Masayo Ukita

YAP1 Suppression by ZDHHC7 Is Associated with Ferroptosis Resistance and Poor Prognosis in Ovarian Clear Cell Carcinoma

Abstract Ovarian clear cell carcinoma (OCCC), which has unique clinical characteristics, arises from benign endometriotic cysts, forming an oxidative stress environment because of excess iron accumulation, and exhibits poor prognosis, particularly in advanced stages owing to resistance to conventional therapeutics. Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation and controlled by Hippo signaling. We hypothesized that overcoming ferroptosis resistance is an attractive strategy because OCCC acquires oxidative stress resistance during its development and exhibits chemoresistant features indicative of ferroptosis resistance. This study aimed to determine whether OCCC is resistant to ferroptosis and clarify the mechanism underlying resistance. Unlike ovarian high-grade serous carcinoma cells, OCCC cells were exposed to oxidative stress. However, OCCC cells remained unaffected by lipid peroxidation. Cell viability assays revealed that OCCC cells exhibited resistance to the ferroptosis inducer erastin. Moreover, Samroc analysis showed that the Hippo signaling pathway was enriched in OCCC cell lines and clinical samples. Furthermore, patients with low expression of nuclear yes-associated protein 1 (YAP1) exhibited a significantly poor prognosis of OCCC. Moreover, YAP1 activation enhanced ferroptosis in OCCC cell lines. Furthermore, suppression of zinc finger DHHC-type palmitoyltransferase 7 (ZDHHC7) enhanced ferroptosis by activating YAP1 in OCCC cell lines. Mouse xenograft models demonstrated that ZDHHC7 inhibition suppressed tumor growth via YAP1 activation by erastin treatment. In conclusion, YAP1 activation regulated by ZDHHC7 enhanced ferroptosis in OCCC. Thus, overcoming ferroptosis resistance is a potential therapeutic strategy for OCCC.

Evaluation of neoadjuvant chemotherapy followed by radical hysterectomy in cervical cancer: a single-center study

Abstract Background The efficacy of neoadjuvant chemotherapy (NACT) before radical hysterectomy (RH) in cervical cancer remains unclear. We evaluated stage-specific outcomes of NACT-RH at a high-volume center. Methods This retrospective cohort study included patients with non-metastatic cT1b1–2b cervical cancer who underwent RH between 2013 and 2022. For cT1b cases, prognostic outcomes were compared between patients with cT1b3 (any N) who underwent NACT-RH (High-risk, NACT(+)) and those with cT1b1–1b2 N0 who underwent primary RH (Low-risk, NACT(−)), using propensity score matching. For cT2 cases, NACT-RH versus primary RH was compared using inverse probability weighting to adjust for baseline differences. Results Among 191 patients who underwent RH (cT1: n  = 99; cT2: n  = 92), the matched cT1 cohort comprised 15 High-risk, NACT(+) and 30 Low-risk, NACT(−) patients. Five-year progression-free survival (PFS) was 75.0% (95% confidence interval [CI], 53.4–100.0%) versus 89.9% (95% CI, 79.6–100.0%) ( p  = 0.427). Overall survival (OS) was 100% in both groups with a median follow-up of > 70 months. In cT2, NACT-RH ( n  = 73) versus primary RH ( n  = 19) showed hazard ratios of 2.88 for PFS (95% CI, 0.69–11.97) and 5.64 for OS (95% CI, 0.70–45.35) after baseline adjustment. Among cT2 patients who underwent NACT-RH, PFS and OS were worse in those without an objective response to NACT ( n  = 18, all cT2b) than in responders. Conclusion NACT-RH was associated with encouraging long-term outcomes in cT1b3, whereas outcomes in cT2 cases remain uncertain, supporting careful selection and response-adapted strategies.

CXCL13-producing CD4+ T cells accumulate in the early phase of tertiary lymphoid structures in ovarian cancer

Tertiary lymphoid structures (TLS) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. However, how TLS are induced in the tumor microenvironment (TME) and how they affect patient survival are not well understood. We investigated TLS distribution in relation to tumor infiltrating lymphocytes (TILs) and related gene expression in high-grade serous ovarian cancer (HGSC) specimens. CXCL13 gene expression correlated with TLS presence and the infiltration of T cells and B cells, and it was a favorable prognostic factor for patients with HGSC. Coexistence of CD8+ T cells and B cell lineages in the TME significantly improved the prognosis of HGSC and was correlated with the presence of TLS. CXCL13 expression was predominantly coincident with CD4+ T cells in TLS and CD8+ T cells in TILs, and it shifted from CD4+ T cells to CD21+ follicular DCs as TLS matured. In a mouse ovarian cancer model, recombinant CXCL13 induced TLS and enhanced survival by the infiltration of CD8+ T cells. These results suggest that TLS formation was associated with CXCL13-producing CD4+ T cells and that TLS facilitated the coordinated antitumor response of cellular and humoral immunity in ovarian cancer.