TY - BOOK

T1 - Bioinformatic Analysis of Breast Tumor Interstitial Fluids

T2 - Insights into a Pan-molecular Secretome

AU - Terkelsen, Thilde Bagger

PY - 2019

Y1 - 2019

N2 - Clinicians and biomedical researchers are continuously working on improving the specificity and sensitivity of breast cancer (BC) diagnostics methods, for more personalized and effective patient treatment.Monitoring the levels of circulating molecules within blood has been proposed as a non-invasive and low-cost way of screening for (breast) cancer. Despite the attractiveness of this idea, identification of robust blood-based biomarkers has proven itself difficult, mainly due to a very diluted, fluctuating and complex complement of molecules within serum/plasma. In contrast, tumor interstitial fluids (TIFs) which fill the extracellular space are highly enriched in tumor-secreted molecules, the level of which represents intra-cellular processes, cell-to-cell communication mechanisms and grants us insight into the tumor immune landscape. As the molecular cargo within TIF is exchanged with the lymph and blood system, this fluid represents a great starting point for biomarker discovery.In this PhD project, we studied the levels of different biomolecules within paired tumor and distal normal interstitial fluids, from women with breast cancer. The aim was to elucidate the cellular signaling events within the breast tumor microenvironment and how this cellular communication might contribute to disease development and progression. Specifically, we wanted to identify a panel of molecular biomarkers from fluids, potentially also represented within blood, which could help improve BC diagnostics and/or prognostics.Quantification and analysis of N-glycans revealed that subsets of these post-translational protein modifications could discriminate between tumor and normal interstitial fluids, as well as between fluids from tumors with different degrees of immune cell infiltration. Some of these N-glycans were associated with patient survival and displayed corresponding levels within paired serum samples, indicating that they could have potentials as circulating prognostic markers.Analysis of proteomics data yielded a panel of proteins released from tumor, which segregated the three major BC subtypes luminal, Her2-enriched and triple negative breast cancers. Subtype-specific proteins were highly expressed in tumor tissues, and only at background levels within normal tissues. Importantly, a handful of proteins were also represented in plasma, revealing a possible use for these in blood-based BC subtyping.Integration of interstitial fluid microRNAs and intra-tumor mRNAs yielded interaction networks, which highlighted how tumor cells may regulate gene transcripts within recipient cells in the local tumor microenvironment, or within distantly located target-cells, potentially forming a pre-metastatic niche.In parallel to the analysis of BC fluids, we developed a computational pipeline, which encompassed the bioinformatic methods applied within our studies, the main purpose of which was to provide researchers at the Danish Cancer Society with a standardized and reproducible framework for -omics data analysis

AB - Clinicians and biomedical researchers are continuously working on improving the specificity and sensitivity of breast cancer (BC) diagnostics methods, for more personalized and effective patient treatment.Monitoring the levels of circulating molecules within blood has been proposed as a non-invasive and low-cost way of screening for (breast) cancer. Despite the attractiveness of this idea, identification of robust blood-based biomarkers has proven itself difficult, mainly due to a very diluted, fluctuating and complex complement of molecules within serum/plasma. In contrast, tumor interstitial fluids (TIFs) which fill the extracellular space are highly enriched in tumor-secreted molecules, the level of which represents intra-cellular processes, cell-to-cell communication mechanisms and grants us insight into the tumor immune landscape. As the molecular cargo within TIF is exchanged with the lymph and blood system, this fluid represents a great starting point for biomarker discovery.In this PhD project, we studied the levels of different biomolecules within paired tumor and distal normal interstitial fluids, from women with breast cancer. The aim was to elucidate the cellular signaling events within the breast tumor microenvironment and how this cellular communication might contribute to disease development and progression. Specifically, we wanted to identify a panel of molecular biomarkers from fluids, potentially also represented within blood, which could help improve BC diagnostics and/or prognostics.Quantification and analysis of N-glycans revealed that subsets of these post-translational protein modifications could discriminate between tumor and normal interstitial fluids, as well as between fluids from tumors with different degrees of immune cell infiltration. Some of these N-glycans were associated with patient survival and displayed corresponding levels within paired serum samples, indicating that they could have potentials as circulating prognostic markers.Analysis of proteomics data yielded a panel of proteins released from tumor, which segregated the three major BC subtypes luminal, Her2-enriched and triple negative breast cancers. Subtype-specific proteins were highly expressed in tumor tissues, and only at background levels within normal tissues. Importantly, a handful of proteins were also represented in plasma, revealing a possible use for these in blood-based BC subtyping.Integration of interstitial fluid microRNAs and intra-tumor mRNAs yielded interaction networks, which highlighted how tumor cells may regulate gene transcripts within recipient cells in the local tumor microenvironment, or within distantly located target-cells, potentially forming a pre-metastatic niche.In parallel to the analysis of BC fluids, we developed a computational pipeline, which encompassed the bioinformatic methods applied within our studies, the main purpose of which was to provide researchers at the Danish Cancer Society with a standardized and reproducible framework for -omics data analysis

UR - https://soeg.kb.dk/permalink/45KBDK_KGL/1pioq0f/alma99123532512905763

M3 - Ph.D. thesis

BT - Bioinformatic Analysis of Breast Tumor Interstitial Fluids

PB - Department of Biology, Faculty of Science, University of Copenhagen

ER -