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Nature Medicine Aug 2020Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor...
Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis. To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We found that the previously described immunoreactive and mesenchymal subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells. Malignant cell variability was partly explained by heterogeneous copy number alteration patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in single-cell RNA sequencing of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient ascites-derived xenograft models. Inhibition of the JAK/STAT pathway, which was expressed in both malignant cells and cancer-associated fibroblasts, had potent anti-tumor activity in primary short-term cultures and patient-derived xenograft models. Our work contributes to resolving the HSGOC landscape and provides a resource for the development of novel therapeutic approaches.
Topics: Ascites; Cell Line, Tumor; Cystadenoma, Serous; DNA Copy Number Variations; Drug Resistance, Neoplasm; Female; Fibroblasts; Gene Expression Regulation, Neoplastic; Heterografts; Humans; Janus Kinase 1; Neoplasm Grading; Neoplasm Proteins; Ovarian Neoplasms; Prognosis; STAT Transcription Factors; Sequence Analysis, RNA; Signal Transduction; Single-Cell Analysis
PubMed: 32572264
DOI: 10.1038/s41591-020-0926-0 -
Nature Cancer Aug 2023Ovarian cancer (OC) is an aggressive gynecological tumor usually diagnosed with widespread metastases and ascites. Here, we depicted a single-cell landscape of the OC...
Ovarian cancer (OC) is an aggressive gynecological tumor usually diagnosed with widespread metastases and ascites. Here, we depicted a single-cell landscape of the OC ecosystem with five tumor-relevant sites, including omentum metastasis and malignant ascites. Our data reveal the potential roles of ascites-enriched memory T cells as a pool for tumor-infiltrating exhausted CD8 T cells and T helper 1-like cells. Moreover, tumor-enriched macrophages exhibited a preference for monocyte-derived ontogeny, whereas macrophages in ascites were more of embryonic origin. Furthermore, we characterized MAIT and dendritic cells in malignant ascites, as well as two endothelial subsets in primary tumors as predictive biomarkers for platinum-based chemotherapy response. Taken together, our study provides a global view of the female malignant ascites ecosystem and offers valuable insights for its connection with tumor tissues and paves the way for potential markers of efficacy evaluation and therapy resistance in OC.
Topics: Female; Humans; Ascites; CD8-Positive T-Lymphocytes; Ecosystem; Ovarian Neoplasms; Single-Cell Analysis
PubMed: 37488416
DOI: 10.1038/s43018-023-00599-8 -
Nature Communications Feb 2023Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we...
Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we characterize single-cell transcriptomes of 191,987 ascites cancer/immune cells from 35 patients with/without gastric cancer peritoneal metastasis (GCPM). During GCPM progression, an increase is seen of monocyte-like dendritic cells (DCs) that are pro-angiogenic with reduced antigen-presenting capacity and correlate with poor gastric cancer (GC) prognosis. We also describe the evolution of monocyte-like DCs and regulatory and proliferative T cells following therapy. Moreover, we track GC evolution, identifying high-plasticity GC clusters that exhibit a propensity to shift to a high-proliferative phenotype. Transitions occur via the recently described, autophagy-dependent plasticity program, paligenosis. Two autophagy-related genes (MARCKS and TXNIP) mark high-plasticity GC with poorer prognosis, and autophagy inhibitors induce apoptosis in patient-derived organoids. Our findings provide insights into the developmental trajectories of cancer/immune cells underlying GCPM progression and therapy resistance.
Topics: Humans; Ascites; Peritoneal Neoplasms; Peritoneum; Stomach Neoplasms
PubMed: 36788228
DOI: 10.1038/s41467-023-36310-9 -
British Journal of Cancer Jul 2020The build-up of fluid in the peritoneal cavity-ascites-is a hallmark of ovarian cancer, the most lethal of all gynaecological malignancies. This remarkable fluid, which... (Review)
Review
The build-up of fluid in the peritoneal cavity-ascites-is a hallmark of ovarian cancer, the most lethal of all gynaecological malignancies. This remarkable fluid, which contains a variety of cellular and acellular components, is known to contribute to patient morbidity and mortality by facilitating metastasis and contributing to chemoresistance, but remains largely under-researched. In this review, we will critically analyse the evidence associating ascites with metastasis and chemoresistance in ovarian cancer and provide an update on research in the field. We will argue the case for ascites as a unique and accessible substrate for tracking tumour progression and for translational research that will enhance our understanding of this cancer and lead to improvements in patient outcomes.
Topics: Ascites; Biomarkers, Tumor; Female; Humans; Ovarian Neoplasms; Ovary; Proteomics
PubMed: 32382112
DOI: 10.1038/s41416-020-0875-x -
Experimental & Molecular Medicine Dec 2020Gastric cancer (GC) patients develop malignant ascites as the disease progresses owing to peritoneal metastasis. GC patients with malignant ascites have a rapidly...
