Guoqing Li

LEF1 confers resistance to DNA-damaging chemotherapies through upregulation of PARP1 and NUMA1 in ovarian cancer

Resistance to platinum-based drugs and PARP inhibitors (PARPi) is the leading cause of treatment failure in epithelial ovarian cancer (EOC). This study aimed to identify resistance mechanisms shared by both. Using bioinformatic analyses, EOC tissues, primary tumor cells and organoids, and chemoresistant cell lines, we identified lymphoid enhancer-binding factor 1 (LEF1) as a candidate, whose expression was increased in both platinum-resistant and PARPi-resistant tumors. Moreover, LEF1 deficiency increased EOC cell sensitivity to cisplatin and PARPi in vitro and in vivo. Mechanistically, LEF1 knockdown promoted double-strand breaks and significantly impaired both homologous recombination and nonhomologous end joining by directly downregulating the transcription of PARP1 and NUMA1. In addition, the LEF1 inhibitor niclosamide increased ovarian cancer sensitivity to Cisplatin and PARPi in patient-derived organoids and Niraparib-resistant cell lines. These findings indicate that LEF1 is a potential therapeutic target for overcoming resistance to chemotherapy based on platinum and PARPi in EOC.

Extracellular vesicles from ovarian cancer cells induce senescent lipid-laden macrophages to facilitate omental metastasis

Ovarian cancer exhibits striking metastatic tropism for the omentum, where lipid-laden macrophages are key mediators that fuel disease progression. However, the mechanisms governing their formation and pro-metastatic functions remain poorly understood. As extracellular vesicles (EVs) have as critical regulators of tumor-stroma crosstalk in metastatic niches, we sought to define how ovarian cancer-derived EVs orchestrate macrophages and adipocytes, and their impact on omental metastasis, aiming to explore potential therapeutic interventions. Single-cell transcriptomics of ovarian cancer revealed a distinct lipid-laden macrophage population in omentum, whose abundance correlated with metastatic burden and poor survival. Proteomics revealed that EVs from highly metastatic ovarian cancer cells were enriched in lipid metabolism regulators. In vivo experiments demonstrated that these tumor-derived vesicles mediated macrophage reprogramming, driving the acquisition of a pro-metastatic phenotype. Quantitative lipidomic profiling and lipid staining approaches confirmed the progressive lipid-laden in EV-treated macrophages. Using a patient-derived omentum-macrophage co-culture system, we demonstrated that tumor-derived EVs stimulate lipid release from omental adipocytes, which macrophages subsequently internalize through CD36-dependent uptake to drive lipid accumulation. This metabolic reprogramming culminated in cellular senescence, as evidenced by classical biomarkers including SA-β-galactosidase activity, elevated p16-INK4A and p53 levels, and the development of a matrix metalloproteinase-enriched senescence-associated secretory phenotype. Immunohistochemistry of clinical specimens demonstrated overexpression of CD36 correlated with omental metastasis and poor survival in ovarian cancer. In vivo experiments demonstrated that CD36 inhibition and senolytic therapy attenuated omental metastasis. This study unveils an EV-driven mechanism of adipose tropism in ovarian cancer metastasis, where EVs promote the formation of senescent lipid-laden macrophages via CD36-mediated lipid uptake, remodeling the metastatic niche. Targeting CD36 and senescent cells offers a promising therapeutic strategy against omental metastasis.

ITGA7 loss drives the differentiation of adipose‐derived mesenchymal stem cells to cancer‐associated fibroblasts

