Wenhan Li

Efferocytosis‐Driven Polyamine Metabolism in Macrophages Enhances Cancer Stem Cell Enrichment after Chemotherapy in Ovarian Cancer

Abstract Chemotherapy‐induced enrichment of cancer stem cells (CSCs) is a key mechanism underlying acquired chemoresistance and recurrence of epithelial ovarian cancer (OC). Although chemotherapy may enrich CSCs through selection or by inducing dedifferentiation, the dynamic changes in the tumor niche and their impact on CSCs during chemotherapy remain unclear. In this study, single‐cell sequencing and multiplex immunohistochemical analysis are used to define microenvironmental changes, and a post‐chemotherapy increase in efferocytotic macrophages that phagocytosed chemotherapy‐induced apoptotic tumor cells is identified. Efferocytotic macrophages are associated with poor prognosis and CSCs in OC. Their conditioned medium facilitates OC stemness in vitro. Meanwhile, targeting efferocytosis suppresses CSC enrichment, chemoresistance, and regrowth in vivo. Mechanistically, it is demonstrated that enhanced expression of ODC1 driven by efferocytosis increases polyamine flux, particularly putrescine, by integrating metabolomics and transcriptomics. The increase in putrescine content leads to the SPP1 and OPN overexpression in macrophages, conferring cancer stemness to OC cells through the OPN‐CD44 axis. Treatment with an ODC1 selector inhibitor mitigates CSC enrichment, sensitizes tumors to cisplatin, and restricts tumor regrowth. Together, the study shows that efferocytosis and associated polyamine metabolic reprogramming support the chemotherapy‐induced enrichment of CSCs, providing new targets for addressing chemoresistance and recurrence of OC.

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.

CBX2 promotes cervical cancer cell proliferation and resistance to DNA-damaging treatment via maintaining cancer stemness

Cervical cancer is the fourth most common malignancy and the fourth leading cause of cancer-related death among women. Advanced stages and resistance to treatment in cervical cancer induce cancer-related deaths. Although epigenetics has been known to play a vital role in tumor progression and resistance, the function of epigenetic regulators in cervical cancer is an area of investigation. In this study, we focused on an epigenetic regulator, polycomb repressor complex 1 in cervical cancer. Through bioinformatics analysis and immunochemistry, we subsequently identified chromobox 2CBX2), the deregulated subunit of polycomb repressor complex 1, which is upregulated in cervical cancer and associated with poor prognosis and unfavorable clinicopathological characteristics. We provided functional evidence demonstrating that CBX2 promoted cervical cancer cell proliferation. Furthermore, CBX2 exhibited an antiapoptotic effect, which induced resistance to cisplatin and ionizing radiation in cervical cancer cells. Moreover, CBX2 was involved in maintaining cancer stemness. These findings suggest that CBX2 plays an important role in cervical cancer progression and resistance to treatment, and may serve as a potential biomarker for prognosis and resistance as well as a potential therapeutic target.