Proteome-metabolome profiling of ovarian cancer ascites reveals novel components involved in intercellular communication.

Ovarian cancer ascites is a native medium for cancer cells that allows investigation of their secretome in a natural environment. This medium is of interest as a promising source of potential biomarkers, and also as a medium for cell-cell communication. The aim of this study was to elucidate specific features of the malignant ascites metabolome and proteome. In order to omit components of the systemic response to ascites formation, we compared malignant ascites with cirrhosis ascites. Metabolome analysis revealed 41 components that differed significantly between malignant and cirrhosis ascites. Most of the identified cancer-specific metabolites are known to be important signaling molecules. Proteomic analysis identified 2096 and 1855 proteins in the ovarian cancer and cirrhosis ascites, respectively; 424 proteins were specific for the malignant ascites. Functional analysis of the proteome demonstrated that the major differences between cirrhosis and malignant ascites were observed for the cluster of spliceosomal proteins. Additionally, we demonstrate that several splicing RNAs were exclusively detected in malignant ascites, where they probably existed within protein complexes. This result was confirmed in vitro using an ovarian cancer cell line. Identification of spliceosomal proteins and RNAs in an extracellular medium is of particular interest; the finding suggests that they might play a role in the communication between cancer cells. In addition, malignant ascites contains a high number of exosomes that are known to play an important role in signal transduction. Thus our study reveals the specific features of malignant ascites that are associated with its function as a medium of intercellular communication.

Therapy-induced secretion of spliceosomal components mediates pro-survival crosstalk between ovarian cancer cells.

Ovarian cancer often develops resistance to conventional therapies, hampering their effectiveness. Here, using ex vivo paired ovarian cancer ascites obtained before and after chemotherapy and in vitro therapy-induced secretomes, we show that molecules secreted by ovarian cancer cells upon therapy promote cisplatin resistance and enhance DNA damage repair in recipient cancer cells. Even a short-term incubation of chemonaive ovarian cancer cells with therapy-induced secretomes induces changes resembling those that are observed in chemoresistant patient-derived tumor cells after long-term therapy. Using integrative omics techniques, we find that both ex vivo and in vitro therapy-induced secretomes are enriched with spliceosomal components, which relocalize from the nucleus to the cytoplasm and subsequently into the extracellular vesicles upon treatment. We demonstrate that these molecules substantially contribute to the phenotypic effects of therapy-induced secretomes. Thus, SNU13 and SYNCRIP spliceosomal proteins promote therapy resistance, while the exogenous U12 and U6atac snRNAs stimulate tumor growth. These findings demonstrate the significance of spliceosomal network perturbation during therapy and further highlight that extracellular signaling might be a key factor contributing to the emergence of ovarian cancer therapy resistance.

Cells of the tumor microenvironment speak the Wnt language.

Wnt signaling plays numerous functions in cancer, from primary transformation and tumor growth to metastasis. In addition to these cancer cell-intrinsic functions, Wnt signaling emerges to critically control cross-communication among cancer cells and the tumor microenvironment (TME). Here, we summarize the evidence that not only multiple cancer cell types, but also cells constituting the TME 'speak the Wnt language'. Fibroblasts, macrophages, endothelia, and lymphocytes all use the Wnt language to convey messages to and from cancer cells and among themselves; these messages are important for tumor progression and fate. Decoding this language will advance our understanding of tumor biology and unveil novel therapeutic avenues.

Expression level of CD117 (KIT) on ovarian cancer extracellular vesicles correlates with tumor aggressiveness.

Ovarian cancer is known to be the most lethal malignancy among all gynecological cancers affecting a large number of women worldwide. The treatment of ovarian cancer is challenging due to the high recurrence rate of the disease and is further complicated by acquired chemoresistance. Most ovarian cancer deaths are the result of the metastatic spread of drug-resistant cells. The theory of cancer stem cells (CSC) suggests that both tumor initiation and progression are driven by a population of undifferentiated capable of self-renewal, tumor initiation and development of chemoresistance. The CD117 mast/stem cell growth factor receptor (KIT) is the most commonly used marker for ovarian CSCs. Here, we analyze the correlation between CD117 expression and histological tumor type in ovarian cancer cell lines (SK-OV-3 and MES-OV) and in small/medium extracellular vesicles (EVs) isolated from the urine of ovarian cancer patients. We have demonstrated that the abundance of CD117 on cells and EVs is correlated with tumor grade and therapy resistance status. Moreover, using small EVs isolated from ovarian cancer ascites, it was shown that recurrent disease is characterized by a much higher abundance of CD117 on EVs than primary tumor.

Patient blood management in oncology in the Russian Federation: Resolution to improve oncology care.

There is accumulating evidence that anemia and iron deficiency, thrombocytopenia, blood loss and coagulopathy are independent risk factors for adverse patient outcomes in oncology and other settings. Patient blood management (PBM) aims to address these factors by managing and preserving a patient's blood. PBM improves patient health, but also reduces resource utilization, including use of allogeneic blood components, which is another risk factor for adverse outcomes. Supported by the World Health Organization and endorsed in WHA63.12, PBM is recommended by an increasing number of health authorities and is about to become a new standard of care. In support of the Russian National Long-Term Oncology Strategy 2030 to improve quality of oncological care, and with support from the National Association of Specialists in PBM, the PBM Oncology Working Group of the Russian Federation was created. In July 2020, this Group met to discuss the rationale and need for PBM in Russian oncology care. The Group recommended to include PBM as an integral part of standard oncology treatment pathways and developed a national resolution as a call to action on this matter, which was adopted in August 2020. This article details the rationale behind the resolution, delineates the action required from facilitating stakeholders (government; healthcare providers; educational facilities; research entities/institutions; funders; patient representatives/advocates), and proposes a roadmap for implementation. The generation of local health-economic and outcome data and the development of educational programs will be important in the implementation of PBM to help alleviate the health, social and economic burden of cancer.

Deeper insights into transcriptional features of cancer-associated fibroblasts: An integrated meta-analysis of single-cell and bulk RNA-sequencing data.

Cancer-associated fibroblasts (CAFs) have long been known as one of the most important players in tumor initiation and progression. Even so, there is an incomplete understanding of the identification of CAFs among tumor microenvironment cells as the list of CAF marker genes varies greatly in the literature, therefore it is imperative to find a better way to identify reliable markers of CAFs. To this end, we summarized a large number of single-cell RNA-sequencing data of multiple tumor types and corresponding normal tissues. As a result, for 9 different types of cancer, we identified CAF-specific gene expression signatures and found 10 protein markers that showed strongly positive staining of tumor stroma according to the analysis of IHC images from the Human Protein Atlas database. Our results give an insight into selecting the most appropriate combination of cancer-associated fibroblast markers. Furthermore, comparison of different approaches for studying differences between cancer-associated and normal fibroblasts (NFs) illustrates the superiority of transcriptome analysis of fibroblasts obtained from fresh tissue samples. Using single-cell RNA sequencing data, we identified common differences in gene expression patterns between normal and cancer-associated fibroblasts, which do not depend on the type of tumor.