Ping Jin

Label-Free Monitoring of Endometrial Cancer Progression Using Multiphoton Microscopy

AbstractEndometrial cancer is the most common gynecological cancer in the developed world. However, the accuracy of current diagnostic methods is still unsatisfactory and time-consuming. Here, we presented an alternate approach to monitoring the progression of endometrial cancer via multiphoton microscopy imaging and analysis of collagen, which is often overlooked in current endometrial cancer diagnosis protocols but can offer a crucial signature in cancer biology. Multiphoton microscopy (MPM) based on the second-harmonic generation and two-photon excited fluorescence was introduced to visualize the microenvironment of endometrium in normal, hyperplasia without atypia, atypical hyperplasia, and endometrial cancer specimens. Furthermore, automatic image analysis based on the MPM image processing algorithm was used to quantify the differences in the collagen morphological features among them. MPM enables the visualization of the morphological details and alterations of the glands in the development process of endometrial cancer, including irregular changes in the structure of the gland, increased ratio of the gland to the interstitium, and atypical changes in the glandular epithelial cells. Moreover, the destructed basement membrane caused by gland proliferation and fusion is clearly shown in SHG images, which is a key feature for identifying endometrial cancer progression. Quantitative analysis reveals that the formation of endometrial cancer is accompanied by an increase in collagen fiber length and width, a progressive linearization and loosening of interstitial collagen, and a more random arrangement of interstitial collagen. Observation and quantitative analysis of interstitial collagen provide invaluable information in monitoring the progression of endometrial cancer. Label-free multiphoton imaging reported here has the potential to become an in situ histological tool for effective and accurate early diagnosis and detection of malignant lesions in endometrial cancer.

Bepotastine Sensitizes Ovarian Cancer to PARP Inhibitors through Suppressing NF-κB–Triggered SASP in Cancer-Associated Fibroblasts

Abstract Therapy-induced senescence (TIS) is common in tumor cells treated with PARP inhibitors (PARPis) and can serve as a promising target for improving PARPi efficacy. However, whether stromal components within the tumor microenvironment undergo TIS caused by PARPis and contribute to consequential treatment failure remain unclear. We previously revealed that PARPis triggered a senescence-like secretory phenotype in stromal fibroblasts. Here, we further explored PARPi-induced senescence in the stroma, its contribution to PARPi resistance, and opportunities to leverage stromal TIS for improved PARPi sensitivity. In this study, we demonstrated that tumor tissues from patients treated with neoadjuvant PARPis showed a significant senescence-like phenotype in the stroma. Moreover, PARPi-induced senescent cancer-associated fibroblasts (CAFs) displayed a senescence-associated secretory phenotype (SASP) profile that was sufficient to induce tumor resistance to PARPis in both homologous recombination–deficient (HRD) and –proficient ovarian cancer cells. Using the GLAD4U database, we found that bepotastine, an approved H1-antihistamine, inhibited the SASP of PARPi-primed CAFs at clinical serum concentrations. We further demonstrated that bepotastine attenuated fibroblast-facilitated tumor resistance to PARPis in three-dimensional organotypic cultures and HRD-positive patient-derived xenograft models. Mechanistically, bepotastine suppressed PARPi-triggered SASP by inhibiting NF-κB signaling independent of the histamine H1 receptor. Taken together, our results highlight the importance of stromal TIS and SASP in PARPi resistance, and targeting SASP with bepotastine may be a promising therapeutic option for improving PARPi sensitivity in ovarian cancer.

Risk stratification and conservative management of women aged 25–40 years with cervical intraepithelial neoplasia grade 2(CIN2)

Cervical intraepithelial neoplasia grade 2 (CIN2) can progress to CIN3 or worse (CIN3 We conducted a retrospective observational study of 307 women aged ≤ 40 years, diagnosed with CIN2 via colposcopy-guided punch biopsy where the squamocolumnar junction was visible, and who underwent LEEP within three months. We compared the diagnoses from punch biopsies with the histology of the LEEP specimens and developed a stratified management algorithm based on identified risk factors. The risk of CIN3 Patients aged 25-40 years with CIN2 diagnosed in punch biopsy exhibited a substantial risk of CIN3

SNRPD3 promotes endometrial cancer progression via regulating SREBF1 intron retention

Alternative splicing (AS) serves as a pivotal post-transcriptional regulatory mechanism that drives tumorigenesis. Small nuclear ribonucleoprotein D3 (SNRPD3), an indispensable component of the spliceosome, is aberrantly expressed in multiple malignancies. Nevertheless, its biological functions and underlying mechanisms in the pathobiology of endometrial cancer (EC) remains unknown. We demonstrated that SNRPD3 was significantly upregulated in human EC tissues. Knockdown of SNRPD3 markedly inhibited EC cell proliferation, migration, and invasion in vitro and suppressed tumor growth in subcutaneous xenograft models. Mechanistically, silencing SNRPD3 increased intron retention in SREBF1 mRNA. Furthermore, depletion of SREBF1 abolished the enhanced proliferative capacity and lipid metabolism in both parental EC cells and SNRPD3-overexpressing EC cells. Notably, antisense oligonucleotides (ASOs)-mediated silencing of SNRPD3 markedly repressed EC cell growth and metastatic potential in vitro, and effectively impeded tumor progression in patient-derived xenograft (PDX) models. Collectively, our findings reveal that SNRPD3 serves as an oncogenic splicing factor that promotes EC proliferation and metastasis by regulating SREBF1 mRNA splicing. Given its potent antitumor efficacy in preclinical PDX models, ASO-targeted SNRPD3 may represent a promising therapeutic strategy for endometrial cancer.