Autophagy and intratumoral bacteria abundance influence the prognosis of patients with pancreatic carcinoma.
14 affiliations
- 1Department of General, Visceral and Transplantation Surgery, Heidelberg, Germany.
- 2Translational Research Center, University Clinic Heidelberg, Heidelberg, Germany.
- 3Division of Applied Bioinformatics, The German Cancer Research Center (DKFZ), Heidelberg, Germany.
- 4Technical University Munich, Clinic for Surgery, Munich, Germany.
- 5Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
- 6Institute of Pathology, University Clinic Heidelberg, Heidelberg, Germany.
- 7Department of Medical Oncology, National Center for Tumor Diseases, University Clinic Heidelberg, Heidelberg, Germany.
- 8Department of Infectious Diseases, Medical Microbiology and Hygiene, University Clinic Heidelberg, Heidelberg, Germany.
- 9Translational Lung Research Center (TLRC) Heidelberg, German Center for Lung Research(DZL), University Clinic Heidelberg, Heidelberg, Germany.
- 10AREA Science Park, 34149, Trieste, Italy.
- 11Gustave Roussy Cancer Campus, ClinicObiome, Villejuif, France. [email protected].
- 12Department of Medical, Surgical, and Health Sciences, University of Trieste, Trieste, Italy. [email protected].
- 13Department of General, Visceral and Transplantation Surgery, Heidelberg, Germany. [email protected].
- 14Translational Research Center, University Clinic Heidelberg, Heidelberg, Germany. [email protected].
Abstract
The biological and clinical significance of the intratumoral microbiota in pancreatic ductal adenocarcinoma (PDAC) remains poorly defined. Using oncogenic Kras-driven mouse models of pancreatic tumorigenesis and human pancreatic tissue from patients with non-metastatic PDAC treated with neoadjuvant (n = 62) or adjuvant therapy (n = 101), along with samples from intraductal papillary mucinous neoplasms (IPMN, n = 24), chronic pancreatitis (CP, n = 33), and healthy donors (n = 9), we determined tissue lipopolysaccharide (LPS), 16S rRNA sequencing, high-resolution quantitative multiplex immunofluorescence of autophagy markers (LAMP2, LC3B) and LPS, 16S rRNA fluorescence in situ hybridization (FISH) staining, and TLR4 signaling. In KrasCre mice, we identified significant bacterial accumulation in the pancreas, indicated by elevated LPS, increased FISH signals, enhanced TLR4 signaling, and activation of autophagy. Administration of exogenous LPS further amplified autophagy and TLR4 signaling, supporting a mechanistic link between microbial sensing and autophagy. In human tissue, both adjuvant and neoadjuvant PDAC samples showed significantly increased bacterial alpha- and beta diversity compared with controls, while CP showed a similar enrichment pattern that IPMN lacks; the underlying microbial diversity differs fundamentally across these conditions. Increased LPS levels, along with elevated autophagy markers and abundant FISH-positive bacteria, support the presence of intratumoral bacteria. Across four independent transcriptomic datasets, PDAC samples showed elevated expression of bacteria-associated pathways (including TLR4) and autophagy-related genes. Clinically, higher autophagy-associated LAMP2-LC3B colocalization and increased densities of FISH-positive cells were independently associated with prolonged survival in both adjuvant and neoadjuvant or combined PDAC patients. Collectively, these findings link intratumoral microbial enrichment to increased autophagy-associated signaling and improved patient outcomes, suggesting that microbial signals within the tumor microenvironment were associated with favorable survival.
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BibTeX
@article{zhang2026autophagy,
title = {{Autophagy and intratumoral bacteria abundance influence the prognosis of patients with pancreatic carcinoma.}},
author = {Yifan Zhang and Toohina L Gobin and Zhenhua Huang and Bingwen Miao and Roma Kurilov and Haitao Sun and Christine Tjaden and Ulrike Heger and Thilo Hackert and Ulf Hinz and Michael Schaefer and Frank Bergmann and Christoph Springfeld and Sadaf S Mughal and Benedikt Brors and Patrick Schaal and Bachar Cheaib and Danilo Licastro and Valerio Iebba and Franco Fortunato},
journal = {Cell death \& disease},
year = {2026},
month = oct,
doi = {10.1038/s41419-026-09256-1},
url = {https://europepmc.org/article/MED/42957626},
note = {CC BY},
}
RIS
TY - JOUR
TI - Autophagy and intratumoral bacteria abundance influence the prognosis of patients with pancreatic carcinoma.
AU - Yifan Zhang
AU - Toohina L Gobin
AU - Zhenhua Huang
AU - Bingwen Miao
AU - Roma Kurilov
AU - Haitao Sun
AU - Christine Tjaden
AU - Ulrike Heger
AU - Thilo Hackert
AU - Ulf Hinz
AU - Michael Schaefer
AU - Frank Bergmann
AU - Christoph Springfeld
AU - Sadaf S Mughal
AU - Benedikt Brors
AU - Patrick Schaal
AU - Bachar Cheaib
AU - Danilo Licastro
AU - Valerio Iebba
AU - Franco Fortunato
PY - 2026
DA - 2026/10/27
JO - Cell death & disease
DO - 10.1038/s41419-026-09256-1
UR - https://europepmc.org/article/MED/42957626
AB - The biological and clinical significance of the intratumoral microbiota in pancreatic ductal adenocarcinoma (PDAC) remains poorly defined. Using oncogenic Kras-driven mouse models of pancreatic tumorigenesis and human pancreatic tissue from patients with non-metastatic PDAC treated with neoadjuvant (n = 62) or adjuvant therapy (n = 101), along with samples from intraductal papillary mucinous neoplasms (IPMN, n = 24), chronic pancreatitis (CP, n = 33), and healthy donors (n = 9), we determined tissue lipopolysaccharide (LPS), 16S rRNA sequencing, high-resolution quantitative multiplex immunofluorescence of autophagy markers (LAMP2, LC3B) and LPS, 16S rRNA fluorescence in situ hybridization (FISH) staining, and TLR4 signaling. In KrasCre mice, we identified significant bacterial accumulation in the pancreas, indicated by elevated LPS, increased FISH signals, enhanced TLR4 signaling, and activation of autophagy. Administration of exogenous LPS further amplified autophagy and TLR4 signaling, supporting a mechanistic link between microbial sensing and autophagy. In human tissue, both adjuvant and neoadjuvant PDAC samples showed significantly increased bacterial alpha- and beta diversity compared with controls, while CP showed a similar enrichment pattern that IPMN lacks; the underlying microbial diversity differs fundamentally across these conditions. Increased LPS levels, along with elevated autophagy markers and abundant FISH-positive bacteria, support the presence of intratumoral bacteria. Across four independent transcriptomic datasets, PDAC samples showed elevated expression of bacteria-associated pathways (including TLR4) and autophagy-related genes. Clinically, higher autophagy-associated LAMP2-LC3B colocalization and increased densities of FISH-positive cells were independently associated with prolonged survival in both adjuvant and neoadjuvant or combined PDAC patients. Collectively, these findings link intratumoral microbial enrichment to increased autophagy-associated signaling and improved patient outcomes, suggesting that microbial signals within the tumor microenvironment were associated with favorable survival.
SN - 2041-4889
ER -