Dong-Joo Cheon

Background/Objectives: Tumor-associated macrophages (TAMs) are critical mediators for immunosuppressive ovarian tumor microenvironments. However, the lipid metabolic features of macrophages at different stages of ovarian tumor development remain poorly understood. Methods: Here, we performed LC-MS-based lipidomic profiling of CD11b⁺/F4/80⁺ macrophages isolated from ID8 tumor-bearing C57/BL6 mice at Days 10, 40, and 80 following tumor cell inoculation. Results: Principal component analysis and hierarchical clustering revealed stage-associated differences in macrophage lipid profiles. Phosphatidylethanolamine (PE), phosphatidylserine (PS), and lysophosphatidylcholine (LPC) were relatively more abundant at earlier time points, whereas triglyceride (TG) species were more abundant in macrophages isolated at Day 80. Detailed analysis revealed an increased abundance of TG species with greater total numbers of double bonds at Day 80. Pathway analysis identified enrichment of glycerolipid metabolism at Day 80. Consistent with these lipidomic findings, macrophages at Day 80 exhibited increased expression of lipogenic regulators, including Fasn, Pparg, and Srebp1, together with a gene expression profile associated with a pro-tumoral macrophage state. Supplementation of oleic acid to macrophages increased expression of selected genes associated with this macrophage state, supporting a potential relationship between altered lipid metabolism and macrophage gene expression changes. Conclusions: These findings identify stage-associated TG accumulation and alterations in macrophage lipid metabolism and provide a basis for future studies to determine whether macrophage lipid metabolism contributes to a pro-tumoral macrophage state.

Lipid droplet-associated hydrolase (LDAH) is a lipid hydrolase abundantly expressed in adipose and ovarian tissues and macrophages. However, LDAH’s functions in ovarian cancer are largely unknown. Analysis of publicly available patient datasets showed decreased LDAH expression in advanced stages of ovarian cancer, and low LDAH levels were associated with poor survival outcomes in ovarian cancer patients. Consistently, knockdown (KD) of LDAH in human ovarian cancer cell lines increased tumor cell proliferation but decreased endoplasmic reticulum (ER) stress and apoptosis upon cisplatin treatment. In addition, compared to scrambled control, LDAH KD ovarian cancer cells showed smaller lipid droplets (LDs), decreased triacylglycerol (TAG) content, and increased expression of adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase 1 A (CPT1A), and phospho-NF-kB. Our xenograft studies also showed increased tumor growth, increased ATGL expression, and decreased apoptosis after cisplatin treatment in LDAH KD tumors. ATGL overexpression increased cisplatin resistance and expression of CPT1A and phospho-NF-kB, whereas treatment of LDAH KD cells with an ATGL inhibitor attenuated the phenotype. Lastly, we observed that high ATGL levels were associated with shorter survival in ovarian cancer patients. Collectively, our results suggest that ovarian cancer cells downregulate LDAH expression, leading to enhanced ATGL-mediated TAG hydrolysis and increased tumor growth and chemoresistance.

