Publications

The diversity of bacteria associated with biopsy material obtained from patients with colorectal cancer was investigated using culture techniques. A novel bacterium, strain CC70A^T, was isolated by diluting a sample of homogenized tissue in anaerobic medium, and then plating to yield a pure culture. Strain CC70A^T was a Gram-positive, strictly anaerobic, motile, rod-shaped bacterium. Formate, but not acetate, was a fermentative end-product from growth in peptone–yeast extract and peptone–yeast–glucose broth. The G+C content of DNA from strain CC70A^T was 34.9 mol%. 16S rRNA gene sequence analysis revealed that the isolate was part of the phylum Bacillota. The closest described relatives of strain CC70A^T were Cellulosilyticum lentocellum (93.3 %) and Cellulosilyticum ruminicola (93.3 and 91.9% sequence similarity across 16S rRNA gene, respectively). According to the data obtained in this work, strain CC70A^T represents a novel bacterium belonging to a new genus for which the name Holtiella tumoricola gen. nov., sp. nov. is proposed. The type strain for our described novel species is CC70A^T (=DSM 27931^T= JCM 30568^T).

Objectives

The purpose of the present study was to characterize co-aggregation interactions between isolates of Fusobacterium nucleatum subsp. Animalis and other colorectal cancer (CRC)-relevant species.

Methods

Co-aggregation interactions were assessed by comparing optical density values following 2-h stationary strain co-incubations to strain optical density values when incubated alone. Co-aggregation was characterized between strains from a previously isolated, CRC biopsy-derived community and F. nucleatum subsp. Animalis, a species linked to CRC and known to be highly aggregative. Interactions were also investigated between the fusobacterial isolates and strains sourced from alternate human gastrointestinal samples whose closest species match aligned with species in the CRC biopsy-derived community.

Results

Co-aggregation interactions were observed to be strain-specific, varying between both F. nucleatum subsp. Animalis strains and different strains of the same co-aggregation partner species. F. nucleatum subsp. Animalis strains were observed to co-aggregate strongly with several taxa linked to CRC: Campylobacter concisus, Gemella spp., Hungatella hathewayi, and Parvimonas micra.

Conclusions

Co-aggregation interactions suggest the ability to encourage the formation of biofilms, and colonic biofilms, in turn, have been linked to promotion and/or progression of CRC. Co-aggregation between F. nucleatum subsp. Animalis and CRC-linked species such as C. concisus, Gemella spp., H. hathewayi, and P. micra may contribute to both biofilm formation along CRC lesions and to disease progression.

Cancer cells originate from a series of acquired genetic mutations that can drive their uncontrolled cell proliferation and immune evasion. Environmental factors, including the microorganisms that colonize the human body, can shift the metabolism, growth pattern and function of neoplastic cells and shape the tumour microenvironment. Dysbiosis of the gut microbiome is now recognized as a hallmark of cancer by the scientific community. However, only a few microorganisms have been identified that directly initiate tumorigenesis or skew the immune system to generate a tumour-permissive milieu. Over the past two decades, research on the human microbiome and its functionalities within and across individuals has revealed microbiota-focused strategies for health and disease. Here, we review the evolving understanding of the mechanisms by which the microbiota acts in cancer initiation, promotion and progression. We explore the roles of bacteria in gastrointestinal tract malignancies and cancers of the lung, breast and prostate. Finally, we discuss the promises and limitations of targeting or harnessing bacteria in personalized cancer prevention, diagnostics and treatment.

Cancer diagnostic and treatment research continue to expand at unprecedented rates with new and promising discoveries being published regularly. However, within the realm of exciting cancer treatment improvements often lays the overlooked need for streamlined engineering systems and efficient data analytical methods. This research looks to achieve both in the framework of improving the ex vivo T-cell culturing environment required for Adoptive Cell Transfer (ACT) cancer immunotherapy. A unique set of Nature Inspired Solutions (Coppens, 2021) was applied to design and analyze 9600, unique, 3D Voronoi scaffolds as potential cell culturing environments. The streamlined design process involved a complex combination of computer languages and platforms and yet, was able to design and calculate various physical parameters of the 9600 scaffolds in just a few hours. To efficiently analyze and process the scaffolds, a novel systems engineering web-based networking software (the 4D Kauffman Fitness Network) was designed. This software integrates both key geometrical characteristics of the scaffolds (such as porosity, surface area and average mean curvature) and biological aspects related to the cells (such as proliferation rate). During testing, this software efficiently processed the 9600 scaffolds in under 20 s, designing a wide variety of networks which filtered the scaffolds selected for future wet lab testing. The highly adaptable and accessible nature of this software provides multiple potential applications in a wide range of scientific, data management and business sectors.

Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrate ketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepatic ketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associated murine models of cancer cachexia, we describe delayed tumor growth but accelerated cachexia onset and shortened survival in mice fed KD. Mechanistically, this uncoupling is a consequence of the biochemical interaction of two NADPH-dependent pathways. Within the tumor, increased lipid peroxidation and, consequently, saturation of the glutathione (GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impair corticosterone biosynthesis. Administration of dexamethasone, a potent glucocorticoid, increases food intake, normalizes glucose levels and utilization of nutritional substrates, delays cachexia onset, and extends the survival of tumor-bearing mice fed KD while preserving reduced tumor growth. Our study emphasizes the need to investigate the effects of systemic interventions on both the tumor and the host to accurately assess therapeutic potential. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.