Circulating tumor cells with increasing aneuploidy predict inferior prognosis and therapeutic resistance in small cell lung cancer.

AIMS: Treatment resistance commonly emerges in small cell lung cancer (SCLC), necessitating the development of novel and effective biomarkers to dynamically assess therapeutic efficacy. This study aims to evaluate the clinical utility of aneuploid circulating tumor cells (CTCs) for risk stratification and treatment response monitoring. METHODS: A total of 126 SCLC patients (two cohorts) from two independent cancer centers were recruited as the study subjects. Blood samples were collected from these patients and aneuploid CTCs were detected. Aneuploid CTC count (ACC) and aneuploid CTC score (ACS), were used to predict progression-free survival (PFS) and overall survival (OS). The performance of the ACC and the ACS was evaluated by calculating the area under the receiver operating characteristic (ROC) curve (AUC). RESULTS: Compared to ACC, ACS exhibited superior predictive power for PFS and OS in these 126 patients. Moreover, both univariate and multivariate analyses revealed that ACS was an independent prognostic factor. Dynamic ACS changes reflected treatment response, which is more precise than ACC changes. ACS can be used to assess chemotherapy resistance and is more sensitive than radiological examination (with a median lead time of 2.8 months; P < 0.001). When patients had high ACS levels (> 1.115) at baseline, the combination of immunotherapy and chemotherapy resulted in longer PFS (median PFS, 7.7 months; P = 0.007) and OS (median OS, 16.3 months; P = 0.033) than chemotherapy alone (median PFS, 4.9 months; median OS, 13.6 months). CONCLUSIONS: ACS could be used as a biomarker for risk stratification, treatment response monitoring, and individualized therapeutic intervention in SCLC patients.

SERPINB5 promotes colorectal cancer invasion and migration by promoting EMT and angiogenesis via the TNF-α/NF-κB pathway.

This study aimed to investigate the role of SERPINB5 in colorectal cancer (CRC). We established knockdown and overexpression models of SERPINB5 in CRC cells and conducted bioinformatics analysis to assess the clinicopathological significance of SERPINB5 expression in CRC patients. Human CRC cells were transfected with LV-SERPINB5 and sh-SERPINB5 lentivirus for subsequent functional and mechanistic studies. Results showed that high SERPINB5 expression correlated positively with CEA levels, N stage and lymphatic infiltration, while displaying a negative correlation with progression-free survival. Overexpression of SERPINB5 in CRC cells upregulated the expression of TNF-α, p-NF-κB/p65, N-cadherin, MMP2 and MMP9, accompanied by decreased E-cadherin expression. In addition, SERPINB5 overexpression enhanced the migration, invasion, and proliferation of CRC cells. Furthermore, overexpression of SERPINB5 in CRC cells increased VEGFA expression, and the conditioned medium from SERPINB5-overexpressing CRC cells promoted tube formation of HUVECs. Conversely, overexpression of SERPINB5 in HUVECs decreased VEGFA expression and inhibited tube formation. Notably, these changes in CRC cells were reversed by QNZ, a specific inhibitor of the TNF-α/NF-κB pathway. In summary, our findings revealed that high SERPINB5 expression correlated with poor progression-free survival in CRC patients. Moreover, SERPINB5 could induce EMT and angiogenesis by activating the TNF-α/NF-κB pathway, thereby promoting the invasion and migration of CRC cells.

Identification of a DNA-methylome-based signature for prognosis prediction in driver gene-negative lung adenocarcinoma.

"Driver gene-negative" lung adenocarcinoma (LUAD) was of rare treatment options and a poor prognosis. Presently, for them, few biomarkers are available for stratification analysis to make appropriate treatment strategy. This study aimed to develop a DNA-methylome-based signature to realize the precise risk-stratifying. Here, an Illumina MethylationEPIC Beadchip was applied to obtain differentially methylated CpG sites (DMCs). A four-CpG-based signature, named as TLA, was successfully established, whose prognosis-predicting power was well verified in one internal (n = 78) and other external (n = 110) validation cohorts. Patients with high-risk scores had shorter overall survival (OS) in all cohorts [hazard ratio (HR): 11.79, 5.16 and 2.99, respectively]. Additionally, it can effectively divide patients into low-risk and high-risk groups, with significantly different OS in the diverse subgroups stratified by the standard clinical parameters. As an independent prognostic factor, TLA may assist in improving the nomogram's 5-year OS-predicting ability (AUC 0.756, 95% CI:0.695-0.816), superior to TNM alone (AUC 0.644, 95% CI: 0.590-0.698). Additionally, the relationship of TLA-related genes, TAC1, LHX9, and ALX1, with prognosis and tumour invasion made them serve as potential therapy targets for driver gene-negative LUAD.

Combining TIGIT blockade with IL-15 stimulation is a promising immunotherapy strategy for lung adenocarcinoma.

