The role of the microbiome in pancreatic oncogenesis.

Bacterial dysbiosis is evolving as an advocate for carcinogenesis and has been associated with pancreatic cancer progression and survival outcomes. The gut and pancreas of cancer patients harbor a unique microbiome that differs significantly from that of healthy individuals. We believe that the pancreatic cancer microbiome regulates tumorigenesis by altering host cell function and modulating immune cells, skewing them toward an immunosuppressive phenotype. Moreover, altering this pathogenic microbiome may enhance the efficacy of current therapies in pancreatic cancer and improve survival outcomes. This review highlights the findings on microbial modulation across various pre-clinical and clinical studies and provides insight into the potential of targeting the microbiome for pancreatic cancer therapy.

Daley D 《-》

Microbiota Alterations and Their Association with Oncogenomic Changes in Pancreatic Cancer Patients.

Sammallahti H ，Kokkola A ，Rezasoltani S ，Ghanbari R ，Asadzadeh Aghdaei H ，Knuutila S ，Puolakkainen P ，Sarhadi VK ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

The Gut Microbiome and Pancreatic Cancer Development and Treatment.

Changes in the gut microbiome have been increasingly shown to accompany oncogenesis across various tumors. Similarly, microbial dysbiosis was found to be associated with pancreatic cancer progression and survival outcomes, expanding the field of tumor microenvironment research in pancreatic cancer. Mechanistic studies in pancreatic cancer models implicate components of the gut and pancreatic cancer microbiome in regulating tumorigenesis by altering cancer cell signaling, modulating immune function, and influencing the efficacy of current therapies in pancreatic cancer. This review discusses the outcomes of microbial modulation across various preclinical and clinical studies and highlights ongoing trials targeting the microbiome for pancreatic cancer therapy.

Attebury H ，Daley D 《-》

Microbiome and pancreatic cancer: A comprehensive topic review of literature.

Ertz-Archambault N ，Keim P ，Von Hoff D 《-》

The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression.

We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression.Significance: We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. Cancer Discov; 8(4); 403-16. ©2018 AACR.See related commentary by Riquelme et al., p. 386This article is highlighted in the In This Issue feature, p. 371.

Pushalkar S ，Hundeyin M ，Daley D ，Zambirinis CP ，Kurz E ，Mishra A ，Mohan N ，Aykut B ，Usyk M ，Torres LE ，Werba G ，Zhang K ，Guo Y ，Li Q ，Akkad N ，Lall S ，Wadowski B ，Gutierrez J ，Kochen Rossi JA ，Herzog JW ，Diskin B ，Torres-Hernandez A ，Leinwand J ，Wang W ，Taunk PS ，Savadkar S ，Janal M ，Saxena A ，Li X ，Cohen D ，Sartor RB ，Saxena D ，Miller G ... -  《-》