Despite a significant decrease in cancer mortality, PC remains a therapeutic challenge for incidence and mortality. Indeed, early detection screenings are not available at the moment. On the other hand, differentially expressed gut microbes have been proposed as stool biomarkers. The results so far are, however, sparce and controversial. The aim of this study was to expand the current understanding of PC gut microbiota taking into account the population differences and to contribute to the development of an early screening method. Here the major findings.

Alpha diversity in PC gut microbiota

• Finnish and Iranian PDAC patients showed significantly lower alpha diversity than healthy controls. Indeed, Shannon entropy, Chao 1 index, and phylogenetic diversity were significantly reduced in PDAC patients.
• No significant impact of age, alcohol consumption, biliary stenting, neoadjuvant treatment, sex, or smoking on microbial diversity were found in the Finnish cohort. However, obese Finns had significantly lower species richness than normal weight individuals of the same group.
• Smoking and age significantly impacted alpha diversity in the Iranian cohort.
• Shannon entropy and Chao 1 index were significantly lower in smokers than nonsmokers.

Microbial community composition in PC patients and healthy controls

• 16,343 OTUs were identified and assigned to 15 phyla, 26 classes, 110 families, and 348 genera.
• The Finnish PDAC gut microbiota showed the following composition: 41% Firmicutes, 40% Bacteroidota, 8% Proteobacteria, 5% Verrucomicrobiota, 3% Actinobacteriota, 1% Fusobacteriota. There was a difference for the healthy Finnish with 50% Firmicutes, 34% Bacteroidota, 5% Proteobacteria, 4% Verrucomicrobiota, and Fusobacteriota, but higher Actinobacteriota.
• Iranian PDAC gut microbiota showed: 48% Firmicutes, 25% Bacteroidota, 15% Proteobacteria, 6% Actinobacteriota, 5% Verrucomicrobiota.
• Top ten genera in Finnish PDAC patients were: Bacteroides, Alistipes, Faecalibacterium, Akkermansia, Parabacteroides, Bifidobacterium, Escherichia-Shigella, Roseburia, Ruminococcus, and Subdoligranulum.
• Patients and controls within and between cohorts showed significant differences in microbial community composition.
• There were no significant differences between treated and untreated patients or those with and without biliary stents in the Finnish cohort.
• There were significant differences in the Iranian cohort between age groups, sexes, and smoking habits.

PC gut microbiota in the Finnish and Iranian cohorts

After a general comparison, the researchers compared the microbiota composition at phylum, family and genus level.

Phylum-level Differences

• PDAC patients in both Finnish and Iranian cohorts showed greater abundances of Fusobacteriota and Synergistota.
• Iranian PDAC patients had higher abundances of Verrucomicrobiota and Proteobacteria and a lower abundance of Elusimicrobiota while Finnish patients had a greater abundance of Campylobacterota than their respective healthy controls.

Family-level Differences

• 26 families differed between patients and controls in the Finnish cohort, 23 in the Iranian cohort.
• Families with higher abundance in PDAC patients included Entererococcaceae, Fusobacteriaceae, and Enterobacteriaceae.
• In detail, Finnish PDAC patients presented with higher abundances of Yersiniaceae, Hafniaceae, and Campylobacteraceae while Iranian PDAC patients showed higher levels of Lactobacillaceae, Akkermansiaceae, and Streptococcaceae compared with their respective healthy controls.

Genus-level Differences

• 78 taxa differentially abundant between patients and controls were detected in the Finnish, 67 in the Iranian cohort
• The most abundant genera in PDAC in both populations included Enterococcus, Sellimonas, Veillonella, Klebsiella, Hungatella, Eisenbergiella, Fusobacterium, Enterobacter, Flavonifractor, and Coprobacillus.
• Genera with lower abundance common to both populations were Asteroleplasma, Clostridia UCG-014, and Butyricicoccaceae UCG-009.