BACKGROUND: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) is an immune checkpoint molecule that suppresses CD8+ T-cell function in cancer. However, the expression profile and functional significance of TIGIT in the immune microenvironment of lung adenocarcinoma (LUAD) remain elusive. Interleukin (IL)-15 has emerged as a promising candidate for enhancing CD8+ T-cell mediated tumour eradication. Exploring therapeutic strategies that combine IL-15 with TIGIT blockade in LUAD is warranted. METHODS: We investigated the regulatory network involving coinhibitory TIGIT and CD96, as well as costimulatory CD226 in LUAD using clinical samples. The potential role of TIGIT in regulating the pathogenesis of LUAD was addressed through a murine model with transplanted tumours constructed in Tigit-/- mice. The therapeutic strategy that combines TIGIT blockade with IL-15 stimulation was verified using a transplanted tumour murine model and a patient-derived organoid (PDO) model. RESULTS: The frequency of TIGIT+ CD8+ T cells was significantly increased in LUAD. Increased TIGIT expression indicated poorer prognosis in LUAD patients. Furthermore, the effector function of TIGIT+ CD8+ tumour-infiltrating lymphocytes (TILs) was impaired in LUAD patients and TIGIT inhibited antitumour immune response of CD8+ TILs in tumour-bearing mice. Mechanistically, IL-15 enhanced the effector function of CD8+ TILs but stimulated the expression of TIGIT on CD8+ TILs concomitantly. The application of IL-15 combined with TIGIT blockade showed additive effects in enhancing the cytotoxicity of CD8+ TILs and thus further increased the antitumour immune response in LUAD. CONCLUSIONS: Our findings identified TIGIT as a promising therapeutic target for LUAD. LUAD could benefit more from the combined therapy of IL-15 stimulation and TIGIT blockade.

m6A modification mediates SLC3A2/SLC7A5 translation in 3-methylcholanthrene-induced uroepithelial transformation.

3-Methylcholanthracene (3-MC) is one of the most carcinogenic polycyclic aromatic hydrocarbons (PAHs). Long-term exposure to PAHs has been thought of as an important factor in urothelial tumorigenesis. N6-methyladenosine (m6A) exists widely in eukaryotic organisms and regulates the expression level of specific genes by regulating mRNA stability, translation efficiency, and nuclear export efficiency. Currently, the potential molecular mechanisms that regulate m6A modification for 3-MC carcinogenesis remain unclear. Here, we profiled mRNA, m6A, translation and protein level using "-omics" methodologies, including transcriptomes, m6A profile, translatomes, and proteomics in 3-MC-transformed urothelial cells and control cells. The key molecules SLC3A2/SLC7A5 were screened and identified in 3-MC-induced uroepithelial transformation. Moreover, SLC7A5/SLC3A2 promoted uroepithelial cells malignant phenotype in vitro and in vivo. Mechanically, METTL3 and ALKBH5 mediated m6A modification of SLC3A2/SLC7A5 mRNA in 3-MC-induced uroepithelial transformation by upregulating the translation of SLC3A2/SLC7A5. Furthermore, programmable m6A modification of SLC3A2/SLC7A5 mRNA affected the expression of its proteins. Taken together, our results revealed that the m6A modification-mediated SLC3A2/SLC7A5 translation promoted 3-MC-induced uroepithelial transformation, suggesting that targeting m6A modification of SLC3A2/SLC7A5 may be a potential therapeutic strategy for bladder cancer related to PAHs.

New insights into the correlations between circulating tumor cells and target organ metastasis.

Organ-specific metastasis is the primary cause of cancer patient death. The distant metastasis of tumor cells to specific organs depends on both the intrinsic characteristics of the tumor cells and extrinsic factors in their microenvironment. During an intermediate stage of metastasis, circulating tumor cells (CTCs) are released into the bloodstream from primary and metastatic tumors. CTCs harboring aggressive or metastatic features can extravasate to remote sites for continuous colonizing growth, leading to further lesions. In the past decade, numerous studies demonstrated that CTCs exhibited huge clinical value including predicting distant metastasis, assessing prognosis and monitoring treatment response et al. Furthermore, increasingly numerous experiments are dedicated to identifying the key molecules on or inside CTCs and exploring how they mediate CTC-related organ-specific metastasis. Based on the above molecules, more and more inhibitors are being developed to target CTCs and being utilized to completely clean CTCs, which should provide promising prospects to administer advanced tumor. Recently, the application of various nanomaterials and microfluidic technologies in CTCs enrichment technology has assisted to improve our deep insights into the phenotypic characteristics and biological functions of CTCs as a potential therapy target, which may pave the way for us to make practical clinical strategies. In the present review, we mainly focus on the role of CTCs being involved in targeted organ metastasis, especially the latest molecular mechanism research and clinical intervention strategies related to CTCs.