Deciphering the role of colorectal cancer-associated bacteria in the fibroblast-tumor cell interaction

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 ▲]

Mapping the Metabolic Networks of Tumor Cells and Cancer-Associated Fibroblasts

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 ▲]

Microbiome in Colorectal Cancer: How to Getfrom Meta-omics to Mechanism?

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 ▲]