Jian Xiang’s research while affiliated with Jinan University and other places

Resistance to platinum is the main challenge in the chemotherapy of ovarian cancer (OV). Therefore, developing a response signature to platinum is essential for the precision therapy of OV. Existing quantitative signatures of platinum are susceptible to batch effects and sequencing platform variations. To address this, we developed a transcriptome-based platinum signature, named PRSM, consisting of 15 genes, based on within-sample prognostic and relative expression ordering of genes, to predict individual responses to platinum in OV. The PRSM model demonstrated superior classification accuracy compared to previous quantitative signatures. Resistant samples classified by PRSM exhibited poorer overall survival, lower SNV neoantigen load, tumor mutational burden, and distinct methylation patterns compared to sensitive samples. Pathway analysis revealed the activation of MYC targets V2 and oxidative phosphorylation in resistant tumors. Single-cell analysis highlighted the roles of NK and epithelial cells in resistance. Among the 15 core genes, five (TFAP2B, KRT81, PAGE1, CRNN, UGT2B17) were linked to poor prognosis, with TFAP2B having the highest contribution to PRSM. Overexpression of TFAP2B in A2780 cells enhanced cisplatin sensitivity, while in A2780cis cells, it inhibited growth. In brief, our findings provide a multi-dimensional view of platinum resistance in ovarian cancer, introducing a robust predictive model and identifying potential therapeutic targets.

Background Meningioma is the most common primary intracranial tumor with a high frequency of postoperative recurrence, yet the biology of the meningioma malignancy process is still obscure. Methods To identify potential therapeutic targets and tumor suppressors, we performed single-cell transcriptome analysis through meningioma malignancy, which included 18 samples spanning normal meninges, benign and high-grade in situ tumors, and lung metastases, for extensive transcriptome characterization. Tumor suppressor candidate gene and molecular mechanism were functionally validated at the animal model and cellular levels. Results Comprehensive analysis and validation in mice and clinical cohorts indicated clusterin (CLU) had suppressive function for meningioma tumorigenesis and malignancy by inducing mitochondria damage and triggering type 1 interferon pathway dependent on its secreted isoform, and the inhibition effect was enhanced by TNFα as TNFα also induced type 1 interferon pathway. Meanwhile, both intra- and extracellular CLU overexpression enhanced macrophage polarization towards M1 phenotype and TNFα production, thus promoting tumor killing and phagocytosis. Conclusions CLU might be a key brake of meningioma malignance by synchronously modulating tumor cells and their microenvironment. Our work provides comprehensive insights into meningioma malignancy and a potential therapeutic strategy.

Human immune system functions over an entire lifetime, yet how and why the immune system becomes less effective with age are not well understood. Here, we characterize peripheral blood mononuclear cell transcriptome from 132 healthy adults with 21-90 years of age using the weighted gene correlation network analyses. In our study, 113 Caucasian from the 10KIP database and RNA-seq data of 19 Asian (Chinese) are used to explore the differential co-expression genes in PBMC aging. These two dataset reveal a set of insightful gene expression modules and representative gene biomarkers for human immune system aging from Asian and Caucasian ancestry, respectively. Among them, the aging-specific modules may show an age-related gene expression variation spike around early-seventies. In addition, we find the top hub genes including NUDT7, CLPB, OXNAD1, and MLLT3 are shared between Asian and Caucasian aging related modules and further validated in human PBMCs from different age groups. Overall, the impact of age and race on transcriptional variation elucidated from this study may provide insights into the transcriptional driver of immune aging.

Human immune system functions over an entire lifetime, yet how and why the immune system becomes less effective with age are not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 21~90 years of age using RNA-seq and the weighted gene correlation network analysis (WGCNA). These data have revealed a meaningful of gene expression modules or representative biomarkers for human immune system aging in Aisan and White ancestry. Among them, several gene modules demonstrated a remarkably correlation with human immune aging progress. Besides, further analysis on these ageing related modules show age-related gene expression changes spike is around early-seventies. More importantly, we also focus on how race and ethnicity affect immune aging as race-specific effects on these gene expression changes have clinical applications for diagnosis and interpretation of immunosenescence. Thus, the top hub genes including NUDT7, CLPB, OXNAD1 and MLLT3 are identified from Asian and white aging related modules and further validated in humans PBMC at different ages. Finally, the impact of age and race on immune phenotypes we discuss may provide insights into future studies.

Dendritic epidermal T cells (DETCs) are γδ T cells expressing invariant Vγ5Vδ1 T cell receptor (TCR) in murine epidermis. Initially, the development and the maturation of DETC progenitors are mediated by skint-1, TCR, and cytokines in the fetal thymus. Then, the DETC progenitors migrate to the epidermis with the guidance of selectins, CCR10, CCR4, etc. Eventually, mature DETCs proliferate and maintain a homeostatic population in the epidermis through IL-15 and aryl hydro-carbon receptor signaling. In “stressed” skin, DETCs are activated, exhibiting features such as a round morphology, cytotoxicity, and production of cytokines. In cutaneous carcinoma, DETCs generally inhibit tumor development directly in non-major histocompatibility complex-restricted manner, with the assistance of cytokines. DETCs also recognize and inhibit tumor via TCR, non-TCR receptors (such as 2B4 and NKG2D), or both. This study summarizes the biogenesis and the function of DETCs in cutaneous carcinoma and clarifies the essential surveillance role in the epidermis that DETCs play. As there are no DETCs in human epidermis but only human epidermis γδ T cells, we need to understand the anti-tumor pathways used by DETCs to find analogous immune pathways in human skin, which could be exploited for novel therapeutics.