Project description:Ovarian cancer can metastasize to the omentum, which is associated with a complex tumor microenvironment. Omental stromal cells facilitate ovarian cancer colonization by secreting cytokines and growth factors. Improved understanding of the tumor supportive functions of specific cell populations in the omentum could identify strategies to prevent and treat ovarian cancer metastasis. Here, we showed that omental preadipocytes enhance the tumor initiation capacity of ovarian cancer cells. Secreted factors from preadipocytes supported cancer cell viability during nutrient and isolation stress and enabled prolonged proliferation. Co-culturing with pre-adipocytes led to upregulation of genes involved in extracellular matrix (ECM) organization, cellular response to stress, and regulation of insulin-like growth factor (IGF) signaling in ovarian cancer cells. IGF-1 induced ECM genes and increased alternative NF-κB signaling by activating RelB. Inhibiting the IGF-1 receptor (IGF1R) initially increased tumor omental adhesion but decreased growth of established preadipocyte-induced subcutaneous tumors as well as established intraperitoneal tumors. Together, this study shows that omental preadipocytes support ovarian cancer progression, which has implications for targeting metastasis.
Project description:ETS1 expression is induced by the microenvironment of ovarian metastasis and this expression allows ETS1 to activate a gene expression program involved in cell invasion and epithelial mesenchymal transision.
Project description:ETS1 expression is induced by the microenvironment of ovarian metastasis and this expression allows ETS1 to activate a gene expression program involved in cell invasion and epithelial mesenchymal transision.
Project description:Ovarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer substantially impaired omental metastasis. Our results highlight hematogenous metastasis as a previously under-recognized mode of ovarian cancer metastasis. These findings have implications for designing new strategies aimed at preventing and treating ovarian cancer metastasis.
Project description:High-grade serous (HGS) ovarian cancer is the most lethal gynaecological disease in the world and metastases is a major cause. The omentum is the preferential metastatic site in HGS ovarian cancer patients and in vitro models that recapitulate the original environment of this organ at cellular and molecular level are being developed to study basic mechanisms that underpin this disease. The tumour extracellular matrix (ECM) plays active roles in HGS ovarian cancer pathology and response to therapy. However, most of the current in vitro models use matrices of animal origin and that do not recapitulate the complexity of the tumour ECM in patients. Here, we have developed omentum gel (OmGel), a matrix made from tumour-associated omental tissue of HGS ovarian cancer patients that has unprecedented similarity to the ECM of HGS omental tumours and is simple to prepare. When used in 2D and 3D in vitro assays to assess cancer cell functions relevant to metastatic ovarian cancer, OmGel performs as well as or better than the widely use Matrigel and does not induce additional phenotypic changes to ovarian cancer cells. Surprisingly, OmGel promotes pronounced morphological changes in cancer associated fibroblasts (CAFs). These changes were associated with the upregulation of proteins that define subsets of CAFs in tumour patient samples, highlighting the importance of using clinically and physiologically relevant matrices for in vitro studies. Hence, OmGel provides a step forward to study the biology of HGS omental metastasis. Metastasis in the omentum are also typical of other cancer types, particularly gastric cancer, implying the relevance of OmGel to study the biology of other highly lethal cancers.
Project description:The omentum is the most common site of ovarian cancer metastasis. Immune cell clusters called milky spots are found throughout the omentum. It is however unknown if these immune cells contribute to ovarian cancer metastasis. Here we report that omental macrophages promote the migration and colonization of ovarian cancer cells to the omentum through the secretion of chemokine ligands that interact with chemokine receptor 1 (CCR1). We found that depletion of macrophages reduces ovarian cancer colonization of the omentum. RNA-sequencing of macrophages isolated from mouse omentum and mesenteric adipose tissue revealed a specific enrichment of CCL6 chemokine ligand in omental macrophages. CCL6 and the human homolog CCL23 were both necessary and sufficient to promote ovarian cancer migration by activating ERK1/2 and PI3K pathways. Importantly, inhibition of CCR1 reduced ovarian cancer colonization. These findings demonstrate a critical mechanism of omental macrophage induced colonization by ovarian cancer cells via CCR1 signaling.
Project description:The transcription factor Ets-1 is over-expressed in a wide variety of cancers, and has been strongly associated with the upregulation of factors involved in metastasis and angiogenesis. In this study, we created an inducible Ets-1 over-expressing ovarian cancer cell line from parental 2008 ovarian cancer cells that do not express detectable levels of Ets-1 protein. This microarray compares the stable over-expressing Ets-1 ovarian cancer cell line (2008-Ets1) to their parental 2008 cells to examine differences in gene expression beyond metastasis and angiogenesis. Two samples were used: 2008 ovarian cancer cells, and 2008-Ets1 ovarian cancer cells which over-express Ets-1. Included in this analysis are three independent replicates for each sample.
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.