metallothioneins, key regulators of metal and redox homeostasis Notably, DUS2 KO cells cannot sustain normal levels of metallothioneins, a class of very cysteine rich proteins that serve as key regulators of both metal and redox homeostasis. Accordingly, DUS2 knockout cells are more susceptible to zinc intoxication and have lower levels of reduced glutathione, which partially explains their sensitivity to ferroptosis. Our findings demonstrate that DUS2 is required to support tRNACys levels and fend off ferroptosis in lung cancer cells. This highlights that individual tRNA substrates can play an outsized role in the biological functions of tRNA modifying enzymes, and demonstrates the therapeutic potential of targeting DUS2 in cancer. Citation Format: Austin Draycott, Matthew C. Wang, Diana Martínez Saucedo, Luisa Escobar-Hoyos, Wendy Gilbert. Dihydrouridine synthase 2 sustains levels of tRNACys and prevents ferroptosis in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB299.

79 The routine use of Granulocyte-colony stimulating factor (G-CSF) with chemo-immunotherapy does not affect clinical outcomes in lung adenocarcinoma

79 The routine use of Granulocyte-colony stimulating factor (G-CSF) with chemo-immunotherapy does not affect clinical outcomes in lung adenocarcinoma

The Dual Role of the NFATc2/galectin-9 Axis in Modulating Tumor-Initiating Cell Phenotypes and Immune Suppression in Lung Adenocarcinoma.

Tumor-initiating cells (TICs) resilience and an immunosuppressive microenvironment are aggressive oncogenic phenotypes that contribute to unsatisfactory long-term outcomes in lung adenocarcinoma (LUAD) patients. The molecular mechanisms mediating the interaction between TICs and immune tolerance have not been elucidated. The role of Galectin-9 in oncogenesis and immunosuppressive microenvironment is still unknown. This study explored the potential role of galectin-9 in TIC regulation and immune modulation in LUAD. The results show that galectin-9 supports TIC properties in LUAD. Co-culture of patient-derived organoids and matched peripheral blood mononuclear cells showed that tumor-secreted galectin-9 suppressed T cell cytotoxicity and induced regulatory T cells (Tregs). Clinically, galectin-9 is upregulated in human LUAD. High expression of galectin-9 predicted poor recurrence-free survival and correlated with high levels of Treg infiltration. LGALS9, the gene encoding galectin-9, is found to be transcriptionally regulated by the nuclear factor of activated T cells 2 (NFATc2), a previously reported TIC regulator, via in silico prediction and luciferase reporter assays. Overall, the results suggest that the NFATc2/galectin-9 axis plays a dual role in TIC regulation and immune suppression.

High expression of VTA1 is an adverse prognostic factor in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is a common pathological type of non-small cell lung cancer; identifying preferable biomarkers has become one of the current challenges. Given that VTA1 has been reported associated with tumor progression in various human solid cancers but rarely reported in LUAD, herein, RNA sequencing data from TCGA and GTEx were obtained for analysis of VTA1 expression and differentially expressed gene (DEG). Furthermore, functional enrichment analysis of VTA1-related DEGs was performed by GO/KEGG, GSEA, immune cell infiltration analysis, and protein-protein interaction (PPI) network. In addition, the clinical significance of VTA1 in LUAD was figured out by Kaplan-Meier Cox regression and prognostic nomogram model. R package was used to analyze incorporated studies. As a result, VTA1 was highly expressed in various malignancies, including LUAD, compared with normal samples. Moreover, high expression of VTA1 was associated with poor prognosis in 533 LUAD samples, as well as T stage T2&T3&T4, N stage N1&N2&N3, M stage M1, pathologic stage II&III&IV, and residual tumor R1&R2, et al. (P < 0.05). High VTA1 was an independent prognostic factor in Cox regression analysis; Age and cytogenetics risk were included in the nomogram prognostic model. Furthermore, a total of 4232 DEGs were identified between the high- and the low-expression group, of which 736 genes were up-regulated and 3496 genes were down-regulated. Collectively, high expression of VTA1 is a potential biomarker for adverse outcomes in LUAD. The DEGs and pathways recognized in the study provide a preliminary grasp of the underlying molecular mechanisms of LUAD carcinogenesis and progression.

