Background Estrogen-related receptor α (ERRα) has been reported to play a critical role in endometrial cancer (EC) progression. However, the underlying mechanism of ERRα-mediated lipid reprogramming in EC remains elusive. The transcription factor EB (TFEB)-ERRα axis induces lipid reprogramming to promote progression of EC was explored in this study. Methods TFEB and ERRα were analyzed and validated by RNA-sequencing data from the Cancer Genome Atlas (TCGA). The TFEB-ERRα axis was assessed by dual-luciferase reporter and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The mechanism was investigated using loss-of-function and gain-of-function assays in vitro. Lipidomics and proteomics were performed to identify the TFEB-ERRα-related lipid metabolism pathway. Pseudopods were observed by scanning electron microscope. Furthermore, immunohistochemistry and lipidomics were performed in clinical tissue samples to validate the ERRα-related lipids. Results TFEB and ERRα were highly expressed in EC patients and correlated to EC progression. ERRα is the direct target of TFEB to mediate EC lipid metabolism. TFEB-ERRα axis mainly affected glycerophospholipids (GPs) and significantly elevated the ratio of phosphatidylcholine (PC)/sphingomyelin (SM), which indicated the enhanced membrane fluidity. TFEB-ERRα axis induced the mitochondria specific phosphatidylglycerol (PG) (18:1/22:6) + H increasing. The lipid reprogramming was mainly related to mitochondrial function though combining lipidomics and proteomics. The maximum oxygen consumption rate (OCR), ATP and lipid-related genes acc, fasn, and acadm were found to be positively correlated with TFEB/ERRα. TFEB-ERRα axis enhanced generation of pseudopodia to increase the invasiveness. Mechanistically, our functional assays indicated that TFEB promoted EC cell migration in an ERRα-dependent manner via EMT signaling. Consistent with the in vitro, higher PC (18:1/18:2) + HCOO was found in EC patients, and those with higher TFEB/ERRα had deeper myometrial invasion and lower serum HDL levels. Importantly, PC (18:1/18:2) + HCOO was an independent risk factor positively related to ERRα for lymph node metastasis. Conclusion Lipid reprogramming induced by the TFEB-ERRα axis increases unsaturated fatty acid (UFA)-containing PCs, PG, PC/SM and pseudopodia, which enhance membrane fluidity via EMT signaling to promote EC progression. PG (18:1/22:6) + H induced by TFEB-ERRα axis was involved in tumorigenesis and PC (18:1/18:2) + HCOO was the ERRα-dependent lipid to mediate EC metastasis.

Rationale:Primary leiomyosarcoma (LMS) of the fallopian tube is extremely uncommon. To the best of our knowledge, so far only 21 cases of primary fallopian tube LMS have been reported in English-language literature. No new case has been reported in the past 7 years.Patient concerns:A 44-year-old premenopausal patient presented with a 5-day history of lower abdominal pain.Diagnoses:Pelvic ultrasonography detected an 8.8 × 7.8 × 6.5 cm solid and cystic mass in the left side of the pelvic cavity. The tumor was diagnosed as a primary fallopian tube LMS on paraffin section.Interventions:The patient treated surgically followed by 4 cycles of postoperative chemotherapy with dacarbazine and DDP.Outcomes:The patient succumbed to the disease 27 months after the initial therapy.Lessons:Tube LMS is a rare malignant tumor with unknown etiology, difficult early diagnosis, highly invasiveness, high local recurrence and distant metastasis rate, rapid progress, and poor prognosis. It is extremely rare so we can only summarize limited experience from limited data. Every case of tubal LMS is worth being reported.