Overall, the two populations showed several differences. In particular:
• Iranian patients presented significantly greater abundances of Thermoplasmatota, Synergistota, Proteobacteria, Actinobacteriota, and Firmicutes then Finnish PDACs
• Finnish PDAC patients showed significant enrichment of the phyla Campylobacteriota, Cyanobacteria, and Bacteroidota.
• In terms of biomarkers, both populations of PDAC samples were enriched in Klebsiella and Hungatella and depleted of Agathobacter, Anaerostipes, and Clostridia. Finnish PDAC samples were enriched in Christensenellales, Rhodospirillales, Enterobacter, Enterococcus, Citrobacter, Campylobacter, and Oscillospira and depleted in Prevotella_9, Butyrivibrio, Butyricicoccus, Lachnospira, and Romboutsia. Iranian PDAC samples instead showed higher presence of Subdoligranulum, Streptococcus, Lactobacillus, Limosilactobacillus, Klauyvera, and Pantotea with a depletion of Faecalibacterium, Bifidobacterium, Dialister, Blautia, Roseburia, Parasutterella, and Ruminococcus.

Functions of PC gut microbes and pathway analysis

Applying KEGG term analysis, 6417 functions remained after filtering.

• Significant differences were observed between the Finnish and the Iranian PC patients in microbial functions.
• Only 40 of the 500 most distinctive predicted microbial functions overlapped between populations.
• Top four differing predicted functions in PDAC patients versus healthy controls – i.e. Clumping factor B, accessory secretory protein Asp3, and ATP-binding cassette subfamily C.
• The Finnish cohort showed high depletion of predicted functions including rsbT antagonist protein RsbS, serine/threonine-protein kinase RsbT, and rsbT coantagonist protein RsbR; membrane-bound hydrogenase subunit alpha in Iranian patients.
• Pathway analysis revealed enriched peptidoglycan biosynthesis, galactose metabolism, lysine biosynthesis, and furfural degradation pathways.

Statistical analyses and machine learning models were then applied to validate the predictions showing great results (AUC of 0.85 at phylum level).

To conclude, “We observed consistent trends in PC-related microbial diversity and community composition in our two populations—Finnish and Iranian—with profoundly different environments and lifestyles.” This suggests how the gut microbiota plays a crucial role in the development of PC, with increased pathogenic microbes and depletion of protective ones. This unique microbial profile could be used for noninvasive early PC screening, but further research is needed to explore integrating probiotics with conventional drugs.

What this research adds
Working in mice, researchers found that P. gingivalis travels from the mouth to the pancreas, resulting in alterations of the pancreatic microbiota and in lesions that lead to the development of pancreatic cancer. P. gingivalis could also be detected in lesions that precede pancreatic cancer in humans. In mice, the microbe accelerated the transformation of these lesions into cancer — likely by protecting tumor cells from reactive oxygen species-mediated cell death.

Conclusions
The findings suggest that P. gingivalis can cause the development of pancreatic cancer.

Pancreatic cancer is one of the top causes of cancer-related deaths in the United States, and only 12% of patients survive five years after being diagnosed. Now, research done in mice shows that the mouth-dwelling bacterium Porphyromonas gingivalis can travel from the mouth to the pancreas, resulting in lesions that lead to cancer.

The findings, published in Gut, suggest that P. gingivalis can cause the development of malignancies in the pancreas. Strategies aimed at eradicating these bacteria may improve the clinical outcomes of pancreatic cancer, the researchers say.

Several epidemiological studies have linked P. gingivalis, which is typically involved in gum disease, to pancreatic tumors. Research also showed that P. gingivalis survives in human pancreatic cancer cells and promotes their proliferation, but whether — and how — the microbe contributes to cancer growth remains unclear.

So, researchers led by Elias Saba at the Hebrew University-Hadassah in Jerusalem, Israel, set out to investigate the effects of P. gingivalis on the pancreas of wild-type mice and mice that are prone to pancreatic cancer.

Accelerating cancer

The researchers found that P. gingivalis travels from the mouth to the pancreas, where it remains viable. The microbe could also be detected in lesions that precede pancreatic cancer in humans.

Coating the oral cavity of wild-type mice with P. gingivalis three times a week over a 12-week period resulted in alterations of the pancreatic microbiota. P. gingivalis infection increased the pancreatic levels of Mycoplasmatacea, Helicobacteraceae and Paraprevotellaceae — bacterial families that have been associated with pancreatic cancer in mice.

P. gingivalis administration also led to a type of lesions called acinar-to-ductal metaplasia, which is thought to be one of the earliest steps toward the development of pancreatic cancer. 

Harmful cooperation

Cancer-promoting mutations can transform acinar-to-ductal metaplasia to pancreatic intraepithelial neoplasia, a precursor lesion to pancreatic cancer. So, the researchers tested whether long-term exposure to P. gingivalis could promote tumor development in mice that had been genetically engineered to develop pancreatic intraepithelial neoplasia.