CENPF Upregulation is Associated with Immunosuppressive Status and Poor Clinical Outcomes in Lung Adenocarcinoma Validated by qRT-PCR.

CENPF-differentially expressed in various types of cancers-is a marker of poor prognosis. However, studies on the impact of CENPF on patient prognosis in lung adenocarcinoma regarding immune infiltration are lacking. CENPF expression profiles were analyzed in the GEO and TCGA databases. qRT-PCR was used to verify CENPF mRNA expression in lung adenocarcinoma cell lines. The prognostic value of CENPF was evaluated by combining data from clinical samples in the GEPIA2 and TCGA databases. Metascape and WebGestalt were used for enrichment analysis of gene sets most positively associated with CENPF. Immune cell infiltration score data were retrieved from TCGA and the correlation between CENPF expression and immune cell infiltration was analyzed. CENPF expression was elevated in 29 types of cancer. CENPF was highly expressed and increased with tumor grade in lung adenocarcinoma. Immunohistochemical and qRT-PCR analyses revealed that CENPF expression was upregulated in lung adenocarcinoma tissues and cells. High expression of CENPF significantly worsened prognoses in patients with multiple malignancies, including lung adenocarcinoma. Results from gene set enrichment analysis indicated significant enrichment of the progesterone-mediated oocyte maturation pathway. Immune infiltration analysis revealed that CD4+ Th2 cell infiltration was significantly higher in the high CENPF expression group. Upregulation of CENPF expression was related to poor progression-free survival, disease- free survival, and overall survival in patients with lung adenocarcinoma. High expression of CENPF was markedly related to genes associated with the immune checkpoint. Lung adenocarcinoma samples with high CENPF expression had increased CD4+ Th2 cell infiltration. Our findings indicate that CENPF promotes CD4+ Th2 cell infiltration through oncogenic activity and may be used as a biomarker for predicting patient outcomes in lung adenocarcinoma.

Endobronchial spread of adenocarcinoma is a distinct pattern of invasion and associated with inferior clinical outcomes in lung adenocarcinoma.

The spread of lung adenocarcinoma cells into the bronchi and bronchioles is not well documented. We termed this histological finding "endobronchial spreading of adenocarcinoma" (EBSA) and investigated its prevalence and clinical significance. We reviewed 320 resected specimens from patients diagnosed with invasive adenocarcinoma, and EBSA was observed in 144 patients (45%). EBSA was significantly associated with advanced pathological stage, higher histological grade, larger tumour invasion, lymphovascular infiltration, and spread through air spaces. Patients with EBSA had significantly shorter relapse-free survival (RFS) and cancer-specific survival (CSS) in univariate analysis (P < 0.001). In a subgroup analysis of patient with small-sized (invasion size ≤30 mm) adenocarcinoma in the localized stage, EBSA was an independent inferior prognostic indicator in multivariate analysis. In a subgroup analysis of patients with small-sized Grade 1 nonmucinous adenocarcinoma (n = 61), EBSA was observed in 11 patients, and the presence of EBSA was associated with significantly shorter RFS and CSS (P = 0.026 and P = 0.001, respectively). Our results demonstrated that EBSA is a significant risk factor for disease recurrence and cancer-related deaths. EBSA can be regarded as a distinctive pattern of invasion and its recognition can be beneficial in the diagnosis of lung adenocarcinoma.

