Cell Communication and Signaling最新文献

Colorectal cancer (CRC) liver metastases remain refractory to immunotherapy due to a profoundly immunosuppressive tumor microenvironment. Here, we conducted a prospective clinical study enrolling 18 patients with microsatellite-stable CRC liver metastases treated with high-dose radiotherapy (RT) followed by anti-PD-1 immune checkpoint inhibitors (RT-ICI). Integrative analysis of single-cell RNA-sequencing, spatial transcriptomics, and peripheral immune profiling revealed that RT-ICI therapy reprograms both tumor-intrinsic and immune compartments. RT triggered the emergence of an APOA2⁺ tumor cell state characterized by enhanced lipid metabolic activity and transient elevation of circulating HDL. This metabolic reprogramming, in turn, promoted systemic activation of CETP⁺ M2-like macrophages, a population marked by high LXR/RXR transcriptional activity and enriched expression of immunosuppressive and lipid-processing genes. Despite their expansion, CETP⁺ macrophages localized preferentially to non-irradiated tumor regions, suggesting a distal immunometabolic effect driven by HDL-mediated signaling. Concurrently, combination therapy expanded GZMB⁺ effector T cells and induced a novel population of inflammatory-toxic T cells (IT_T), which exhibited high cytotoxicity and spatial co-localization with CXCL10⁺ macrophages. Ligand-receptor analysis and pseudotime modeling revealed that irradiated tumor cells acted as "in situ vaccines" by enhancing MHC-TCR interactions and promoting T cell differentiation along non-exhausted cytotoxic lineages. Together, these findings reveal a dual mechanism by which RT-ICI therapy enhances local anti-tumor immunity while modulating systemic lipid metabolism and macrophage polarization, offering insights for combinatorial immunotherapy design in immunologically "cold" tumors.

Background: Delayed detection of recurrence significantly contributes to colorectal cancer (CRC) mortality, underscoring the need for robust prognostic biomarkers. Although extrachromosomal circular DNA (eccDNA) is a known oncogenic driver, its prognostic utility in CRC remains largely unexplored.

Methods: In this 6-year prospective cohort study, full-length eccDNA profiling of 153 plasma samples was performed using Nanopore sequencing. Differential eccDNA signatures between recurrence (R, n = 20) and non-recurrence (NR, n = 133) patients enabled construction of predictive models for recurrence and mortality. Functional validation of eccDNAs was conducted in HCT116 cells.

Results: Compared to NR patients, R patients exhibited enrichment of eccDNAs derived from chromosome 9, shorter median eccDNA lengths, and reduced variability in eccDNA length. All 4.9-5.0 kb eccDNAs derived from CKM, while other eccDNAs showed a strong genomic distribution correlation between groups (Spearman's ρ = 0.73). Promoter-derived eccDNAs were enriched in R patients, particularly from the promoter of CARD9 (eccPromoter-CARD9, 10.4-fold increase). Overexpression of eccPromoter-CARD9 significantly promoted CRC cell proliferation and migration. R patients exhibited elevated eccDNAs harboring the hsa-mir-374c cluster in plasma and tissues, and their corresponding miRNAs demonstrated exceptional diagnostic accuracy in CRC-related TCGA cohorts. An eccDNA-based random forest classifier achieved superior recurrence prediction accuracy (AUC > 0.8), correlating with shorter time-to-recurrence (HR = 3.79) and elevated CA125 and CEA levels. Additional eccDNA-based models effectively predicted recurrence-associated mortality (AUC ≥ 0.93).

Conclusions: The plasma eccDNA landscape may serve as an early and powerful non-invasive biomarker for CRC prognostication, optimizing risk stratification and guiding personalized treatment.

Background: Hypomyelinating leukodystrophies (HLDs) are rare genetic neurodevelopmental disorders characterized by defective myelin formation. The genetic cause of these disorders has been ascribed to mutations in genes encoding myelin protein components, such as proteolipid protein 1 (PLP1) and myelin basic protein (MBP), or in genes encoding for transcription and translation-related proteins. Particularly, biallelic pathogenic variants in POLR3A, POLR3B, POLR3K, POLR3D, POLR1C lead to the insurgence of RNA Polymerase III (Pol III)-related HLDs (POLR3-HLDs). The molecular mechanisms linking Pol III dysfunction to hypomyelination remain largely elusive, though the main hypothesis is that impaired Pol III activity likely disrupts gene expression and cellular homeostasis processes critical for myelin development and lipid metabolism.

Methods: In this study, we analyzed a family trio consisting of unaffected carrier parents and a proband affected by POLR3A-related HLD, carrying compound heterozygous variants (p.Phe601Tyr and p.Gly1358Arg). We investigated the structural and functional consequences of two POLR3A variants using protein modeling, functional assays and multi-omics profiling in subject-specific primary fibroblasts.

Results: Structural analysis revealed alterations in DNA-binding regions and a likely impact on protein stability, whilst functional assays showed an impairment in cellular proliferation. Lipidomic and transcriptomic profiling revealed that p. Gly1358Arg mutation predominantly affects lipidomic metabolism, while p. Phe601Tyr was associated with a widespread transcriptional dysregulation. Both mutations ultimately caused a significant reduction in lipid droplets in the proband's cells.

Conclusions: These results demonstrate mutation-specific pathogenetic mechanisms in POLR3A-HLD and underline the utility of integrative multi-omics approaches in elucidating the molecular basis of rare neurodevelopmental disorders.

Cancer metastasis is the leading cause of mortality associated with cancer, and the prognosis for patients diagnosed with colorectal cancer(CRC) largely depends on the occurrence of metastasis during the progression of the disease. A comprehensive understanding of the mechanisms underlying metastasis in CRC is essential for advancing treatment strategies. Through integrated bioinformatics analysis of mRNA expression profiles and epigenetic modifiers, we identified SMYD3 as the top differentially expressed histone modifier in CRC. Clinically, SMYD3 overexpression significantly associates with poor prognosis and enhances metastatic potential. Utilizing immunoprecipitation-mass spectrometry, we discovered RACK1 as a novel SMYD3-interacting protein. Subsequent mechanistic studies revealed a tripartite interaction network: SMYD3 recruits SMAD3 through RACK1-mediated scaffolding, facilitating transcriptional activation of the downstream effector TSKU. Notably, RACK1 depletion disrupts SMYD3-SMAD3 complex formation, establishing the critical role of this axis in metastasis regulation. Consequently, inhibiting the SMYD3-SMAD3 interaction may represent a promising therapeutic strategy for addressing CRC metastasis. In conclusion, targeting the SMYD3-RACK1-SMAD3 transcriptional complex presents a viable approach for the treatment of CRC metastasis.