Science China Life Sciences

Targeting senescent cells in aged adipose tissue induced by ovarian cancer with the NF-κB inhibitor quercetin and resveratrol impedes the growth and metastasis of ovarian cancer

As a lipophilic tumour, ovarian cancer (OC) preferentially metastasizes to adipose-rich environments including the omentum and the peritoneum. Current research regarding the OC microenvironment has focused primarily on tumour-associated immune cells, whereas little attention has been given to the adipose tissue and the adipose-derived stem cells (ADSCs) within it. Here, from the perspective of senescence, we hypothesized that the continuous presence and accumulation of tumour cells disrupts the homeostasis of adipose tissue by intercellular interactions. Through a series of in vitro and in vivo experiments, we found that OC cells induce adipose tissue ageing and ADSC senescence, leading to adipose tissue dysfunction, glucose intolerance, and insulin resistance. OC extracellular vesicle (OC-EV) and ADSC coculture revealed that OC-EVs trigger ADSC ageing and dysfunction. Moreover, coculture promoted the formation of inflammasomes in ADSCs and increased the levels of the inflammatory factors IL-1β and IL-18. RNA-sequencing and bioinformatics analysis revealed that the nuclear factor kappa B (NF-κB) signalling pathway is involved in ADSC senescence induced by OC cells. Immunofluorescence staining and Western blotting confirmed that increased expression of NF-κB signalling-related proteins is associated with senescent ADSCs. Further mechanistic studies revealed that OC-EVs deliver IL-1β to promote ADSC senescence and regulate the NF-κB signalling pathway in ADSCs. On the basis of these findings, we attempted to ameliorate the ovarian cancer microenvironment by eliminating senescent ADSCs, aiming to develop a therapeutic strategy against ovarian cancer. Both treatment with the senolytic cocktail dasatinib plus quercetin and treatment with the NF-κB inhibitor resveratrol (RSV) alleviated adipose tissue ageing, improved glucose tolerance and insulin sensitivity, and ultimately decreased OC progression and metastasis. Together, these results indicate an important role of ovarian cancer in adipose tissue ageing, and identify the elimination of senescent ADSCs in adipose tissue as a new potential strategy for the treatment of OC.

Development and application of antibody-drug conjugates in gynecological cancers

Selective expansion of TCF7-expressing tumor-reactive T cell subpopulations during ovarian tumor-infiltrating T cell production ex vivo

Tumor-infiltrating lymphocyte (TIL) therapy was recently approved for melanoma patients; however, the dynamic changes in T cell subpopulations during TIL production remain poorly understood. Here, we analyzed epithelial ovarian cancer samples at various stages of ex vivo TIL culture using paired single-cell RNA and TCR sequencing. We also assessed the expansion potential and tumor reactivity of the identified TIL subpopulations. Single-cell transcriptomic analysis revealed that CD8

Palmitoylation of MDH2 by ZDHHC18 activates mitochondrial respiration and accelerates ovarian cancer growth

Epithelial ovarian cancer (EOC) exhibits strong dependency on the tricarboxylic acid (TCA) cycle and oxidative phosphorylation to fuel anabolic process. Here, we show that malate dehydrogenase 2 (MDH2), a key enzyme of the TCA cycle, is palmitoylated at cysteine 138 (C138) residue, resulting in increased activity of MDH2. We next identify that ZDHHC18 acts as a palmitoyltransferase of MDH2. Glutamine deprivation enhances MDH2 palmitoylation by increasing the binding between ZDHHC18 and MDH2. MDH2 silencing represses mitochondrial respiration as well as ovarian cancer cell proliferation both in vitro and in vivo. Intriguingly, re-expression of wild-type MDH2, but not its palmitoylation-deficient C138S mutant, sustains mitochondrial respiration and restores the growth as well as clonogenic capability of ovarian cancer cells. Notably, MDH2 palmitoylation level is elevated in clinical cancer samples from patients with high-grade serous ovarian cancer. These observations suggest that MDH2 palmitoylation catalyzed by ZDHHC18 sustains mitochondrial respiration and promotes the malignancy of ovarian cancer, yielding possibilities of targeting ZDHHC18-mediated MDH2 palmitoylation in the treatment of EOC.

Unlocking the potential: advancements and future horizons in ROR1-targeted cancer therapies

Targeting LTA4H facilitates the reshaping of the immune microenvironment mediated by CCL5 and sensitizes ovarian cancer to Cisplatin

Ovarian cancer is the most lethal and aggressive gynecological cancer with a high recurrence rate and is often diagnosed late. In ovarian cancer, multiple metabolic enzymes of lipid metabolism are abnormally expressed, resulting in metabolism disorder. As a characteristic pathway in polyunsaturated fatty acid (PUFA) metabolism, arachidonic acid (AA) metabolism is disturbed in ovarian cancer. Therefore, we established a 10-gene signature model to evaluate the prognostic risk of PUFA-related genes. This 10-gene signature has strong robustness and can play a stable predictive role in datasets of various platforms (TCGA, ICGC, and GSE17260). The high association between the risk subgroups and clinical characteristics indicated a good performance of the model. Our data further indicated that the high expression of LTA4H was positively correlated with poor prognosis in ovarian cancer. Deficiency of LTA4H enhanced sensitivity to Cisplatin and modified the characteristics of immune cell infiltration in ovarian cancer. Additionally, our results indicate that CCL5 was involved in the aberrant metabolism of the AA/LTA4H axis, which contributes to the reduction of tumor-infiltrating CD8

Multi-omics analysis revealed the addiction to glutamine and susceptibility to de novo lipogenesis of endometrial neoplasm

The endometrium is a proliferative tissue controlled by the menstrual cycle. Endometrial hyperplasia (EH) is a type of neoplastic disease that may develop into endometrial hyperplasia with atypia (EHA) or endometrial adenocarcinoma (EA). We performed a multi-omics analysis of a collection of endometrial tissues with four different proliferative statuses from two independent cohorts of patients. A positive association between the level of glutamine and malignancy, as well as addiction of EHA/EA neoplasms to glutamine, was identified. Further investigation revealed the dual mechanism by which glutamine influences the development of endometrial neoplasms. On one hand, glutamine regulates the level of c-MYC by controlling its translational process. On the other hand, glutamine is a major source of energy for endometrial neoplasms. Reprogramming the glutamine metabolism towards de novo lipogenesis affects the growth of endometrial adenocarcinoma in vitro, ex vivo and in vivo. Our study revealed the importance of maintaining metabolic homeostasis in endometrial tissues. The enhancement of de novo lipogenesis is a promising therapeutic strategy for treating endometrial adenocarcinoma.