The team found that P. gingivalis accelerated the transformation of pancreatic intraepithelial neoplasia into pancreatic cancer — likely by protecting cancer cells from reactive oxygen species-mediated cell death.

“Cooperation between intracellular bacteria and cancer cells in settings of extreme stress is an additional molecular mechanism by which the tumor microbiome can promote the pathogenesis of cancer,” the authors say.

This partnership aims to leverage Microba’s advanced technology platform for measuring the human gut microbiome to discover novel biomarkers for pancreatic cancer detection. 

The joint research project holds the potential to enhance the technical profile of the PancAlert screening test, combining DNA biomarkers with microbiome biomarkers.

Pancreatic Cancer and its Challenges

Pancreatic cancer is a highly lethal malignancy with one of the highest mortality rates among major cancers. It ranks as the seventh leading cause of cancer-related deaths globally, claiming approximately 466,000 lives each year. 

The disease is often diagnosed at late stages, resulting in poor outcomes despite current standard of care treatments. The overall 5-year survival rate is only around 11% in the United States and 9% worldwide. However, early-stage detection significantly improves the chances of successful treatment and higher survival rates.

The Collaborative Research Project

Mainz Biomed expressed excitement about collaborating with Microba, citing the growing understanding of the microbiome’s role in pancreatic cancer. 

By integrating diagnostic microbiome biomarkers into the PancAlert test, the goal is to develop a first-in-class screening tool for early-stage pancreatic cancer. 

Microba’s proprietary metagenomic sequencing technology and bioinformatic tools will be utilized to identify disease-specific microbiome biomarkers.

Microba’s Metagenomic Platform Technology

The research project, expected to run through late 2023, will make use of Microba’s Community Profiler (MCP), a state-of-the-art metagenomic platform technology. MCP is renowned for its ability to provide comprehensive and accurate species profiles of human gastrointestinal samples. 

By leveraging this technology, the collaboration aims to discover new insights into the microbiome’s role in pancreatic cancer and identify potential biomarkers that can enhance the PancAlert screening test’s efficacy.

Mainz Biomed’s Commitment to Cancer Detection

Mainz Biomed is already at the forefront of cancer detection with its flagship product, ColoAlert®, a highly effective and user-friendly diagnostic test for colorectal cancer. 

The company is currently commercializing ColoAlert® in select international territories and has initiated a U.S. Pivotal Clinical Study (ReconAAsense) for a colorectal cancer screening test that may incorporate novel gene expression biomarkers. 

These biomarkers show promise in identifying advanced adenomas, a precursor to colorectal cancer. Mainz Biomed expects results from ongoing studies and plans to begin enrolling participants for ReconAAsense in the second half of 2023.

The collaboration between Mainz Biomed and Microba Life Sciences marks a significant step toward the development of an innovative screening test, PancAlert, for early-stage pancreatic cancer detection. 

By combining the expertise of Mainz Biomed in molecular genetics diagnostics and Microba’s proficiency in microbiome analysis, the research project aims to uncover valuable microbiome biomarkers. 

Ultimately, the integration of these biomarkers into the PancAlert test could improve the early detection and treatment outcomes for pancreatic cancer, addressing an urgent need in the fight against this deadly disease.

What this research adds
Researchers assessed 30 PDAC patients and found that the microbial metabolite indole-3-acetic acid (3-IAA) is enriched in people who respond to treatment. Transferring the gut microbiota from responders or administering oral 3-IAA increases the efficacy of chemotherapy in a mouse model of PDAC. The microbial metabolite induces the release of reactive oxygen species (ROS) by neutrophils through a reaction mediated by the enzyme myeloperoxidase. ROS are toxic products that downregulate autophagy — a process during which old and damaged cell parts are degraded and reused. Reducing autophagy in cancer cells ultimately blocks their proliferation.

Conclusions
The findings suggest that the microbial metabolite 3-IAA could help to treat PDAC, highlighting the potential of nutritional interventions during the treatment of patients with this aggressive cancer.

The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma or PDAC, is expected to be the second most deadly cancer by 2040. Now, researchers have found that the microbial metabolite indole-3-acetic acid (3-IAA) is enriched in PDAC patients who respond to treatment. The metabolite, in combination with chemotherapy, can ultimately kill cancer cells.