Abstract LB_B21: Extracellular RNA signatures of mutant KRAS-driven lung cancer

Abstract RAS genes are the most frequently mutated oncogenes in cancer, yet the effects of oncogenic RAS signaling on the noncoding transcriptome remain unclear. We analyzed the transcriptomes of human airway and bronchial epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We find that oncogenic KRAS signaling upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements (TEs). These TE RNAs exhibit differential expression and are regulated by KRAB zinc-finger (KZNF) genes, which are broadly downregulated in mutant KRAS cells and lung adenocarcinomas in vivo. Using both affinity- and nanofiltration-based EV isolation approaches, we show that specific TE RNAs, lncRNAs, and mRNAs, some of which are prognostic for lung adenocarcinoma (LUAD) patient survival, are preferentially released in extracellular vesicles (EVs). Moreover, we find that inhibition of oncogenic KRAS signaling broadly reprograms the noncoding transcriptome, as evidenced by a substantial increase in TE RNA secretion. Mutant KRAS inhibition also increases the abundance of secreted lncRNAs and retained intron-containing transcripts, while decreasing the mRNA content of EVs. Notably, oncogenic KRAS signaling is required for the secretion of mRNAs from a set of 20 genes that are significantly associated with unfavorable clinical outcomes in LUAD. Our results indicate that mutant KRAS remodels the repetitive noncoding transcriptome, demonstrating the broad scope of intracellular and extracellular RNAs regulated by this oncogenic signaling pathway. Our study also suggests that both coding and noncoding RNAs that are secreted in EVs may serve as mutant KRAS-specific signatures for diagnosing lung cancer via minimally invasive RNA liquid biopsy technology, which we are currently developing as a companion diagnostic for mutant KRAS-targeting therapies. Citation Format: Sree Lakshmi Velandi Maroli, Roman E Reggiardo, Reem Khojah, Daniel H Kim. Extracellular RNA signatures of mutant KRAS-driven lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B21.

Whole stromal fibroblast signature is linked to specific chemokine and immune infiltration patterns and to improved survival in NSCLC

ABSTRACT Cancer associated fibroblasts (CAF) are known to orchestrate multiple components of the tumor microenvironment, whereas the influence of the whole stromal-fibroblast compartment is less understood. Here, an extended stromal fibroblast signature was investigated to define its impact on immune cell infiltration. The lung cancer adenocarcinoma (LUAD) data set of the cancer genome atlas (TCGA) was used to test whole stroma signatures and cancer-associated fibroblast signatures for their impact on prognosis. 3D cell cultures of the NSCLC cancer cell line A549 together with the fibroblast cell line SV80 were used in combination with infiltrating peripheral blood mononuclear cells (PBMC) for in-vitro investigations. Immune cell infiltration was assessed via flow cytometry, chemokines were analyzed by immunoassays and RNA microarrays. Results were confirmed in specimens from NSCLC patients by flow cytometry or immunohistochemistry as well as in the TCGA data set. The TCGA analyses correlated the whole stromal-fibroblast signature with an improved outcome, whereas no effect was found for the CAF signatures. In 3D microtumors, the presence of fibroblasts induced infiltration of B cells and CD69+CD4+ T cells, which was linked to an increased expression of CCL13 and CXCL16. The stroma/lymphocyte interaction was confirmed in NSCLC patients, as stroma-rich tumors displayed an elevated B cell count and survival in the local cohort and the TCGA data set. A whole stromal fibroblast signature was associated with an improved clinical outcome in lung adenocarcinoma and in vitro and in vivo experiments suggest that this signature increases B and T cell recruitment via induction of chemokines.

Inflammation in the tumor-adjacent lung as a predictor of clinical outcome in lung adenocarcinoma

Approximately 30% of early-stage lung adenocarcinoma patients present with disease progression after successful surgical resection. Despite efforts of mapping the genetic landscape, there has been limited success in discovering predictive biomarkers of disease outcomes. Here we performed a systematic multi-omic assessment of 143 tumors and matched tumor-adjacent, histologically-normal lung tissue with long-term patient follow-up. Through histologic, mutational, and transcriptomic profiling of tumor and adjacent-normal tissue, we identified an inflammatory gene signature in tumor-adjacent tissue as the strongest clinical predictor of disease progression. Single-cell transcriptomic analysis demonstrated the progression-associated inflammatory signature was expressed in both immune and non-immune cells, and cell type-specific profiling in monocytes further improved outcome predictions. Additional analyses of tumor-adjacent transcriptomic data from The Cancer Genome Atlas validated the association of the inflammatory signature with worse outcomes across cancers. Collectively, our study suggests that molecular profiling of tumor-adjacent tissue can identify patients at high risk for disease progression.

Micropapillary Pattern in Invasive Mucinous Adenocarcinoma of the Lung: Comparison With Invasive Non-Mucinous Adenocarcinoma.

