Bacteria in cancer initiation, promotion and 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.

Journal Nature Reviews Cancer
Authors Geniver El Tekle & Wendy S. Garrett
DATE 03 July 2023
A Computational Pipeline to Optimize 3D Scaffolds for Cancer Immunotherapy

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.

Team NexTGen
Journal Computer Aided Chemical Engineering
Authors Lucy Todd , Matthew Chin , Marc-Olivier Coppens
DATE 01 July 2023
Ketogenic diet promotes tumor ferroptosis but induces relative corticosterone deficiency that accelerates cachexia

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.

Journal Cell Metabolism
Authors Miriam Ferrer et al
DATE 12 June 2023
Bayesian risk prediction model for colorectal cancer mortality through integration of clinicopathologic and genomic data

Routine tumor-node-metastasis (TNM) staging of colorectal cancer is imperfect in predicting survival due to tumor pathobiological heterogeneity and imprecise assessment of tumor spread. We leveraged Bayesian additive regression trees (BART), a statistical learning technique, to comprehensively analyze patient-specific tumor characteristics for the improvement of prognostic prediction. Of 75 clinicopathologic, immune, microbial, and genomic variables in 815 stage II–III patients within two U.S.-wide prospective cohort studies, the BART risk model identified seven stable survival predictors. Risk stratifications (low risk, intermediate risk, and high risk) based on model-predicted survival were statistically significant (hazard ratios 0.19–0.45, vs. higher risk; P < 0.0001) and could be externally validated using The Cancer Genome Atlas (TCGA) data (P = 0.0004). BART demonstrated model flexibility, interpretability, and comparable or superior performance to other machine-learning models. Integrated bioinformatic analyses using BART with tumor-specific factors can robustly stratify colorectal cancer patients into prognostic groups and be readily applied to clinical oncology practice.

Journal npj precision oncology
Authors Melissa Zhao et al
DATE 10 June 2023
Microcalcification crystallography as a potential marker of DCIS recurrence

Ductal carcinoma in-situ (DCIS) accounts for 20–25% of all new breast cancer diagnoses. DCIS has an uncertain risk of progression to invasive breast cancer and a lack of predictive biomarkers may result in relatively high levels (~ 75%) of overtreatment. To identify unique prognostic biomarkers of invasive progression, crystallographic and chemical features of DCIS microcalcifications have been explored. Samples from patients with at least 5-years of follow up and no known recurrence (174 calcifications in 67 patients) or ipsilateral invasive breast cancer recurrence (179 microcalcifications in 57 patients) were studied. Significant differences were noted between the two groups including whitlockite relative mass, hydroxyapatite and whitlockite crystal maturity and, elementally, sodium to calcium ion ratio. A preliminary predictive model for DCIS to invasive cancer progression was developed from these parameters with an AUC of 0.797. These results provide insights into the differing DCIS tissue microenvironments, and how these impact microcalcification formation.

Journal Scientific Reports
Authors Sarah B. Gosling et al
DATE 08 June 2023