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See detailDeciphering the role of colorectal cancer-associated bacteria in the fibroblast-tumor cell interaction
Karta, Jessica UL

Doctoral thesis (2022)

Dysbiosis is an imbalance in the gut microbiome that is often associated with inflammation and cancer. Several microbial species, such as Fusobacterium nucleatum, have been suggested to be involved in ... [more ▼]

Dysbiosis is an imbalance in the gut microbiome that is often associated with inflammation and cancer. Several microbial species, such as Fusobacterium nucleatum, have been suggested to be involved in colorectal cancer (CRC). To date, most studies have focused on the interaction between CRC-associated bacteria and tumor cells. However, the tumor microenvironment (TME) is composed of various types of cells, among which cancer-associated fibroblasts (CAFs), one of the most vital players in the TME. The interaction between CRC-associated bacteria and CAFs and especially the impact of their cross-talk on tumor cells, remains largely unknown. In this regard, this thesis investigated the interaction between a well described and accepted CRC-associated bacteria, Fusobacterium nucleatum, and CAFs and their subsequent effects on tumor progression in CRC. Our findings show that F.nucleatum binds to CAFs and induces phenotypic changes. F.nucleatum promotes CAFs to secrete several pro-inflammatory cytokines and membrane-associated proteases. Upon exposure with F.nucleatum, CAFs also undergo metabolic rewiring with higher mitochondrial ROS and lactate secretion. Importantly, F.nucleatum-treated CAFs increase the migration ability of tumor cells in vitro through secreted cytokines, among which CXCL1. Furthermore, the co-injection of F.nucleatum-treated CAFs with tumor cells in vivo leads to a faster tumor growth as compared to the co-injection of untreated CAFs with tumor cells. Taken together, our results show that CAFs are an important player in the gut microbiome-CRC axis. Targeting the CAF-microbiome crosstalk might represent a novel therapeutic strategy for CRC. [less ▲]

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See detailThe gut microbial metabolite formate exacerbates colorectal cancer progression
Ternes, Dominik UL; Tsenkova, Mina UL; Pozdeev, Vitaly UL et al

in Nature Metabolism (2022)

The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the ... [more ▼]

The gut microbiome is a key player in the immunomodulatory and protumorigenic microenvironment during colorectal cancer (CRC), as different gut-derived bacteria can induce tumour growth. However, the crosstalk between the gut microbiome and the host in relation to tumour cell metabolism remains largely unexplored. Here we show that formate, a metabolite produced by the CRC-associated bacterium Fusobacterium nucleatum, promotes CRC development. We describe molecular signatures linking CRC phenotypes with Fusobacterium abundance. Cocultures of F. nucleatum with patient-derived CRC cells display protumorigenic effects, along with a metabolic shift towards increased formate secretion and cancer glutamine metabolism. We further show that microbiome-derived formate drives CRC tumour invasion by triggering AhR signalling, while increasing cancer stemness. Finally, F. nucleatum or formate treatment in mice leads to increased tumour incidence or size, and Th17 cell expansion, which can favour proinflammatory profiles. Moving beyond observational studies, we identify formate as a gut-derived oncometabolite that is relevant for CRC progression. [less ▲]

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See detailMapping the Metabolic Networks of Tumor Cells and Cancer-Associated Fibroblasts
Karta, Jessica UL; Bossicard, Ysaline UL; Kotzamanis, Konstantinos UL et al

in Cells (2021)

Metabolism is considered to be the core of all cellular activity. Thus, extensive studies of metabolic processes are ongoing in various fields of biology, including cancer research. Cancer cells are known ... [more ▼]

Metabolism is considered to be the core of all cellular activity. Thus, extensive studies of metabolic processes are ongoing in various fields of biology, including cancer research. Cancer cells are known to adapt their metabolism to sustain high proliferation rates and survive in unfavorable environments with low oxygen and nutrient concentrations. Hence, targeting cancer cell metabolism is a promising therapeutic strategy in cancer research. However, cancers consist not only of genetically altered tumor cells but are interwoven with endothelial cells, immune cells and fibroblasts, which together with the extracellular matrix (ECM) constitute the tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs), which are linked to poor prognosis in different cancer types, are one important component of the TME. CAFs play a significant role in reprogramming the metabolic landscape of tumor cells, but how, and in what manner, this interaction takes place remains rather unclear. This review aims to highlight the metabolic landscape of tumor cells and CAFs, including their recently identified subtypes, in different tumor types. In addition, we discuss various in vitro and in vivo metabolic techniques as well as different in silico computational tools that can be used to identify and characterize CAF–tumor cell interactions. Finally, we provide our view on how mapping the complex metabolic networks of stromal-tumor metabolism will help in finding novel metabolic targets for cancer treatment. [less ▲]

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See detailUnderstanding the role of Fusobacterium nucleatum metabolism in colon cancer initiation and progression
Ternes, Dominik UL; Karta, Jessica UL; Tsenkova, Mina UL et al

Poster (2020, February 22)

Accumulating evidence suggests that dysbiosis, a state of pathological imbalance in the human gut microbiome, is present in patients suffering from colorectal cancer (CRC). 16S rRNA gene sequencing, as ... [more ▼]

Accumulating evidence suggests that dysbiosis, a state of pathological imbalance in the human gut microbiome, is present in patients suffering from colorectal cancer (CRC). 16S rRNA gene sequencing, as well as metagenomic and metatranscriptomic analyses, identified specific bacteria being associated with CRC. Among others, Fusobacterium ssp. have been found to directly interact with cancer or immune cells of their host. However, only a limited number of CRC-associated microbes have been examined for host-microbial interactions and, as such, the role of bacteria in the etiology of the disease remains largely elusive. Our aim is the development of predictive and experimental models that allow to not only study the host-microbiota interactions but are also amenable to high-throughput experimentation and large-scale omics-data integration. Ultimately, such models should help to get from meta-omics to cellular mechanism and, moreover, serve as tools for reproducible analyses of host-microbial interaction mechanisms of on a transcriptomic, proteomic, and metabolomic level. Our research proposes an integrative study approach allowing us to bridge meta-omics with functional mechanisms by focusing on the interaction taking place between F. nucleatum and patient-derived CRC cells. [less ▲]

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See detailMicrobiome in Colorectal Cancer: How to Getfrom Meta-omics to Mechanism?
Ternes, Dominik UL; Karta, Jessica UL; Tsenkova, Mina UL et al

in Trends in Microbiology (2020)

Mounting evidence from metagenomic analyses suggests that a state of pathological microbial imbalance or dysbiosis is prevalent in the gut of patients with colorectal cancer. Several bacterial taxa have ... [more ▼]

Mounting evidence from metagenomic analyses suggests that a state of pathological microbial imbalance or dysbiosis is prevalent in the gut of patients with colorectal cancer. Several bacterial taxa have been identified of which representative isolate cultures interact with human cancer cells in vitro and trigger disease path-ways in animal models. However, how the complex interrelationships in dysbiotic communities may be involved in cancer pathogenesis remains a crucial question.Here, we provide a survey of current knowledge of the gut microbiome in colorectal cancer. Moving beyond observational studies, we outline new experimental approaches for gaining ecosystem-level mechanistic understanding of the gut microbiome’s role in cancer pathogenesis [less ▲]

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