Gastric cancer (GC) patients develop malignant ascites as the disease progresses owing to peritoneal metastasis. GC patients with malignant ascites have a rapidly deteriorating clinical course with short survival following the onset of malignant ascites. Better optimized treatment strategies for this subset of patients are needed. To define the cellular characteristics of malignant ascites of GC, we used single-cell RNA sequencing to characterize tumor cells and tumor-associated macrophages (TAMs) from four samples of malignant ascites and one sample of cerebrospinal fluid. Reference transcriptomes for M1 and M2 macrophages were generated by in vitro differentiation of healthy blood-derived monocytes and applied to assess the inflammatory properties of TAMs. We analyzed 180 cells, including tumor cells, macrophages, and mesothelial cells. Dynamic exchange of tumor-promoting signals, including the CCL3-CCR1 or IL1B-IL1R2 interactions, suggests macrophage recruitment and anti-inflammatory tuning by tumor cells. By comparing these data with reference transcriptomes for M1-type and M2-type macrophages, we found noninflammatory characteristics in macrophages recovered from the malignant ascites of GC. Using public datasets, we demonstrated that the single-cell transcriptome-driven M2-specific signature was associated with poor prognosis in GC. Our data indicate that the anti-inflammatory characteristics of TAMs are controlled by tumor cells and present implications for treatment strategies for GC patients in which combination treatment targeting cancer cells and macrophages may have a reciprocal synergistic effect.
Topics: Ascites; Case-Control Studies; Cell Communication; Cell Plasticity; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; High-Throughput Nucleotide Sequencing; Humans; Macrophages; Peritoneal Neoplasms; Prognosis; Signal Transduction; Single-Cell Analysis; Stomach Neoplasms; Transcriptome; Tumor Microenvironment
PubMed: 33277616
DOI: 10.1038/s12276-020-00538-y -
The Netherlands Journal of Medicine Oct 2016Accumulation of fluid in the peritoneal cavity - ascites - is commonly encountered in clinical practice. Ascites can originate from hepatic, malignant, cardiac, renal,... (Review)
Review
Accumulation of fluid in the peritoneal cavity - ascites - is commonly encountered in clinical practice. Ascites can originate from hepatic, malignant, cardiac, renal, and infectious diseases. This review discusses the current recommended diagnostic approach towards the patient with ascites and summarises future diagnostic targets.
Topics: Ascites; Ascitic Fluid; Culture Techniques; Diagnosis, Differential; Heart Failure; Humans; Laparoscopy; Liver Cirrhosis; Neoplasms; Pancreatic Diseases; Paracentesis; Polymerase Chain Reaction; Practice Guidelines as Topic; Tuberculosis; Ultrasonography
PubMed: 27762220
DOI: No ID Found -
The Journal of Clinical Investigation Feb 2021The development of ascites correlates with advanced stage disease and poor prognosis in ovarian cancer. Vascular permeability is the key pathophysiological change...
The development of ascites correlates with advanced stage disease and poor prognosis in ovarian cancer. Vascular permeability is the key pathophysiological change involved in ascites development. Previously, we provided evidence that perivascular M2-like macrophages protect the vascular barrier through direct contact with endothelial cells (ECs). Here, we investigated the molecular mechanism and its clinical significance in the ovarian cancer setting. We found that upon direct coculture with the endothelium, M2 macrophages tuned down their VLA4 and reduced the levels of VCAM1 in ECs. On the other hand, ectopically overexpressing VLA4 in macrophages or VCAM1 in ECs induced hyperpermeability. Mechanistically, downregulation of VLA4 or VCAM1 led to reduced levels of RAC1 and ROS, which resulted in decreased phosphorylation of PYK2 (p-PYK2) and VE-cadherin (p-VE-cad), hence enhancing cell adhesion. Furthermore, targeting the VLA4/VCAM1 axis augmented vascular integrity and abrogated ascites formation in vivo. Finally, VLA4 expression on the macrophages isolated from ascites dictated permeability ex vivo. Importantly, VLA4 antibody acted synergistically with bevacizumab to further enhance the vascular barrier. Taking these data together, we reveal here that M2 macrophages regulate the vascular barrier though the VCAM1/RAC1/ROS/p-PYK2/p-VE-cad cascade, which provides specific therapeutic targets for the treatment of malignant ascites.
Topics: Animals; Ascites; Capillary Permeability; Female; Human Umbilical Vein Endothelial Cells; Humans; Integrin alpha4beta1; Macrophages; Mice; Neoplasm Proteins; Ovarian Neoplasms; RAW 264.7 Cells; Signal Transduction; THP-1 Cells; Vascular Cell Adhesion Molecule-1
PubMed: 33295887
DOI: 10.1172/JCI140315 -
Methods in Molecular Biology (Clifton,... 2022The accumulation of peritoneal fluid, referred to as ascites, is common in ovarian cancer. This fluid is a complex mixture that may include cells as well as a diverse...