Background. The presence of a micropapillary pattern is associated with poor outcomes in lung adenocarcinoma. This study aimed to assess the clinicopathological features of micropapillary pattern in mucinous adenocarcinoma of the lung. Methods. The patients were stratified into three groups: the invasive mucinous adenocarcinoma group (60 patients), the mixed invasive mucinous adenocarcinoma group (33 patients), and the invasive non-mucinous adenocarcinoma group (237 patients). The presence of micropapillary pattern and its clinicopathological features were analyzed and compared between the three groups. Results. Compared to mixed invasive mucinous adenocarcinoma, invasive mucinous adenocarcinoma had lower frequencies of micropapillary pattern (28.3% vs 87.9%, respectively; P < .001) and lymph node metastasis (00.0% vs 15.1%, respectively; P = .005). The frequency of tumor spread through air space (STAS) in invasive mucinous adenocarcinoma (23.3%) was higher than that in invasive non-mucinous adenocarcinoma (6.3%; P < .001), while lower than that in mixed invasive mucinous adenocarcinoma (60.6%; P < .001). When the three groups were all accompanied by micropapillary pattern, there was no obvious difference in STAS between invasive mucinous adenocarcinoma with micropapillary pattern and mixed mucinous adenocarcinoma with micropapillary pattern (P > .05). No filigree pattern occurred in invasive mucinous adenocarcinoma with micropapillary pattern. Conclusions. The micropapillary pattern is frequently observed in invasive mucinous adenocarcinoma and has a better prognosis compared to mixed invasive mucinous adenocarcinoma and invasive non-mucinous adenocarcinoma. However, the malignancy of the micropapillary pattern in mixed mucinous adenocarcinoma was similar to that in invasive non-mucinous adenocarcinoma, even with the presence of mucus. These findings suggest that the development mechanisms of the micropapillary pattern in invasive mucinous adenocarcinoma and mixed mucinous adenocarcinoma may differ.

Spreading Through Air Spaces And Thinking About Lung Metastases.

Spread through air spaces (STAS) is a novel pattern of invasion in primary lung cancers, which was introduced in the 2015 World Health Organization classification. Several studies have validated STAS to be a predictor of clinical outcome in lung adenocarcinoma. However, little is known about STAS as a mode of intraparenchymal diffusion of pulmonary metastases (PMs). The aim of this study was to investigate the incidence of STAS among PMs and the association between STAS and clinicopathological characteristics of PMs. From August 1, 2017 to July 31, 2022, 50 patients underwent pulmonary metastectomy in our center. Clinicopathological characteristics of patients were retrospectively evaluated. Continuous variables were compared by using unpaired Students t-test or MannWhitney test, as appropriate. Categorical variables were compared by using Qui-squared test or Fishers exact test as appropriate. A total of 50 patients with PMs who underwent surgical resection were analyzed, 68% being male. The median age of the study population was 60 years (range 24-80). Most patients had primary cancer originating from epithelial tissue (n=45) and the remaing from mesenchymal tissue (n=5). Colorectal cancer was the most frequent primary site of PMs (n= 32), followed by kidney (n=4) and osteosarcoma (n=3). 60% of patients (n=30) underwent sublobar resection (wedge resection or anatomic segmentectomy). STAS was observed in 10 patients (20%): 7 patients with PMs from CRC, 1 with PM from palatine tonsil, 1 from kidney and 1 from uterus. STAS was more frequent in elder patients (62 years, SD=7.099 vs 60 years, SD= 13.889; p = 0.034). Notably, STAS was significantly more frequent in PMs with larger dimension (2.8 cm, SD=2.049 vs 2.03 SD=1.104; p = 0.010), patients with lymph node metastases (p = 0.004) and in patients who underwent lobectomy rather than sublobar resection (70% vs 32.5%; p = 0.03). Although without statistically significant difference, locorregional recurrence and mortality was higher in patients with STAS+ (40% vs 22.5% and 40% vs 20%, respectively). VSTAS is nowadays considered to be a lung-specific tumour invasion pattern and is commonly observed in PMs of different origins.

