Investigator
Huazhong University Of Science And Technology
Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response
Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10
LOXL2 reduces susceptibility to PARP inhibitors by promoting super-enhancer-regulated DNA damage repair in high-grade serous ovarian cancer
Poly(ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment of homologous recombination-deficient (HRD) tumors, yet their efficacy in homologous recombination-proficient (HRP) tumors is still limited. Here, we pinpoint lysyl oxidase-like 2 (LOXL2) as a key epigenetic regulator driving PARPi resistance. Our study demonstrate that elevated LOXL2 expression correlates with poor prognosis and disease recurrence in high-grade serous ovarian cancer (HGSOC) patients. Functional studies reveal that LOXL2 depletion or pharmacological inhibition synergizes with PARPi to suppress HRP models of both ovarian and breast cancer. Mechanistically, LOXL2 directly interacts with and transcriptionally activates BRD4, a core component of the super-enhancer complex, thereby amplifying the expression of DNA damage repair (DDR) genes such as MDC1, KAT5, and USP7. Strikingly, LOXL2 inhibition induces a "BRCAness" phenotype in HRP tumors, rendering them more susceptible to PARPi by impairing DDR capacity. Combining BET inhibitors with PARPi abrogates LOXL2-mediated resistance, underscoring BRD4 dependency in this process. Our findings establish LOXL2 as a druggable epigenetic target to overcome PARPi resistance in HRP models of multiple tumor types, presenting a therapeutic strategy independent of HR status and holding significant clinical potential for expanding PARPi benefits to a broader patient population.
Rictor orchestrates β-catenin/FOXO balance by maintaining redox homeostasis during development of ovarian cancer
Rictor/mTORC2 has been demonstrated to have important roles in cancer development and progression in a number of solid and hematologic malignancies. However, little is known about the role of Rictor/mTORC2 in ovarian cancer pathophysiology. Herein, using conditional Rictor knockout mice, we were able to demonstrate that Rictor deletion disrupted glutathione metabolism through AKT/Nrf2 signaling pathway and induced intracellular oxidative stress during the malignant transformation of Kras/Pten-mutant ovarian surface epithelial cells. Elevated reactive oxygen species and activated FOXO3a in Rictor-deleted cells strikingly shifts the functional interaction of β-catenin from TCF to FOXO3a, which strongly inhibits classical Wnt/β-catenin signaling. Our findings emphasize a pivotal role for Rictor in orchestrating crosstalk between the PI3K/AKT and Wnt/β-catenin signaling in the development of ovarian cancer. Illustration of Rictor/mTORC2 in promoting tumor onset by regulating glutathione metabolism and mediating oncogenic signaling.
Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance
Cervical squamous cell carcinoma (CSCC) exhibits a limited response to immune-checkpoint blockade. Here we conducted a multiomic analysis encompassing single-cell RNA sequencing, spatial transcriptomics and spatial proteomics, combined with genetic and pharmacological perturbations to systematically develop a high-resolution and spatially resolved map of intratumoral expression heterogeneity in CSCC. Three tumor states (epithelial-cytokeratin, epithelial-immune (Epi-Imm) and epithelial senescence), recapitulating different stages of squamous differentiation, showed distinct tumor immune microenvironments. Bidirectional interactions between epithelial-cytokeratin malignant cells and immunosuppressive cancer-associated fibroblasts form an immune exclusionary microenvironment through transforming growth factor β pathway signaling mediated by FABP5. In Epi-Imm tumors, malignant cells interact with natural killer and T cells through interferon signaling. Preliminary analysis of samples from a cervical cancer clinical trial ( NCT04516616 ) demonstrated neoadjuvant chemotherapy induces a state transition to Epi-Imm, which correlates with pathological complete remission following treatment with immune-checkpoint blockade. These findings deepen the understanding of cellular state diversity in CSCC.
Tumor cell–derived IFN spatially reprograms osteopontin-enriched macrophage niches to promote PARP inhibitor resistance
Poly (ADP-ribose) polymerase inhibitors (PARPis) benefit homologous recombination-deficient (HRD) malignancies, yet resistance remains a major challenge. Leveraging specimens from a prospective neoadjuvant niraparib monotherapy trial in treatment-naive, high-grade serous ovarian cancer, we integrated PhenoCycler-Fusion spatial profiling, scRNA-Seq, and multiplex immunohistochemistry to identify 2 therapeutic-modulated cellular neighborhoods: an IFN+ tumor cell-enriched niche that expands in resistant lesions and a niche enriched in tumor-associated macrophage (TAM) that persists but acquires enhanced immunosuppressive features. Mechanistically, sustained tumor cell-derived IFN induced osteopontin (SPP1) expression in TAMs via STAT signaling, creating immunosuppressive niches enriched in Tregs and myofibroblastic cancer-associated fibroblasts with intensified cell-cell interactions. SPP1 directly suppressed T cell signaling and effector function. High baseline SPP1+ cells predicted lower response rate (30.0% vs. 76.2%; P = 0.021) and shorter progression-free survival (median 13.5 vs. 28.3 months; P = 0.0006). In HRD mouse models, SPP1 blockade restored PARPi sensitivity, reversed acquired resistance, and enhanced T cell cytotoxicity-effects abrogated in immunodeficient mice, confirming immune dependence. These data establish a spatial IFN-SPP1 axis whereby persistent tumor cell IFN reprograms TAMs to promote PARPi resistance, position SPP1 as a key therapeutic target and prognostic biomarker for this therapy, and underscore therapeutic potential of microenvironment-targeted strategies to overcome PARPi resistance.
Clinical Studies of Endometrial Cytology and Cervical Methylation Assays in Endometrial Cancer Screening and Fertility-Preservation Evaluation
The current study aims to assess high-risk patients using both liquid-based cytology and cervical methylation testing. The results will be compared with the traditional hysteroscopic pathological findings to determine the sensitivity and specificity of these methods for early detection of endometrial cancer, thereby evaluating their potential application in early screening. Primary Objectives： 1. To evaluate the sensitivity, specificity, and accuracy of endometrial cytology for screening endometrial cancer. 2. To assess the sensitivity, specificity, and accuracy of methylation testing for screening endometrial cancer. 3. To perform further molecular testing on tissue samples obtained from endometrial cytology and cervical methylation tests, aiming to explore early screening-sensitive indicators. Secondary Objectives： 1. To determine the value of endometrial cytology in evaluating the efficacy of fertility-sparing treatments for endometrial cancer. 2. To assess the value of methylation testing in evaluating the efficacy of fertility-sparing treatments for endometrial cancer.
Pd-1 Antibody Combined Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer
Cervical cancer is one of the major health problems for chinese women. Besides surgery and radiotherapy, neoadjuvant chemotherapy has been proved to be an effective program by many studies. However, not all patients respond well to neoadjuvant chemotherapy. This is an open-label, single-arm, multi-center clinical trial to evaluate whether PD-1 in combination with neoadjuvant chemotherapy will achieve better objective response rate.