The accumulation of peritoneal fluid, referred to as ascites, is common in ovarian cancer. This fluid is a complex mixture that may include cells as well as a diverse array of cytokines and growth factors. Here we describe a comprehensive method to process ascites to maximize data collection. The cellular fraction and fluid are first separated by centrifugation. The fluid can be frozen for later analysis of soluble factors or for use in in vitro experiments. The cellular fraction can be processed to analyze its composition or stored for future use.
Topics: Ascites; Ascitic Fluid; Cytokines; Female; Humans; Intercellular Signaling Peptides and Proteins; Ovarian Neoplasms
PubMed: 34918288
DOI: 10.1007/978-1-0716-1956-8_5 -
Journal For Immunotherapy of Cancer Feb 2022Despite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced...
BACKGROUND
Despite unprecedented benefit from immune checkpoint inhibitors (ICIs) in patients with mismatch repair deficient (dMMR)/microsatellite instability high (MSI-H) advanced gastrointestinal cancers, a relevant proportion of patients shows primary resistance or short-term disease control. Since malignant effusions represent an immune-suppressed niche, we investigated whether peritoneal involvement with or without ascites is a poor prognostic factor in patients with dMMR/MSI-H metastatic colorectal cancer (mCRC) and gastric cancer (mGC) receiving ICIs.
METHODS
We conducted a global multicohort study at Tertiary Cancer Centers and collected clinic-pathological data from a cohort of patients with dMMR/MSI-H mCRC treated with anti-PD-(L)1 ±anti-CTLA-4 agents at 12 institutions (developing set). A cohort of patients with dMMR/MSI-high mGC treated with anti-PD-1 agents±chemotherapy at five institutions was used as validating dataset.
RESULTS
The mCRC cohort included 502 patients. After a median follow-up of 31.2 months, patients without peritoneal metastases and those with peritoneal metastases and no ascites had similar outcomes (adjusted HR (aHR) 1.15, 95% CI 0.85 to 1.56 for progression-free survival (PFS); aHR 0.96, 95% CI 0.65 to 1.42 for overall survival (OS)), whereas inferior outcomes were observed in patients with peritoneal metastases and ascites (aHR 2.90, 95% CI 1.70 to 4.94; aHR 3.33, 95% CI 1.88 to 5.91) compared with patients without peritoneal involvement. The mGC cohort included 59 patients. After a median follow-up of 17.4 months, inferior PFS and OS were reported in patients with peritoneal metastases and ascites (aHR 3.83, 95% CI 1.68 to 8.72; aHR 3.44, 95% CI 1.39 to 8.53, respectively), but not in patients with only peritoneal metastases (aHR 1.87, 95% CI 0.64 to 5.46; aHR 2.15, 95% CI 0.64 to 7.27) when compared with patients without peritoneal involvement.
CONCLUSIONS
Patients with dMMR/MSI-H gastrointestinal cancers with peritoneal metastases and ascites should be considered as a peculiar subgroup with highly unfavorable outcomes to current ICI-based therapies. Novel strategies to target the immune-suppressive niche in malignant effusions should be investigated, as well as next-generation ICIs or intraperitoneal approaches.
Topics: Aged; Ascites; Colorectal Neoplasms; Female; Humans; Immune Checkpoint Inhibitors; Male; Microsatellite Instability; Neoplasm Metastasis; Retrospective Studies; Stomach Neoplasms; Survival Analysis
PubMed: 35110358
DOI: 10.1136/jitc-2021-004001 -
International Journal of Molecular... Sep 2022Ovarian cancer (OC) has a specific type of metastasis, via transcoelomic, and most of the patients are diagnosed at advanced stages with multiple tumors spread within... (Review)
Review
Ovarian cancer (OC) has a specific type of metastasis, via transcoelomic, and most of the patients are diagnosed at advanced stages with multiple tumors spread within the peritoneal cavity. The role of Malignant Ascites (MA) is to serve as a transporter of tumor cells from the primary location to the peritoneal wall or to the surface of the peritoneal organs. MA comprise cellular components with tumor and non-tumor cells and acellular components, creating a unique microenvironment capable of modifying the tumor behavior. These microenvironment factors influence tumor cell proliferation, progression, chemoresistance, and immune evasion, suggesting that MA play an active role in OC progression. Tumor cells induce a complex immune suppression that neutralizes antitumor immunity, leading to disease progression and treatment failure, provoking a tumor-promoting environment. In this review, we will focus on the High-Grade Serous Carcinoma (HGSC) microenvironment with special attention to the tumor microenvironment immunology.
Topics: Ascites; Carcinoma, Ovarian Epithelial; Female; Humans; Ovarian Neoplasms; Peritoneal Neoplasms; Tumor Microenvironment
PubMed: 36142615
DOI: 10.3390/ijms231810692