Biology subjects

Liu, Y. S.

Publications and source records attributed to Liu, Y. S..

2 recordsLinked to original sources

bioRxiv2025

Increasing Stemness Drives Prostate Cancer Progression, Plasticity, Therapy Resistance and Poor Patient Survival

BackgroundCancer progression is often accompanied by dedifferentiation and acquisition of stem cell-like properties (stemness). In prostate cancer (PCa), lineage plasticity and therapy resistance remain major clinical challenges, yet a unified quantitative transcriptomic framework connecting stemness, androgen receptor (AR) signaling, castration resistance, and disease progression across the PCa continuum is lacking. MethodsWe integrated 87,339 transcriptomic profiles from 33 preclinical and clinical datasets spanning the PCa continuum from normal prostate and treatment-naive primary PCa (Pri-PCa) to PCa treated with neoadjuvant ADT (nADT) and metastatic castration-resistant PCa (mCRPC), with single-cell RNA-seq analyses encompassing 115,197 cells. Cancer stemness was quantified using a transcriptome-derived mRNA-based Stemness Index (mRNAsi; hereafter Stemness), and a 12-gene PCa-Stem signature was developed to capture PCa-specific stemness. Stemness, PCa-Stem, canonical AR activity (c_AR-A), castration-reprogrammed AR activity (cr_AR-A), RB1-loss, PTEN-loss, and MYC activity signatures were quantified across cohorts. Functional validation included MYC inhibition and representative PCa-Stem signature gene depletion in PCa models. Clinical prognostic significance was evaluated in independent patient cohorts. ResultsThe Stemness score and c_AR-A increased concordantly during early prostate tumorigenesis but diverged with PCa progression: as Gleason grade increased, c_AR-A declined while Stemness continually increased. mCRPC exhibited the highest Stemness and lowest c_AR-A, a pattern recapitulated in Pten/Rb1/Trp53-deficient mouse models. Global Stemness increased progressively across the PCa continuum, was enriched in aggressive PAM50-LumB and PCS1 subtypes, associated with proliferative and lineage plasticity programs, and predicted poor patient survival. The newly derived 12-gene PCa-Stem signature provided a PCa-specific molecular representation of Stemness and tracked disease progression and poor patient survival. Network analyses identified a coordinated mitotic regulatory program linking MYC activity, RB1-loss, cr_AR-A, and the PCa-Stem signature. Spatial and single-cell transcriptomic analyses localized the PCa-Stem program to lineage plasticity-related epithelial cells and demonstrated progressive expansion of PCa-Stem epithelial cells during PCa progression. Functional perturbation of representative PCa-Stem signature genes, as well as genetic and pharmacological MYC inhibition, consistently suppressed Stemness-associated phenotypes in diverse PCa models. ConclusionsCancer Stemness quantitatively captures PCa aggressiveness, lineage plasticity, treatment resistance, disease progression, and poor patient survival. cr_AR-A, RB1 loss, and MYC activation cooperate to reinforce the high-Stemness state and therapy resistance in mCRPC. Collectively, our work establishes a trajectory-integrated transcriptomic framework defining cancer Stemness as a quantifiable molecular and clinical determinant of PCa aggressiveness, lineage plasticity, disease progression, therapy resistance and patient survival.

cancer biology↗

bioRxiv2020

The human liver microenvironment shapes the homing and function of CD4+ T-cell populations

Background & AimsTissue-resident memory T cells (TRM) are important immune sentinels that provide efficient in situ immunity. Liver-resident CD8+ TRM have been previously described, and contribute to viral control in persistent hepatotropic infections. However, little is known regarding liver CD4+ TRM cells. Here we profiled resident and non-resident intrahepatic CD4+ T cell subsets, assessing their phenotype, function, differential generation requirements and roles in hepatotropic infection. MethodsLiver tissue was obtained from 173 subjects with (n=109) or without (n=64) hepatic pathology. Multiparametric flow cytometry and immunofluorescence imaging examined T cell phenotype, functionality and location. Liver T cell function was determined after stimulation with anti-CD3/CD28 and PMA/Ionomycin. Co-cultures of blood-derived lymphocytes with hepatocyte cell lines, primary biliary epithelial cells, and precision-cut autologous liver slices were used to investigate the acquisition of liver-resident phenotypes. ResultsCD69 expression delineated two distinct subsets in the human liver. CD69HI cells were identified as CD4+ TRM due to exclusion from the circulation, a residency-associated phenotype (CXCR6+CD49a+S1PR1-PD-1+), restriction to specific liver niches, and ability to produce robust type-1 multifunctional cytokine responses. Conversely, CD69INT were an activated T cell population also found in the peripheral circulation, with a distinct homing profile (CX3CR1+CXCR3+CXCR1+), and a bias towards IL-4 production. Frequencies of CD69INT cells correlated with the degree of fibrosis in chronic hepatitis B virus infection. Interaction with hepatic epithelia was sufficient to generate CD69INT cells, while additional signals from the liver microenvironment were required to generate liver-resident CD69HI cells. ConclusionsIntermediate and high CD69 expression demarcates two discrete intrahepatic CD4+ T cell subsets with distinct developmental and functional profiles. Graphical Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY HighlightsO_LICD69HI (CXCR6+CD49a+S1PR1-PD-1+) are the CD4+ TRM of the human liver C_LIO_LIHepatic CD69INTCD4+ T-cells are distinct, activated, and recirculation-competent C_LIO_LIStimulation evokes respective IFN-{gamma} and IL-4 responses in CD69HI and CD69INT cells C_LIO_LICD69INT cell frequencies correlate with worsening fibrosis in chronic HBV patients C_LIO_LILiver slice cultures allow differentiation of CD69INT and CD69HI cells from blood C_LI Lay summaryTissue-resident memory T cells (TRM) orchestrate regional immune responses, but much of the biology of liver-resident CD4+ TRM remains unknown. We found high expression of cell-surface protein CD69 defined hepatic CD4+ TRM, while simultaneously uncovering a distinct novel recirculatory CD69INT CD4+ T cell subset. Both subsets displayed unique immune receptor profiles, were functionally skewed towards type-1 and type-2 responses respectively, and had distinct generation requirements, highlighting the potential for differential roles in the immunopathology of chronic liver diseases.

immunology↗