High-grade Serous Ovarian Cancer Metastasis Research Articles

Imaging Mass Spectrometry Reveals Crosstalk between the Fallopian Tube and the Ovary that Drives Primary Metastasis of Ovarian Cancer

High grade serous ovarian cancer (HGSOC) is the fifth leading cause of cancer deaths among women. New evidence suggests that HGSOC arises in the fallopian tube and then colonizes the ovary before spreading into the peritoneal space. Therefore, due to the proximity of this metastasis, an experimental design was optimized using imaging mass spectrometry to capture the spatial composition of small molecules uniquely expressed when fallopian-tube-derived tumor cells were grown in the microenvironment of the ovary as a model of primary metastasis. The observed mass-to-charge ratios (m/z’s) that were induced specifically in coculture represent small molecules that may contribute to the metastasis of HGSOC selectively to the ovary. Human fallopian tube epithelial HGSOC and tumorigenic murine oviductal epithelial cells, but not normal cell types, repeatedly induced a signal from the ovary at m/z 170. This signal was identified as norepinephrine, which was confirmed to stimulate invasion of ovarian cancer cells lacking wild-type p53. These molecules may reveal pathways that contribute to metastasis and biological targets for therapeutic intervention to block ovarian metastasis of fallopian-tube-derived HGSOC. The developed mass spectrometry method can be adapted to other mammalian-based model systems for investigation of untargeted metabolomics that facilitate metastasis.

Abstract IA06: Stromal regulation of metastasis

Abstract Most patients with high-grade serous ovarian cancer (HGSOC) develop metastasis early and, while they are initially chemoresponsive, the existence of disseminated, solid tumors generally leads to the grim prognosis associated with the disease. Many studies of metastasis in HGSOC focus on the epithelial cancer cell and its genetic and epigenetic makeup, underestimating the contribution of the host microenvironment. The metastatic pattern of HGSOC is very different from other epithelial cancers (e.g., breast cancer), since metastasis is mostly limited to the mesothelial cell covered surfaces of the abdominal cavity or retroperitoneal lymph nodes. Even before they metastasize, ovarian cancer cells at the primary site use exosomes to prime the metastatic sites. In parallel, the stromal cells of the primary metastatic sites, generally the omentum and peritoneum, release cytokines that attract the cancer cells. Once the individual HGSOC cells or cell spheroids “land” on the omentum or peritoneum, an intensive bidirectional signaling ensues between the cancer cells and host fibroblasts, mesothelial cells, adipocytes, and immune cells. Mesothelial cells and macrophages initially fight the local invasion by blocking the attachment of cancer cells or recruiting various inflammatory cells to the site of micrometastasis, where the immune cells surround the metastasis. Subsequently, the cancer cells activate the dispersal of the mesothelial cells, attach to the sub-mesothelial basement membrane and reprogram fibroblasts. Within a short period of time, cancer cells transform normal fibroblasts within the ECM into cancer-associated fibroblasts (CAF). Eventually, most stromal cells become cancer associated stromal cells, releasing pro-proliferative and migratory cytokines. In addition, metabolic reprogramming takes place, involving reciprocal metabolic interactions between the cancer and stromal cells. The cancer cells are able to extract fatty acids, to be used as fuel, from cancer-associated adipocytes. Also, a hypoxic environment is produced. This advantages the cancer cells, since they readily adapt to a low-oxygen environment and hypoxia is known to impair the efficacy of chemotherapy. Ultimately, the metastatic site is taken over by the tumor organ. We will present data from our use of organotypic 3D cultures of the metastatic site and systematic metabolic and proteomic analysis of the interactions between stromal and cancer cells, which has informed our attempts to understand the complexities of HGSOC metastasis. Only an improved understanding of the biology of metastasis and the metabolic symbiosis within the tumor will allow the identification of novel targets that can be used to disrupt the metastatic process and impair the ability of HGSOC to recruit the stroma. Citation Format: Ernst Lengyel, Mark Eckert, Iris Romero, Hilary Kenny. Stromal regulation of metastasis. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA06.

Deconstruction of a Metastatic Tumor Microenvironment Reveals a Common Matrix Response in Human Cancers.

