Cigarette smoke (CS) affects the expression of microRNAs (miRNAs), which are important regulators of gene expression by inducing DNA methylation. However, the effects of smoking on miRNA expression have not been fully elucidated in smoking-related lung carcinogenesis. Therefore, in this study, to investigate the change of miRNA expression pattern and to identify tumor suppressor miRNAs by smoking in lung carcinogenesis, we used lung carcinogenesis model cell lines that, derived from a murine xenograft model with human bronchial epithelial cells (BEAS-2B), exposed CS or not. The microarray analysis revealed that miR-584-5p expression was downregulated with cancer progression in lung carcinogenesis model cell lines. We confirmed by pyrosequencing that the methylation level of the miR-584-5p promoter increased with cancer progression. In vitro and in vivo experiments showed that miR-584-5p suppressed migration and invasion in non-small cell lung cancer (NSCLC) cells by targeting YKT6. Furthermore, we showed that high level of YKT6 was associated with a poor survival rate in NSCLC patients with a history of smoking. These results suggest that miR-584-5p acts as a tumor suppressor and is a potential molecular biomarker for smoking-related NSCLC.

Background & Aims: The application of circulating tumor DNA (ctDNA) has been studied for predicting recurrent disease after surgery and treatment response during systemic treatment. Metastasectomy can be curative for well-selected patients with metastatic colorectal cancer (mCRC). This prospective study investigated the ctDNA level before and after metastasectomy in patients with mCRC to explore its potential as a predictive biomarker. Methods: We collected data on 98 metastasectomies for mCRC performed from March 2017 to February 2020. Somatic mutations in the primary and metastatic tumors were identified and tumor-informed ctDNAs were selected by ultra-deep targeted sequencing. Plasma samples were mandatorily collected before and 3–4 weeks after metastasectomy and serially, if patients agreed. Results: Data on 67 of 98 metastasectomies (58 patients) meeting the criteria were collected. ctDNA was detected in 9 (29%) of 31 cases treated with upfront metastasectomy and in 7 (19.4%) of 36 cases treated with metastasectomy after upfront chemotherapy. The detection rate of ctDNA was higher in liver metastasis (p = 0.0045) and tumors measuring ≥1 cm (p = 0.0183). ctDNA was less likely to be detected if the response to chemotherapy was good. After metastasectomy, ctDNA was found in 4 (6%) cases with rapid progressive disease. Conclusion: The biological factors affecting the ctDNA shedding from the tumor should be considered when applying ctDNA assays in a clinical setting. After metastasectomy for oligometastatic lesions in good responders of chemotherapy, most ctDNA was cleared or existed below the detection level. To assist clinical decision making after metastasectomy for mCRC using ctDNA, further studies for improving specific outcomes are needed.

This study aimed to identify novel biomarkers for metastatic colorectal cancer progression using exosomal RNA expression profiling. The exosomal RNA expression profiles of 54 patients with mCRC were investigated. Exosomal RNA profiling was performed at the time of relapse immediately before metastasectomy and cancer recurrence or progression after metastasectomy. The up- and down-regulated RNA expression profiles were screened and analyzed using H-cluster, principle component analysis and gene ontology. The tissue expression profile of the liver metastases was compared with the GSE 41258 set using GSEA tools. We identified two distinctive biological process gene sets (IFNA and PCDB families) related to metastatic progression. The interferon-α response gene set was enriched, especially when the tumor volume was ≥1 cm³. CXCL10, CXCL11 and SAMD 9 mRNA were highly expressed in the plasma exosome samples of patients with mCRC to the liver. Furthermore, high expression of CXCL10 but not CXCL11 or SAMD9 was associated with a poor prognosis and shorter progression-free survival. Conclusions: Cancer-derived exosomal CXCL10 may be a novel biomarker for liver metastasis of mCRC and a potential target for the prevention and treatment of mCRC with liver metastasis.

Pancreatic ductal adenocarcinoma (PDAC) remains among the most therapeutically intractable malignancies, with a 5-year survival rate of approximately 10% and near-universal resistance to immune checkpoint inhibitor (ICI) therapy. This refractoriness arises from the convergence of pronounced intratumoral heterogeneity (ITH) and a profoundly immunosuppressive tumor microenvironment (TME), which together configure PDAC as a prototypical immune-excluded tumor. Beyond low tumor mutational burden, PDAC exhibits layered genetic, epigenetic, transcriptional, and metabolic heterogeneity that enables rapid adaptation and immune evasion under selective pressure, while dense desmoplastic stroma, cancer-associated fibroblasts (CAFs), and immunosuppressive immune populations collectively impose formidable physical and immunologic barriers to antitumor immunity. In this review, we synthesize multi-omics, spatial transcriptomic, and immunologic evidence to elucidate how ITH and the TME dynamically interact to reinforce immune resistance. We examine reciprocal crosstalk mechanisms—including immune-driven clonal selection, interclonal cooperation, metabolic niche specialization, and metabolic–epigenetic coupling—and discuss emerging platforms such as single-cell spatial omics, patient-derived organoid immune co-culture systems, and longitudinal circulating tumor DNA monitoring that enable high-resolution mapping of ITH–TME dynamics. Finally, we evaluate ITH–TME-guided combination therapeutic strategies targeting oncogenic drivers, stromal architecture, myeloid suppression, and metabolic checkpoints, and propose a prioritized framework for near-term and speculative clinical translation in PDAC.