The Microbiome Tumor Axis: How the Microbiome Could Contribute to Clonal Heterogeneity and Disease Outcome in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers. It is characterized by a poor prognosis with a 5-year survival rate of only around 10% and an ongoing increase in death rate. Due to the lack of early and specific symptoms, most patients are diagnosed at an advanced or even metastasized stage, essentially limiting curative treatment options. However, even curative resection of the primary tumor and adjuvant therapy often fails to provide a long-term survival benefit. One reason for this dismal situation can be seen in the evolution of therapy resistances. Furthermore, PDAC is characterized by high intratumor heterogeneity, pointing towards an abundance of cancer stem cells (CSCs), which are regarded as essential for tumor initiation and drug resistance. Additionally, it was shown that the gut microbiome is altered in PDAC patients, promotes Epithelial-Mesenchymal-Transition (EMT), determines responses towards chemotherapy, and affects survival in PDAC patients. Given the established links between CSCs and EMT as well as drug resistance, and the emerging role of the microbiome in PDAC, we postulate that the composition of the microbiome of PDAC patients is a critical determinant for the abundance and plasticity of CSC populations and thus tumor heterogeneity in PDAC. Unravelling this complex interplay might pave the way for novel treatment strategies.

Challenges in precision medicine in pancreatic cancer: A focus in cancer stem cells and microbiota

“…As outlined above, evidence supporting a tumor-promoting role of an altered host microbiome at different sites is accumulating ( 34 , 53 , 71 ). This altered diversity may be a consequence of tumorigenesis, as the evolution of an inflammatory tumor microenvironment might promote bacterial translocation from the gut into the pancreas ( 25 , 34 , 56 ). Considering all the above evidence it is reasonable to speculate that the interplay between the intratumoral microbiota and oncogenic mutations promotes a specific PDAC-SC niche thereby impacting the tumor progression, chemoresistance and patient prognosis.…”

“…According to the current model, CSCs are not a fixed cell population but a plastic one, i.e. the aforementioned characteristics can be acquired and lost dependent on environmental stimuli ( 25 )Therefore, CSC are highly dependent on their niche, i.e. microanatomical structures of TME in which CSCs are maintained and protected from therapy ( 26 , 27 )…”

“…Since the early evidence of bacteria presence in PDAC TME ( 16 , 34 ) and despite substantial inter-individual variability of the gut flora, some studies concur in their findings, pointing at different bacterial species potentially involved in PDAC tumorigenesis thought their interaction with the desmoplastic stroma ( 49 ). The formation of a new desmoplastic niche that offers lower colonization resistance and provides nutrition in the form of increased glycan levels might favor the migration of specific bacteria ( 25 , 50 , 51 ). In turn, new resident bacteria might remodulate the TME to promote tumor development and progression by favoring a PDAC-SC niche refractive to chemotherapy by inducing EMT-dependent stemness state or metabolizing chemotherapeutic agents ( 25 , 34 , 51 ), processes that could even cooperate to enhance therapy resistance ( 52 ).…”

“…The formation of a new desmoplastic niche that offers lower colonization resistance and provides nutrition in the form of increased glycan levels might favor the migration of specific bacteria ( 25 , 50 , 51 ). In turn, new resident bacteria might remodulate the TME to promote tumor development and progression by favoring a PDAC-SC niche refractive to chemotherapy by inducing EMT-dependent stemness state or metabolizing chemotherapeutic agents ( 25 , 34 , 51 ), processes that could even cooperate to enhance therapy resistance ( 52 ).…”

“…The most prominent, although not exclusive, microbes identified in pancreatic tissue samples and associated with PDAC TME are Gram-negative bacteria, more specifically from the phylum Proteobacteria ( 25 , 50 , 53 ). Among Proteobacteria, Gammaproteobacteria was associated with poor patient prognosis ( 34 , 53 ).…”