Qian Liu

Humanized patient-derived xenograft mouse model bearing ovarian clear cell carcinoma

The study aimed to establish humanized patient-derived xenograft (PDX) mouse models of ovarian clear cell carcinoma (OCCC) and evaluate their therapeutic responses. PDX models and their humanized counterparts (CD34+ humanized PDX models) derived from the same tumor source were developed, and the therapeutic responses were compared between the models. Treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor significantly reduced tumor size in traditional OCCC PDX models (p=0.021). Although differences in tumor growth between traditional PDX models and humanized PDX models were observed, they were not statistically significant (p=0.438). However, treatment effects of PI3K inhibitor differed significantly between conventional and humanized mice (p=0.006). In the Humanized PDX cohort, both programmed cell death protein-1 antibody monotherapy and PI3K inhibitor treatment slowed tumor growth relative to controls, with a synergistic effect noted during the latter part of the study, though these effects were not statistically significant. This pioneering study successfully develop a humanized PDX model for OCCC, highlighting differential responses to treatments compared to conventional PDX models.

SERPINH1 functions as a multifunctional regulator to promote the malignant progression of cervical cancer

Cervical cancer remains the second leading cause of female cancer mortality worldwide, with metastasis representing a critical therapeutic challenge. This study systematically reveals the key role of SERPINH1 (Serpin Family H Member 1) as a hub regulator of malignant progression in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Through analysis of TCGA-CESC datasets, we identified that high SERPINH1 expression is significantly correlated with poor prognosis and contributes to tumor progression by promoting cell proliferation, invasion, and metastatic phenotypes. In vitro experiments validated these findings, demonstrating that SERPINH1 overexpression markedly enhanced the proliferation, invasion, and metastasis of cervical cancer cells, whereas its knockdown substantially inhibited these processes. Furthermore, based on the SERPINH1-related differentially expressed genes, a prognostic risk model was constructed, successfully identifying PLOD1, ITGA5, and ESM1 as core collaborative genes affecting patient prognosis. Overall, our findings underscore the multiple functions of SERPINH1 as a hub for cervical cancer metastasis regulation, suggesting its potential as a promising biomarker for tailoring strategies in metastasis patients of CESC.

NC410, a bivalent LAIR-2 construct, remodels collagen in the tumor microenvironment and abrogates neutrophil-driven T cell suppression

Abstract We previously observed that circulating human neutrophils exposed to epithelial ovarian cancer (OC) ascites fluid supernatants (ASC) and malignant effusions from other tumors acquire T cell suppressor function. Collagen motifs ligate LAIR-1, an inhibitory SHP-1-dependent checkpoint broadly expressed on immune cells. We hypothesized that NC410, a bivalent LAIR-2 construct that inhibits LAIR-1-collagen binding, would rescue neutrophil-driven T cell non-responsiveness. NC410 remodeled ASC collagen resulting in neutrophil clustering and reduction in neutrophil-T cell contact, abrogated ASC-induced neutrophil trogocytosis of T cell membranes and rescued stimulated T cell proliferation. Mean ASC pro-collagen-1α levels were >100-fold greater than serum samples. In a single-center retrospective analysis, after adjusting for age, stage and optimal debulking, ASC pro-collagen-1α and serum sLAIR-1 levels were each associated with worse overall survival (OS), and ASC LAIR-2 levels were associated with better OS. Multispectral imaging of high-grade serous ovarian cancer and non-small cell lung cancer showed highly variable LAIR-1 staining in both tumor cell and immune infiltrates. The proportion of collagen-1-positive cells was highest among tumor cells and tumor-infiltrating immune cells versus stromal immune cells, raising the potential role of tumor-associated collagen limiting immune cell infiltration into tumor. Our results support further evaluation of circulating and tumor-associated collagen products and LAIR-1 and LAIR-2 as prognostic biomarkers in advanced OC and as biomarkers for clinical response to NC410 and to other collagen- and LAIR-directed therapies.