Xin Zhou

Hypoxia-driven remodeling of SELENOP+ macrophages shapes T cell dynamics and promotes ovarian cancer metastasis

Abstract High-grade serous ovarian cancer (HGSOC) is characterized by extensive transcoelomic dissemination and the accumulation of ascites. However, how site-specific tumor microenvironment (TME) drives progression remains unknown. Here we show the co-occurrence and spatial co-localization of SELENOP + macrophages and precursor exhausted CD8 + T cells and demonstrate that SELENOP + macrophages activate T cells via selenoprotein P in vitro and in vivo. We further identify a dynamic transition in the SELENOP + / SPP1 + macrophage populations as tumor metastasis, driven by increased hypoxia malignant epithelial cells through VEGFA-EPHB2 signaling. We also reveal that anti-VEGFA intervention controls ovarian tumor growth by increasing SELENOP + macrophages and cytotoxicity of CD8 + T cells in vivo. Taken together, these findings spotlight the role of tumor-induced TME remodeling in subverting immune-mediated tumor control and thus facilitating HGSOC metastasis in females. Collectively, our results provide a foundation for the development of targeted therapeutic interventions aimed at impeding HGSOC metastatic trajectory.

Heterogeneous cellular responses to hyperthermia support combined intraperitoneal hyperthermic immunotherapy for ovarian cancer mouse models

The benefit of hyperthermic intraperitoneal chemotherapy (HIPEC) in ovarian cancer remains controversial, hindering the development of rational combination therapies based on hyperthermia (HT). This study reports the preliminary results of the neoadjuvant HIPEC (NHIPEC) trial (ChiCTR2000038173), demonstrating enhanced tumor response in high-grade serous ovarian cancer with NHIPEC. Through single-cell RNA sequencing analysis, we identified both homogeneous and heterogeneous cellular responses to HT within the tumor and microenvironment. Epithelial-mesenchymal transition–activated tumor cells and matrix metallopeptidase 11 (MMP-11) + cancer-associated fibroblasts (CAFs) exhibited greater reductions and higher sensitivity to HT. CUT&Tag and RNA sequencing integration unveiled the differential binding programs and transcriptional regulatory mechanisms of HSF1 under normothermia (NT) and HT in tumor cells and CAFs. Furthermore, HT ameliorated the immunosuppressive tumor microenvironment, and in vivo mouse models confirmed the combined antitumor effects of HT and programmed cell death ligand 1 blockade. These findings provide an innovative strategy for rational combination therapy with HT in ovarian cancer.

CAF-derived GLUT1 and its role in modulating ovarian cancer progression: a multi-dimensional analysis of the tumor microenvironment

Deciphering the reprogramming of glucose metabolism in cancer-associated fibroblasts (CAFs) within the ovarian cancer (OC) microenvironment is essential for understanding tumor progression. While CAFs are known to influence tumor metabolism, the specific mechanisms underlying their role in metabolic adaptation remain unclear. Here, we show that GLUT1 is highly expressed in CAFs and promotes glucose uptake, glycolysis, and lactate production, which in turn drives OC cell proliferation and migration via the TGF-β1/p38/MMP2/MMP9 pathway. Single-cell RNA sequencing and bioinformatics analyses identify GLUT1 as a key metabolic regulator in CAFs, and 3D bioprinting models further confirm its role in shaping the tumor microenvironment. These findings highlight GLUT1 as a potential therapeutic target for OC and provide new insights into tumor metabolism and metastasis.

Overexpression of Epithelial Splicing Regulatory Protein 1 in Metastatic Lesions of Serous Ovarian Carcinoma Correlates with Poor Patient Prognosis

Correlation of immediate prevalence of cervical precancers and cancers with HPV genotype and age in women with atypical glandular cells cytology: A retrospective analysis of 369 cases

AbstractBackgroundThis study aims to assess the immediate risk of cervical precancers and cancers in women with atypical glandular cells (AGC) cytology, based on high‐risk human papillomavirus (hrHPV) genotypes and age.MethodsA retrospective analysis was conducted on 369 cases of AGC with immediate follow‐up biopsy results, including 299 AGC‐not otherwise specified (NOS) and 70 AGC‐favor neoplastic (FN).ResultsAmong the 369 AGC cases, 127 tested positive for hrHPV (34.4%). The predominant high‐risk type was other 11 genotypes (44.1%), followed by 16+ (29.1%), 18/45+ (26.0%), and 16 and 18/45 double‐positive (0.79%). Precancers and cancers were detected in 30.4% (112 of 369) and 9.8% (36 of 369) of cases, respectively. The HPV‐18/45+ group had notably higher adenocarcinoma in situ and adenocarcinoma (AIS+) prevalence compared to other 11 genotype groups (p < .0001 and p = .001, respectively). The HPV‐16+ group showed significantly higher high‐grade cervical squamous epithelial lesion and squamous cell carcinoma prevalence than other 11 genotype groups (p < .0001 and p = .017, respectively). Using 40‐year cutoff, older women had significantly higher prevalence of abnormal glandular lesion+ lesions (17.6% vs. 7.6%, p = .005) and adenocarcinoma (AC) (12.4% vs. 2.5%, p = .001). Using 50‐year cutoff, older women had higher prevalence of squamous cell carcinoma (SCC) (3.3% vs. 0.4%, p = .042) and AC (15.2% vs. 5.8%, p = .005). Subgroup analysis revealed that AGC‐FN women showed more severe cervical pathology than AGC‐NOS women (p < .001).ConclusionsAGC women have a significantly increased risk of cervical precancerous lesions and cancer. HPV genotyping and patient age factors need to be taken into consideration in the clinical management process of AGC patients.