PARP inhibitors (PARPis) have remarkable antitumor activity in BRCA mutant ovarian carcinoma. Emerging evidence has shown that responses to PARPis are not limited to BRCA mutant tumors, but could expand to other homologous recombination deficiency (HRD) carcinomas. However, relatively little is known about the efficacy of PARPis in patients with HRD when compared to non‐HRD carriers. In this systematic review, 13 clinical trials were included and analyzed for the treatment effect of PARPis on progression free survival (PFS) and overall survival (OS) for HRD (BRCA mutant HRD, n = 697; BRCA wild‐type HRD, n = 478) vs. non‐HRD (n = 1,417) patients. Pooled analyses of the effect of PARPis in both ovarian and nonovarian carcinoma groups showed significantly higher PFS rates at 6 months and 12 months (PFS6 and PFS12) in the HRD subgroup, as compared to the non‐HRD subgroup. Within the HRD subgroup, the BRCA‐mutant population achieved significantly higher PFS6 (OR: 2.29, 95% CI: 1.03–5.08) and PFS12 (OR: 1.95, 95% CI: 1.26–3.01) when compared to BRCA wild‐type patients. Furthermore, within BRCA wild‐type carcinomas, mutations in other HRD‐related genes also led to increased PFS6 (OR: 1.72, 95% CI: 1.27–2.43) and PFS12 (OR: 1.85, 95% CI: 1.31–2.62), as compared to non‐HRD counterparts. Therefore, patients with HRD carcinomas exhibited pronounced PFS advantages upon treatment with PARPis, as compared to non‐HRD carcinomas. In addition to BRCA mutations, other non‐BRCA HRD‐related aberrations may serve as novel biomarkers for the prediction of PARPi efficacy.

Background: Endometrial cancer (EC) is one of the most common tumors in women. Estrogen-related receptor α (ERRα) has been reported to play a critical role in EC progression. However, the underlying mechanism of ERRα-mediated lipid reprogramming in EC remains elusive. Here, we show that transcription factor EB (TFEB)-ERRα axis promote lipid reprogramming to enhance invasion and metastasis of EC.Methods: TFEB and ERRα were analyzed and validated by RNA-sequencing data of EC tissues from the Cancer Genome Atlas (TCGA). TFEB-ERRα axis were assessed by dual-luciferase reporter and chromatin immunoprecipitation quantitative polymerase chain reaction (ChIP-qPCR). The mechanism of TFEB-ERRα was investigated using loss-of-function and gain-of-function assays in vitro. Lipidomics and proteomics were performed to identify the ERRα-related lipid metabolism pathway. Furthermore, immunohistochemistry and lipidomics were performed in the tissues to verify the ERRα-related lipids.Results: Both TFEB and ERRα were highly expression in EC patients and related to EC progression. ERRα was the directly target of TFEB to mediate EC lipid metabolism. Lipidomics assays demonstrated that ERRα mainly effects on glycerophospholipids (GPs) and phosphatidylcholine (PC) and significantly elevates the ratio of PC/sphingomyelin (SM) in EC cells, which indicated the enhanced membrane fluidity. Specifically, ERRα induced unsaturated fatty acid (UFA)-containing PCs, phosphatidylglycerol (PGs), SMs etc. Combined proteomics analysis revealed the increase of UFA-containing GPs mainly related to mitochondrial function. Then, the levels of maximum oxygen consumption rates (OCRs), adenosine triphosphate (ATP) and lipid metabolism-related genes acc, fasn, acadm were found to be positively correlated with TFEB/ERRα expression. Mechanistically, our functional assays indicate that TFEB promoted EC cell migration in a ERRα-dependent manner by epithelial-mesenchymal transformation (EMT) signaling. Consistent with in vitro, higher PC(18:1/18:2)+HCOO were found in EC patients and those who with higher expression of TFEB/ERRα had a deeper myometrial invasion and lower serum high-density lipoprotein (HDL). Moreover, PC(18:1/18:2)+HCOO was an independent risk factor of the patients with lymph node metastasis and positively related to ERRα. Conclusion: Lipid reprogramming induced by TFEB-ERRα axis increases UFA- containing PC, PG and SM, which enhanced membrane fluidity via EMT signaling to promote EC progression. Of note, PC(18:1/18:2)+HCOO was the ERRα-associated potential predictor of EC metastasis.

Ewing's sarcoma/peripheral primitive neuroectodermal tumors (ES/pPNET) are a group of small round cell sarcomas that show varying degrees of neuroectodermal differentiation characterized by translocation involving the EWS gene. Uterine ES/pPNET is a rare entity. A 29-year-old Chinese female who presented with abdominal swelling and pain was diagnosed with a primary uterine ES/pPNET on the basis of clinicopathologic, immunohistochemical and fluorescence in situ hybridization (FISH) data. She was given a multimodal treatment, including neoadjuvant, 95% cytoreductive, chemotherapy and radiotherapy. The patient is currently alive with persistent disease after 18 months of follow-up. We emphasized the crucial role of molecular techniques in the differential diagnosis of small round cell tumors in this unusual location. Multimodal therapy may improve the outcomes of patients.