Molecular physiopathology of epithelial ovarian cancer: role of inflammation Inflammation emerges as an important risk factor associated with epithelial ovarian cancer (EOC), the most common type of ovarian cancer. Increased inflammation and inflammatory mediators are also associated with poor prognosis and shorter survival in EOC patients. Inflammation can be caused by several factors such as repeated ovulation, peritoneal infection, endometriosis, obesity, or exposure to foreign particles (e.g., pollutants). A chronic inflammatory microenvironment is established by increased levels of reactive oxygen species (ROS), cytokines, chemokines, and growth factors produced by the ovaries, immune cells, tumor cells, and tumor stroma. This inflammatory microenvironment can cause DNA damage, activation of signaling pathways, epigenetic alterations, chromosomal aberrations, and the impaired innate and adaptive immune response to promote tumor cell initiation, progression, metastasis, and drug resistance (reviewed in Savant SS et al., Cancers (Basel). 2018 Jul 30;10(8):251). This Research Topic was proposed to collect new studies that address how chronic inflammation, caused by individual characteristics (e.g., genetics and hormone levels) and environmental factors (e.g., infections and pollutants), can promote EOC initiation, progression, immunosuppression, and therapy resistance. Five articles in this Research Topic provide some insights on how inflammation could affect EOC progression. Pyroptosis is a type of inflammatory-based cell death in response to various molecular patterns associated with damage and pathogens. The process activates a characteristic inflammasome and the executing proteins belong to the gasdermine family. Canonical pyroptosis is characterized by influx of sodium with water, swelling of cells, and osmotic cellular lysis, which results in release of pro-inflammatory intracellular content. Pyroptosis function is to destroy the intracellular pathogenic niche by inducing pro-inflammatory responses in neighboring cells. The tumor's immune microenvironment can be influenced by pyroptosis in such a way as to favor the anti-tumor immune response. Liu et al.

Most ovarian cancer patients develop recurrent cancers which are often resistant to commonly employed chemotherapy agents, such as cisplatin. We have previously shown that the inhibition of heat shock protein 27 (HSP27) or fatty acid oxidation (FAO) sensitizes cisplatin-resistant ovarian cancer cell lines to cisplatin and dual inhibition of both HSP27 and FAO induces substantial cell death in vitro. However, it is unclear how HSP27 and FAO promote cisplatin resistance, and if dual inhibition of both HSP27 and FAO would augment cisplatin treatment in vivo. Here we showed that HSP27 knockdown in two cisplatin-resistant ovarian cancer cell lines (A2780CIS and PEO4) resulted in more ROS production upon cisplatin treatment. HSP27-knockdown cancer cells exhibited decreased levels of reduced glutathione (GSH) and glucose6phosphate dehydrogenase (G6PD), a crucial pentose phosphate pathway enzyme. ROS depletion with the compound N-acetyl cysteine (NAC) attenuated cisplatin-induced upregulation of HSP27, FAO, and markers of apoptosis and ferroptosis in cisplatin-resistant ovarian cancer cell lines. Finally, inhibition of HSP27 and FAO with ivermectin and perhexiline enhanced the cytotoxic effect of cisplatin in A2780CIS xenograft tumors in vivo. Our results suggest that two different cisplatin-resistant ovarian cancer cell lines upregulate HSP27 and FAO to deplete cisplatin-induced ROS to attenuate cisplatin’s cytotoxic effect.

Ovarian cancer is the second most common gynecological cancer and has the highest mortality rate of all female reproductive cancers in the United States. A lack of early detection, typically aggressive progression, and rapid development of resistance to chemotherapy are key contributing factors to the mortality rate. Dr. Dong-Joo (Ellen) Cheon and her team at Albany Medical College are working to determine the role of key players in the resistance to chemotherapy treatments and examining how best we can target these therapeutically to improve survival.

Cancer-associated fibroblasts (CAFs) are a heterogenous population of stromal cells found in solid malignancies that coexist with the growing tumor mass and other immune/nonimmune cellular elements. In certain neoplasms (e.g., desmoplastic tumors), CAFs are the prominent mesenchymal cell type in the tumor microenvironment, where their presence and abundance signal a poor prognosis in multiple cancers. CAFs play a major role in the progression of various malignancies by remodeling the supporting stromal matrix into a dense, fibrotic structure while secreting factors that lead to the acquisition of cancer stem-like characteristics and promoting tumor cell survival, reduced sensitivity to chemotherapeutics, aggressive growth and metastasis. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Clarifying the molecular basis for such multidirectional crosstalk among the various normal and neoplastic cell types present in the tumor microenvironment may yield novel targets and new opportunities for therapeutic intervention. This review highlights the most recent concepts regarding the complexity of CAF biology including CAF heterogeneity, functionality in drug resistance, contribution to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes.

