Delineating dysbiosis-induced multimodal biomarker signatures to optimize precision medicine
Precision or personalized medicine appreciates the significant influence interindividual differences can have on treatment success. Recently, through the use of next-generation proteomic and epigenomic approaches new key carcinogenic and treatment resistance pathways were identified, which led to increasing treatment success in the clinic.
Microbial imbalance, or dysbiosis, has systemic and long-lasting deleterious effects on the homeostasis of various processes. Although they fight infections, antibiotics (ABX) significantly alter the gut microbiota, disrupting commensal bacteria crucial for maintaining anti-cancer immune responses. Epidemiological studies show a direct correlation between the use of ABX and carcinogenesis. However, due to the great interindividual variability, causal relationships are difficult to identify in patients at this time.
It is increasingly recognized that the initial reductionist ideal of identifying one single bacterial species central in dysbiosis, is highly unlikely. This is, at least in part, due to the compensatory abilities of bacteria. Thus, we and others have shifted our attention towards the actual effector molecules of microbiota. Our preliminary results show that certain short-chain fatty acids (SCFA), key microbial metabolites, induce epigenetic changes in tumor-associated cells. However, a multimodal examination of the effector microbial metabolites, tumor epigenome, and host immune responses after ABX usage would provide a needed mechanistic insight into carcinogenesis and treatment response during dysbiosis.
Our long-term goal is to define the systemic effects of dysbiosis on the tumor microenvironment and develop therapies to promote antitumor immunity. The overall objective of this proposal is to use cutting edge technological advances in proteomics and epigenomics to integrate microbial metabolite signatures and changes in chromatin topology in the tumor microenvironment as a result of specific ABX use. We and others have found that certain ABX cause tumor growth acceleration, whereas other ABX do not. Our central hypothesis is that ABX cause changes in serum SCFA quantities, resulting in chromatin modifications in the tumor.
These absolute and relative changes in SCFA and their induced chromatin modifications will generate specific multimodal biomarker signatures per ABX. We will initially derive these signatures from clinical-relevant ABX in our established murine cancer models, to determine the causal relationships between specific ABX, SCFA serum levels, chromatin topology in tumor-associated cells and tumor progression. Ultimately, we will apply our methodology to clinical samples for use in personalized medicine.
We are very motivated to pursue this new avenue in our lab, but realize we need the expertise in metabolomics and transcriptomics to lay the foundation for successfully obtaining future interdisciplinary extramural funding.
- Translational Research