We have profiled, for the first time, an evolving human metastatic microenvironment by measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, extracellular matrix organization, and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer metastases that ranged from minimal to extensive disease, we show how nonmalignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the different components allowed us to define, for the first time, gene and protein profiles that predict extent of disease and tissue stiffness, while also revealing the complexity and dynamic nature of matrisome remodeling during development of metastases. Although we studied a single metastatic site from one human malignancy, a pattern of expression of 22 matrisome genes distinguished patients with a shorter overall survival in ovarian and 12 other primary solid cancers, suggesting that there may be a common matrix response to human cancer.Significance: Conducting multilevel analysis with data integration on biopsies with a range of disease involvement identifies important features of the evolving tumor microenvironment. The data suggest that despite the large spectrum of genomic alterations, some human malignancies may have a common and potentially targetable matrix response that influences the course of disease. Cancer Discov; 8(3); 304-19. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 253.

Abstract 5558: Deconstruction of a human tumor microenvironment

Abstract The purpose of this study was to understand the relationships between the molecular mechanisms of disease progression and higher-order features such as tissue stiffness, extent of disease and cellularity in the tumor microenvironment, TME. Using samples of human high-grade serous ovarian cancer metastases, ranging from normal to heavily diseased, we identified molecular components of the TME using transcriptomic and proteomic analysis. We integrated these data against higher-order features of the tissue, namely the biomechanics, cellularity, and disease score. We then used bioinformatics and multivariate statistics to identifying components of the TME that best model the higher-order features. For the first time, we revealed the complexity of extracellular matrix remodeling during metastases development, defining patterns of extracellular-matrix associated genes and proteins that predicted both extent of disease and tissue modulus. This allowed us to identify a core group of twenty-two matrix-associated molecules that modeled the dynamic process of tissue remodeling during tumor progression. We used these data to generate a ‘matrix index’, a quantitative measure of the gene expression of the twenty-two molecules. In cancer transcriptomic databases, this matrix index had prognostic significance in thirteen solid cancers including high-grade serous ovarian cancer, even after multivariate analysis. We conclude that there may be a common host matrix response to human solid cancers. Citation Format: Frances R. Balkwill, Oliver M. Pearce, Robin Delaine-Smith, Eleni Maniati, Sam Nichols, Jun Wang, Conrad Bessant, Martin Knight. Deconstruction of a human tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5558. doi:10.1158/1538-7445.AM2017-5558

Abstract 455: B cells actively participate to the anti-cancer immune response in high grade serous ovarian cancer metastases

Abstract Intra-tumor B cells and immunoglobulin signatures have been associated with a better clinical prognosis in ovarian cancer (Iglesia et al, 2014; Nielsen et al, 2012). However little is known about the mechanisms by which B cells influence the anti-cancer immune response. The aim of our research is to evaluate B cell dependent anti-cancer immune responses in peritoneal metastases in high grade serous ovarian cancer (HGSOC) patients. We have found that in these peritoneal metastases, B cells are mainly located in lymphoid structures and a high proportion of these (60%) display a CD27+ memory phenotype. HGSOC B cells are able to secrete Th1 related cytokines as well as high levels of IL8, which is a chemo-attractant for T cells, granulocytes and macrophages. Interestingly CD4+ and CD8+ T cells express high levels of the IL8 receptor, CXCR1, which suggests B cells help recruiting T cells to lymphoid structures. Plasma cells were also detected in the peritoneal metastases along with IgG deposits. Secreted IgGs were mainly located in stromal areas suggesting that the associated matrix may prevent their infiltration into tumour islets and/or that they target specific stromal antigens. Interestingly, we observed that neoadjuvant chemotherapy and residual disease after chemotherapy influence the type of IgG subclasses expressed in the omentum of HGSOC patients. Chemotherapy enhances the expression of IgG1, IgG2 and IgG3 immunoglobulins in omentum with residual disease. This supports the notion that B cells are involved in the anti-tumor immune response in HGSOC metastases. In conclusion, our data suggest that B cells actively participate to the anti-tumor immune response in HGSOC metastases. This response is preferentially Th1 oriented through the production of cytokines and dominant expression of IgG1 immunoglobulins. Enhancing the B cell dependent anti-tumor immune response could be a potential strategy for the treatment of HGSOC patients. Iglesia MD, Vincent BG, Parker JS, Hoadley KA, Carey LA, Perou CM, Serody JS (2014) Prognostic B-cell signatures using mRNA-seq in patients with subtype-specific breast and ovarian cancer. Clin Cancer Res 20: 3818-3829 Nielsen JS, Sahota RA, Milne K, Kost SE, Nesslinger NJ, Watson PH, Nelson BH (2012) CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin Cancer Res 18: 3281-3292 Citation Format: Anne Montfort, Steffen Boehm, Thomas Dowe, Joanne Topping, Michelle Lockley, Melania Capasso, Frances Balkwill. B cells actively participate to the anti-cancer immune response in high grade serous ovarian cancer metastases. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 455. doi:10.1158/1538-7445.AM2015-455