Project description:Gastric cancer (GC) constitutes a significant cause of cancer-related mortality worldwide, with metastatic patterns including hematogenous, peritoneal, and ovarian routes. Although GC gene expression patterns have been extensively researched, the metastasis-specific gene expression landscape remains largely unexplored. This study undertook a whole transcriptome sequencing analysis of 66 paired primary and metastatic (hematogenous, peritoneal, or ovarian) GC tumors from 14 patients, leading to the identification of 122 unique metastasis-specific epithelial-mesenchymal transition (msEMT) genes. These genes demonstrated varying expression patterns depending on the metastatic route, suggesting route-specific molecular mechanisms in GC metastasis. High expression of msEMT genes in primary tumors was associated with more frequent CDH1 mutations, the genomically stable subtype, and poor prognosis in The Cancer Genome Atlas GC cohort. This association was further corroborated by poor prognosis and high predictive performance for peritoneal or ovarian recurrence in two independent cohorts (GSE66229; n=300, GSE84437; n=433). Single-cell RNA sequencing analysis of primary tumors (GSE167297) and four independent ascites samples from GC patients revealed that msEMT genes were predominantly expressed in diverse fibroblast sub-populations, rather than cancer cells. This study illuminates the route-specific mechanisms and underlines the significance of msEMT genes and cancer-associated fibroblasts in GC metastasis, highlighting potential directions for future research.
Project description:High-grade serous (HGS) ovarian cancer is the most common and aggressive ovarian cancer type, and the most lethal gynaecological disease 1,2. The major cause is its highly metastatic nature and the limited availability of effective therapies to oppose it. The omentum is a highly vascularised visceral depot of adipose tissue with immune functions, which becomes the preferential metastatic site in patients with HGS ovarian cancer 1,2. The omentum provides an environment that supports the rapid growth of metastatic tumours and their spread within the peritoneal cavity and adjacent organs 2,3. Research aimed at understanding the biology of metastatic tumours in the omentum is therefore essential to find strategies to oppose HGS ovarian cancer. To this aim, there is the need for in vitro models that faithfully recapitulate the microenvironment of HGS omental metastasis in patients.
Project description:High-grade serous (HGS) ovarian cancer is the most common and aggressive ovarian cancer type, and the most lethal gynaecological disease 1,2. The major cause is its highly metastatic nature and the limited availability of effective therapies to oppose it. The omentum is a highly vascularised visceral depot of adipose tissue with immune functions, which becomes the preferential metastatic site in patients with HGS ovarian cancer 1,2. The omentum provides an environment that supports the rapid growth of metastatic tumours and their spread within the peritoneal cavity and adjacent organs 2,3. Research aimed at understanding the biology of metastatic tumours in the omentum is therefore essential to find strategies to oppose HGS ovarian cancer. To this aim, there is the need for in vitro models that faithfully recapitulate the microenvironment of HGS omental metastasis in patients.
Project description:Spheroid formation during epithelial ovarian cancer progression correlates with peritoneal organ colonization, disease recurrence, and poor prognosis. Although cancer progression has been demonstrated to be associated with and driven by metabolic changes within transformed cells, possible associations between metabolic dynamics and metastatic morphological transitions remain unexplored. To address this problem, performed quantitative proteomics was performed to identify protein signatures associated with three distinct morphologies (2D monolayers and two geometrically individual three-dimensional spheroidal states) of the high-grade serous ovarian cancer line OVCAR-3. Integrating the protein states into genome-scale metabolic models allowed the construction of context-specific metabolic models for each morphological stage of the OVCAR-3 cell line and systematically evaluate their metabolic functionalities.
Project description:Purpose: Most molecular characterizations of high-grade serous ovarian cancer (HGSOC) have been done in primary ovarian tumors. Such data may not be fully representative of HGSOC, which is characterized by widespread peritoneal metastases at the time of diagnosis and upon relapse. The most common site of HGSOC metastasis is the omentum. The omentum is characterized by strong immune and fibrotic activities and is a rich source of mesenchymal stem cells (MSCs), which have the capacity to differentiate into cancer-associated fibroblasts (CAFs) and promote ovarian cancer progression. The omentum is also rich in tertiary lymphoid structures (TLS), which are transient aggregates of leukocytes structurally and functionally comparable to secondary lymphoid tissues. Experimental design: With the goal of elucidating expression patterns in a large number of omental metastases, we profiled expression of immune- and cancer progression-related genes in pretreatment omental metastasis samples from 152 patients diagnosed with HGSOC.
Project description:Mouse models of ovarian cancer commonly involve tumor cell transfer into the peritoneal cavity to establish metastatic disease. However, once disease has become established and disseminated through the abdomen, surgical cytoreduction in mice is not feasible. We set out to develop an ovarian cancer model amenable to surgical cytoreduction to mimic clinical treatment paradigms.
Project description:Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of less than 30% due to persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of β-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. β-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa.
Project description:Ovarian cancer is the leading cause of gynecological cancer related death. The overall 5 year survival rate is only 29%. Over 85% of ovarian cancer patients present with advanced stage III or IV disease characterized by intraperitoneal metastasis when diagnosed. However, the process and mechanism of ovarian tumor metastasis remain poorly understood partially because of the lack of a mouse model which could recapitulate the development of metastatic lesion in an appropriate timeframe. In order to generate a convenient ovarian cancer model with accelerated peritoneal metastasis, we performed an in vivo selection study using ID8 ovarian cancer cells to establish a rapid metastasizing mouse ovarian cancer cell line, designated ID8-M. Syngeneic mice with intraperitoneal inoculation of ID8-M cells showed measurable ascites average 35 days after the inoculation and survived only an average of 52 days, while those inoculated with parental ID8 cells showed measurable ascites after 67 days and survived over 81 days. Further analysis showed that, compared with ID8 tumors, ID8-M tumors resulted in more macrophages in the ascites; and compared to ID8 cells, ID8-M cells were more potent to promote macrophages to acquire a M2 phenotype. A microarray analysis provided information to explain the accelerated metastatic phenotype of ID8-M cells.