AbstractCancer‐associated fibroblasts (CAFs) represent a major cellular component of the tumor (pre‐)metastatic niche and play an essential role in omental dissemination of ovarian cancer. The omentum is rich in adipose, and adipose‐derived mesenchymal stem cells (ADSCs) have been identified as a source of CAFs. However, the molecular events driving the phenotype shift of ADSCs remain largely unexplored. In this research, we focus on integrins, transmembrane receptors that have been widely involved in cellular plasticity. We found that integrin α7 (ITGA7) was the only member of the integrin family that positively correlated with both overall survival and progression‐free survival in ovarian cancer through GEPIA2. The immunohistochemistry signal of ITGA7 was apparent in the tumor stroma, and a lower omental ITGA7 level was associated with metastasis. Primary ADSCs were isolated from the omentum of patients with ovarian cancer and identified by cellular morphology, biomarkers, and multilineage differentiation. The conditional medium of ovarian cancer cells induced ITGA7 expression decrease and phenotypic changes in ADSCs. Downregulation of ITGA7 in primary omental ADSCs led to decrease in stemness properties and emerge of characteristic morphology and biomarkers of CAFs. Moreover, the conditioned medium of ADSCs with ITGA7 depletion exhibited enhanced abilities to improve the migration and invasion of ovarian cancer cells in vitro. Overall, these findings indicate that loss of ITGA7 may induce the differentiation of ADSCs to CAFs that contribute to a tumor‐supportive niche.

The autophagy-related gene PEA15 is a potential prognostic biomarker for early-stage endometrial carcinoma

Background The Cancer Genome Atlas (TCGA) molecular classification has advanced risk stratification for endometrial carcinoma but has demonstrated comparable survival outcomes between the microsatellite instability (MSI) and copy-number low (CN-L) subtypes. In this study, we aimed to identify potential autophagy-related molecular signatures to increase the precision of TCGA-based prognostic stratification in early-stage endometrial carcinoma. Methods Univariate Cox regression analysis of the TCGA-Uterine Corpus Endometrial Carcinoma cohort was used to identify autophagy-related genes associated with survival outcomes in patients with endometrial carcinoma. The candidates were analyzed by the Kaplan–Meier method. Multivariate Cox regression was used to assess whether PEA15 served as an independent prognostic factor, especially for the MSI and CN-L subtypes. We examined the correlation between PEA15 protein expression and patient survival through immunohistochemical analysis of tissue microarrays from our institutional cohort of stage I endometrial cancer patients. Results Univariate analysis revealed that NRG3, PEA15, DNAJB1, BAK1, DRAM1, KLHL24, ATF6, CDKN2A, MBTPS2, and UVRAG were significantly associated with survival outcomes in early-stage endometrial carcinoma patients. Multivariate analysis established PEA15 as an independent prognostic factor. Immunohistochemical analysis of tissue microarrays revealed that elevated PEA15 expression was significantly correlated with poorer overall survival and disease-free survival. Both univariate and multivariate Cox regression confirmed high PEA15 expression as an independent prognostic factor for recurrence in patients with stage I endometrioid adenocarcinoma. Conclusions The autophagy-related gene PEA15 is an independent prognostic biomarker in early-stage endometrial carcinoma, improving risk stratification between the MSI and CN-L subtypes. Immunohistochemical detection has clinical potential for molecular classification, offering opportunities for personalized postoperative management strategies.

Tumour-derived exosomal piR-25783 promotes omental metastasis of ovarian carcinoma by inducing the fibroblast to myofibroblast transition

Ovarian carcinoma inherently possesses a distinct metastatic organotropism for the adipose-rich omentum, contributing to disease progression. Although the premetastatic microenvironment (PMM) has been known to often play a prometastatic role during the process, incomplete mechanistic insight into PMM formation has prevented its therapeutic targeting. Omental fibroblasts can be activated by tumour cells to differentiate into myofibroblasts, termed the fibroblast-to-myofibroblast transition (FMT), which, in turn, enhances cancer aggressiveness. Here, we report crosstalk between cancer cells and omental fibroblasts through exosomal piR-25783, which fuels tumour metastasis. Tumour cell-secreted exosomal piR-25783 activates the TGF-β/SMAD2/SMAD3 pathway in fibroblasts and promotes the FMT in the omentum along with the secretion of various cytokines and elevation of proliferative, migratory, and invasive properties, contributing to the formation of PMMs. Furthermore, piR-25783-induced myofibroblasts promote tumour implantation and growth in the omentum. In addition, the overexpression of piR-25783 in ovarian carcinoma is associated with unfavourable clinicopathological characteristics and shorter survival. In this study, we provide molecular, functional, and translational evidence suggesting that exosomal piR-25783 plays an important role in the formation of PMMs and the development of metastatic diseases in vitro and in vivo and may serve as a potential therapeutic target for ovarian carcinoma with metastasis.