Collagen type XI alpha 1 (COL11A1) is a novel biomarker associated with cisplatin resistance in ovarian cancer. We have previously reported that COL11A1 activates Src-Akt signaling through the collagen receptors discoidin domain receptor 2 (DDR2) and integrin α1β1 to confer cisplatin resistance to ovarian cancer cells. To identify the potential signaling molecules downstream of COL11A1 signaling, we performed protein kinase arrays and identified heat shock protein 27 (HSP27) as a potential mediator of COL11A1-induced cisplatin resistance. Through receptor knockdown and inhibitor experiments, we demonstrated that COL11A1 significantly upregulates HSP27 phosphorylation and expression via DDR2/integrin α1β1 and Src/Akt signaling in ovarian cancer cells. Furthermore, genetic knockdown and pharmacological inhibition of HSP27, via ivermectin treatment, significantly sensitizes ovarian cancer cells cultured on COL11A1 to cisplatin treatment. HSP27 knockdown or inhibition also decreases NFκB activity as well as the expression of inhibitors of apoptosis proteins (IAPs), which are known downstream effector molecules of COL11A1 that promote cisplatin resistance. Interestingly, HSP27 knockdown or inhibition stimulates ovarian cancer cells to upregulate fatty acid oxidation (FAO) for survival and cisplatin resistance, and dual inhibition of HSP27 and FAO synergistically kills ovarian cancer cells that are cultured on COL11A1. Collectively, this study identifies HSP27 as a novel and druggable COL11A1 downstream effector molecule that may be targeted to overcome cisplatin resistance in recurrent ovarian cancer, which often overexpress COL11A1.

Collagen type XI alpha 1 (COL11A1), one of the three alpha chains of type XI collagen, is crucial for bone development and collagen fiber assembly. Interestingly, COL11A1 expression is increased in several cancers and high levels of COL11A1 are often associated with poor survival, chemoresistance, and recurrence. This review will discuss the recent discoveries in the biological functions of COL11A1 in cancer. COL11A1 is predominantly expressed and secreted by a subset of cancer-associated fibroblasts, modulating tumor-stroma interaction and mechanical properties of extracellular matrix. COL11A1 also promotes cancer cell migration, metastasis, and therapy resistance by activating pro-survival pathways and modulating tumor metabolic phenotype. Several inhibitors that are currently being tested in clinical trials for cancer or used in clinic for other diseases, can be potentially used to target COL11A1 signaling. Collectively, this review underscores the role of COL11A1 as a promising biomarker and a key player in cancer.

Significance: Why women carrying a pathogenic germlineBRCA1mutation are predisposed to ovarian and breast cancer remains elusive. This study points to ovarian progesterone as a culprit. Generally,BRCA1-mutation carriers exhibit high yet individually varying levels of progesterone during the menstrual cycle. Although not allBRCA1-mutation carriers develop these cancers, all of them are advised to undergo prophylactic surgeries at a young age (under 40 y to 45 y) to prevent ovarian and breast cancer. Insights from robust in vivo findings in this study offer a novel concept: Targeting progesterone signaling with antiprogestins could be an effective nonsurgical prophylactic option for ovarian and breast cancer prevention for these high-risk women.

Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies. Rarely does an experimental model fully replicate the clinical metastases of a human malignancy. Faithfully representing the clinical metastases of human high-grade serous ovarian cancer with complete penetrance, coupled with histopathological, molecular, and genomic similarities, these mouse models, particularly one harboring mutant p53, will be vital to elucidating the underlying pathogenesis of human ovarian cancer. In-depth understanding of the development and progression of ovarian cancer is crucial to medical advances in the early detection, effective treatment, and prevention of ovarian cancer. Also, these robust mouse models, as well as cell lines established from the mouse primary and metastatic tumors, will serve as useful preclinical tools to evaluate therapeutic target genes and new therapies in ovarian cancer.