Dissection of paracrine/autocrine interplay in lung tumor microenvironment mimicking cancer cell-monocyte co-culture models reveals proteins that promote inflammation and metastasis

BackgroundTumor cell-monocyte interactions play crucial roles in shaping up the pro-tumorigenic phenotype and functional output of tumor-associated macrophages. Within the tumor microenvironment, such heterotypic cell–cell interactions are known to occur via secretory proteins. Secretory proteins establish a diabolic liaison between tumor cells and monocytes, leading to their recruitment, subsequent polarization and consequent tumor progression.MethodsWe co-cultured model lung adenocarcinoma cell line A549 with model monocytes, THP-1 to delineate the interactions between them. The levels of prototypical pro-inflammatory cytokines like TNF-\U0001d6fc, IL-6 and anti-inflammatory cytokines like IL-10 were measured by ELISA. Migration, invasion and attachment independence of lung cancer cells was assessed by wound healing, transwell invasion and colony formation assays respectively. The status of EMT was evaluated by immunofluorescence. Identification of secretory proteins differentially expressed in monocultures and co-culture was carried out using SILAC LC–MS/MS. Various insilico tools like Cytoscape, Reacfoam, CHAT and Kaplan–Meier plotter were utilized for association studies, pathway analysis, functional classification, cancer hallmark relevance and predicting the prognostic potential of the candidate secretory proteins respectively.ResultsCo-culture of A549 and THP-1 cells in 1:10 ratio showed early release of prototypical pro-inflammatory cytokines TNF-\U0001d6fc and IL-6, however anti-inflammatory cytokine, IL-10 was observed to be released at the highest time point. The conditioned medium obtained from this co-culture ratio promoted the migration, invasion and colony formation as well as the EMT of A549 cells. Co-culturing of A549 with THP-1 cells modulated the secretion of proteins involved in cell proliferation, migration, invasion, EMT, inflammation, angiogenesis and inhibition of apoptosis. Among these proteins Versican, Tetranectin, IGFBP2, TUBB4B, C2 and IFI30 were found to correlate with the inflammatory and pro-metastatic milieu observed in our experimental setup. Furthermore, dysregulated expression of these proteins was found to be associated with poor prognosis and negative disease outcomes in lung adenocarcinoma compared to other cancer types. Pharmacological interventions targeting these proteins may serve as useful therapeutic approaches in lung adenocarcinoma.ConclusionIn this study, we have demonstrated that the lung cancer cell-monocyte cross-talk modulates the secretion of IFI30, RNH1, CLEC3B, VCAN, IGFBP2, C2 and TUBB4B favoring tumor growth and metastasis.

Predicting lung adenocarcinoma prognosis, immune escape, and pharmacomic profile from arginine and proline-related genes

Lung adenocarcinoma (LUAD) is a highly heterogeneous disease that ranks first in morbidity and mortality. Abnormal arginine metabolism is associated with inflammatory lung disease and may influence alterations in the tumor immune microenvironment. However, the potential role of arginine and proline metabolic patterns and immune molecular markers in LUAD is unclear. Gene expression, somatic mutations, and clinicopathological information of LUAD were downloaded from The Cancer Genome Atlas (TCGA) database. Univariate Cox regression analysis was performed to identify metabolic genes associated with overall survival (OS). Unsupervised clustering divided the sample into two subtypes with different metabolic and immunological profiles. Gene set enrichment analysis (GESA) and gene set variation analysis (GSVA) were used to analyze the underlying biological processes of the two subtypes. Drug sensitivity between subtypes was also predicted; then prognostic features were developed by multivariate Cox regression analysis. In addition, validation was obtained in the GSE68465, and GSE50081 dataset. Then, gene expression, and clinical characterization of hub genes CPS1 and SMS were performed; finally, in vitro validation experiments for knockdown of SMS were performed in LUAD cell lines. In this study, we first identified 12 arginine and proline-related genes (APRGs) significantly associated with OS and characterized the clinicopathological features and tumor microenvironmental landscape of two different subtypes. Then, we established an arginine and proline metabolism-related scoring system and identified two hub genes highly associated with prognosis, namely CPS1, and SMS. In addition, we performed CCK8, transwell, and other functional experiments on SMS to obtain consistent results. Our comprehensive analysis revealed the potential molecular features and clinical applications of APRGs in LUAD. A model based on 2 APRGs can accurately predict survival outcomes in LUAD, improve our understanding of APRGs in LUAD, and pave a new pathway to guide risk stratification and treatment strategy development for LUAD patients.