PDK2 leads to cisplatin resistance through suppression of mitochondrial function in ovarian clear cell carcinoma

Ovarian clear cell carcinoma (CCC) exhibits an association with endometriosis, resistance to oxidative stress, and poor prognosis owing to its resistance to conventional platinum-based chemotherapy. A greater understanding of the molecular characteristics and pathogenesis of ovarian cancer subtypes may facilitate the development of targeted therapeutic strategies, though the mechanism of drug resistance in ovarian CCC has yet to be determined. In this study, we assessed exome sequencing data to identify new therapeutic targets of mitochondrial function in ovarian CCC because of the central role of mitochondria in redox homeostasis. Copy number analyses revealed that chromosome 17q21-24 (chr.17q21-24) amplification was associated with recurrence in ovarian CCC. Cell viability assays identified an association between cisplatin resistance and chr.17q21-24 amplification, and mitochondrion-related genes were enriched in patients with chr.17q21-24 amplification. Patients with high expression of pyruvate dehydrogenase kinase 2 (PDK2) had a worse prognosis than those with low PDK2 expression. Furthermore, inhibition of PDK2 synergistically enhanced cisplatin sensitivity by activating the electron transport chain and by increasing the production of mitochondrial reactive oxygen species. Mouse xenograft models showed that inhibition of PDK2 with cisplatin inhibited tumor growth. This evidence suggests that targeting mitochondrial metabolism and redox homeostasis is an attractive therapeutic strategy for improving drug sensitivity in ovarian CCC

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

卵巣がんにおける新たな免疫の仕組みを発見 --三次リンパ様構造の形成メカニズムと予後への影響を解明--. 京都大学プレスリリース. 2022-08-05.Tertiary lymphoid structures (TLSs) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. However, how TLSs 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 was a favorable prognostic factor for HGSC patients. 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 TLSs. CXCL13 expression was predominantly coincident with CD4⁺ T cells in TLSs and CD8⁺ T cells in TILs, and shifted from CD4⁺ T cells to CD21⁺ follicular dendritic cells as TLS matured. In a mouse ovarian cancer model, recombinant CXCL13 induced TLSs 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 TLSs facilitated the coordinated antitumor response of cellular and humoral immunity in ovarian cancer

Acquired Evolution of Mitochondrial Metabolism Regulated by HNF1B in Ovarian Clear Cell Carcinoma

Clear cell carcinoma (CCC) of the ovary exhibits a unique morphology and clinically malignant behavior. The eosinophilic cytoplasm includes abundant glycogen. Although the growth is slow, the prognosis is poor owing to resistance to conventional chemotherapies. CCC often arises in endometriotic cysts and is accompanied by endometriosis. Based on these characteristics, three clinical questions are considered: why does ovarian cancer, especially CCC and endometrioid carcinoma, frequently occur in endometriotic cysts, why do distinct histological subtypes (CCC and endometrioid carcinoma) arise in the endometriotic cyst, and why does ovarian CCC possess unique characteristics? Mutations in AT-rich interacting domain-containing protein 1A and phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit alpha genes may contribute to the carcinogenesis of ovarian CCC, whereas hepatocyte nuclear factor-1-beta (HNF1B) plays crucial roles in sculpting the unique characteristics of ovarian CCC through metabolic alterations. HNF1B increases glutathione synthesis, activates anaerobic glycolysis called the Warburg effect, and suppresses mitochondria. These metabolic changes may be induced in stressful environments. Life has evolved to utilize and control energy; eukaryotes require mitochondria to transform oxygen reduction into useful energy. Because mitochondrial function is suppressed in ovarian CCC, these cancer cells probably acquired further metabolic evolution during the carcinogenic process in order to survive stressful environments