I was reading an article about the tumor biome, and how bacteria & fungi may have a role in treatment resistance. I thought it might be interesting to review the work of Ravid Straussman at the Weizmann Institute of Science, Israel [1].
[2] (2017):
Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2′,2′-difluorodeoxycytidine) into its inactive form, 2′,2′-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDDL), seen primarily in Gammaproteobacteria.
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Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intra-tumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria.
It's an intriguing idea that a course of cipro, say. might inhibit treatment resistance.
[3] (2018):
Treating {pancreatic ductal adenocarcinoma} patients with antibiotics in combination with gemcitabine may not be a straightforward approach, even if bacteria-mediated gemcitabine metabolism is found to be of clinical importance. Long-term treatment with antibiotics can lead to the emergence of antibiotic-resistant bacterial strains. Moreover, antibiotic treatment can affect bacterial communities throughout the body, including that of the gut. Several studies have demonstrated that bacteria present in the gut can profoundly affect the response to cancer treatments.8 Consequently, by using antibiotics, we might unknowingly affect the efficacy of treatment in other ways. An alternative approach to antibiotic treatment might be to utilize a small molecule to target the bacterial CDD enzyme. Such an approach may reduce the global effect on our microbial communities. Our preliminary studies demonstrate that the selective pressure imposed on bacteria by inhibiting CDD activity is negligible compared to that imposed by antibiotic treatment.
[4] (2020):
Bacteria were first detected in human tumors more than 100 years ago, but the characterization of the tumor microbiome has remained challenging because of its low biomass. We undertook a comprehensive analysis of the tumor microbiome, studying 1526 tumors and their adjacent normal tissues across seven cancer types, including breast, lung, ovary, pancreas, melanoma, bone, and brain tumors {but not PCa}. We found that each tumor type has a distinct microbiome composition and that breast cancer has a particularly rich and diverse microbiome. The intratumor bacteria are mostly intracellular and are present in both cancer and immune cells. We also noted correlations between intratumor bacteria or their predicted functions with tumor types and subtypes, patients' smoking status, and the response to immunotherapy.
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The exploration of multiple tumor types with a single platform allowed us to compare different tumor types and uncover cancer type–specific microbial signatures. This is consistent with a recent publication that demonstrated that reexamination of whole-genome and whole-transcriptome sequencing data from The Cancer Genome Atlas (TCGA) for microbial sequences identified associations between different cancer types and specific microbiota (19). Extending our analysis to the functional level demonstrated that, despite a very large variation in taxa levels, certain tumor environments are enriched for common, relevant bacterial functional traits. This observation is somewhat analogous to the relative stability of the human gut microbiome functions compared with its microbial taxa (58, 59). Using multiple visualization methods and culturomics, we were able to validate the presence of bacteria in the tumors and demonstrate their intracellular localization in both cancer and immune cells.
Our data do not establish whether intratumor bacteria play a causal role in the development of cancer or whether their presence simply reflects infections of established tumors (60, 61). As tumors develop, their disorganized, leaky vasculature may allow circulating bacteria to enter, and the immunosuppressed environment may provide a refuge for them (61, 62). Intratumor bacteria may also arise from the NAT, which can explain the high similarity we found between the tumor microbiome and its NAT microbiome. Whether or not bacteria play a causal role in tumorigenesis, it is of interest to further explore the effects that intratumor bacteria may have on different phenotypes of cancer cells and on the immune system and its interactions with tumor cells. Just as manipulation of the gut microbiome has been shown to affect the response of tumors to immune-checkpoint blockade therapy (23-25, 28), we speculate that manipulation of the tumor microbiome may also affect tumor immunity and the response to immune therapy. Thus, better understanding of these effects may pave the way for novel treatment options for cancer patients.
[5] (2020):
While our study added to the growing catalog of intra-tumor bacteria, it is far from answering many of the open questions related to the tumor microbiome. A few of these open questions include the following: What is the origin of intra-tumor bacteria? Are they getting to the tumor from the blood? Or from the tumors’ immediate surroundings? How early in the tumor transformation process do bacteria colonize tumors and does the composition of the microbiome change with tumor progression? Do some of the intra-tumor bacteria have an active role in the transformation process or are they mostly hitchhikers that reach established tumors? Do bacteria ‘travel’ with cancer cells to metastatic sites, or do metastases have a microbiome that is more related to their new location?
It is also not clear if tumor bacteria adapt their genomes to fit the tumor microenvironment conditions and how exactly do they manage to survive inside the cells. Most importantly, there is still a lot that we do not know about the different effects that intra-tumor bacteria may have on different aspects of tumor biology like response to drugs, effects on tumor immunity, angiogenesis, metastasis, and tumor metabolism. Studies of the microbiome in tumors with well-annotated clinical data would be crucial to better understand these effects, as was recently shown for pancreatic cancer.
[6] (2022):
Cancer-microbe associations have been explored for centuries, but cancer-associated fungi have rarely been examined. Here, we comprehensively characterize the cancer mycobiome within 17,401 patient tissue, blood, and plasma samples across 35 cancer types in four independent cohorts. We report fungal DNA and cells at low abundances across many major human cancers, with differences in community compositions that differ among cancer types, even when accounting for technical background. Fungal histological staining of tissue microarrays supported intratumoral presence and frequent spatial association with cancer cells and macrophages. Comparing intratumoral fungal communities with matched bacteriomes and immunomes revealed co-occurring bi-domain ecologies, often with permissive, rather than competitive, microenvironments and distinct immune responses. Clinically focused assessments suggested prognostic and diagnostic capacities of the tissue and plasma mycobiomes, even in stage I cancers, and synergistic predictive performance with bacteriomes.
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We observed strong positive correlations between fungal and bacterial diversities, abundances, and co-occurrences across several cancer types, suggesting tumor microenvironments (TMEs) may be non-competitive spaces for multi-domain microbial colonization, which we term a “permissive” phenotype. This differs from the gut, especially under anti-cancer or antibiotic therapies, where fungal and bacterial populations alternate and compete over shared resources—an “antagonistic” phenotype (Seelbinder et al., 2020; Shiao et al., 2021). It remains unclear whether a permissive phenotype is passively allowed by immunosuppressed, nutrient-rich TMEs (Hinshaw and Shevde, 2019) or denotes active synergy for greater ecosystem multifunctionality (Wagg et al., 2019) or a selection advantage for tumors (Aykut et al., 2019; Geller et al., 2017; Pushalkar et al., 2018). ...
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Note: all study links are to the full text.
-Patrick
[1] weizmann.ac.il/lsc/lab/prof...
[2] ncbi.nlm.nih.gov/pmc/articl...
[3] ncbi.nlm.nih.gov/pmc/articl...
[4] ncbi.nlm.nih.gov/pmc/articl...