The findings, published in Nature, suggest that 3-IAA could help to treat PDAC, highlighting the potential of nutritional interventions during the treatment of patients with this aggressive cancer.

Chemotherapy is the classic treatment for PDAC, but only less than half of patients respond to it. In people with melanoma, the gut microbiota has been shown to influence a person’s response to immunotherapy — a treatment that uses the body’s own immune system to fight cancer. However, it’s unknown whether and how gut microbes affect the efficacy of treatments against PDAC.

To address this question, researchers led by Nicola Gagliani and Joseph Tintelnot at the University Medical Center Hamburg-Eppendorf assessed 30 PDAC patients, some of whom did not respond to treatment.

Boosting treatment efficacy

The researchers found that 3-IAA was enriched in PDAC patients who responded to treatment. Out of the 15 microbial producers of 3-IAA that the team analyzed, Bacteroides fragilis and Bacteroides thetaiotaomicron were increased in responders. Both bacterial species were also able to produce 3-IAA in a test tube. 

Transferring gut bacteria from responders to a mouse model of PDAC increased the efficacy of chemotherapy. Similar results were obtained by supplementing mice with 3-IAA, the researchers found.

Because bacterial species in the gut can synthesize 3-IAA from the amino acid tryptophan, the team tested whether a tryptophan-rich diet could also result in an anticancer effect. They found that such a diet, in combination chemotherapy, increased the treatment’s efficacy. Other tryptophan-derived metabolites did not elicit the same effect.

Killing tumors

Immune-cell profiling revealed that 3-IAA was linked to a group of immune cells called neutrophils. These cells are known to be involved in cancer proliferation. The researchers found that 3-IAA induces the release of reactive oxygen species (ROS) by neutrophils through a reaction mediated by the enzyme myeloperoxidase. 

ROS are toxic products that downregulate autophagy — a body’s process of degrading and reusing old and damaged cell parts. Reducing autophagy in cancer cells ultimately blocked their proliferation, the researchers found. What’s more, the team observed a correlation between the levels of 3-IAA and the efficacy of therapy in two groups of patients with PDAC. 

“Our findings have the potential to be transformative for the treatment of PDAC and other cancer types such as colorectal cancer,” the researchers say. The work, they add, “will trigger the development of studies that address the effects of microbiota-derived metabolites on the ROS-autophagy axis in response to chemotherapeutic treatments.”

What this research adds
Researchers examined the microbiota of 41 pancreatic tumors samples and 14 normal pancreatic tissues. They found that most pancreatic tumors had bacteria that associated with specific cells, but these bacteria were mostly absent in healthy tissues. The bacteria were predominantly located within tumor cells, and their presence was associated with inflammation and poor survival. Modeling results suggested that the immune cells present within the tumor were responding mostly to the microbes rather than the cancer cells.

Conclusions
The findings may help to develop improved diagnostic or treatment approaches for pancreatic cancer.

Microbes have been detected in many organs and even within tumors. Now, researchers have shed light on the interactions between pancreatic tumors and their microbiotas, suggesting that immune cells within the tumor respond predominantly to the tumor microbiota than to cancer cells.

The findings, published in Cancer Cell, may help to develop improved diagnostic or treatment approaches for pancreatic cancer. They may also provide an explanation for why pancreatic cancers are so difficult to treat.

Some studies have suggested that bacteria can travel to the pancreas and induce changes that may promote the development of pancreatic cancer, but how microbes influence tumor development and progression remains unclear.

To identify the bacteria residing in pancreatic tumors and investigate if they affect cancer progression, a team of researchers led by Subhajyoti De at Rutgers University examined the microbiota of 41 pancreatic tumors samples and 14 normal pancreatic tissues.

Tumor microbiota

To identify tumor-associated microbes, the researchers used an approach called SAHMI (Single-cell analysis of Host-Microbiome Interactions), which scours millions of RNA sequences to distinguish human genes from microbial ones. 

The team analyzed samples from two independent groups of pancreatic tumors. They detected microbes in 87% of the pancreatic samples tested and identified 19 bacterial genera that were present in both groups of pancreatic tumors. Bacteria were mostly absent in healthy tissues.

In pancreatic tumors, the most common bacteria were Campylobacter species, which are known to cause inflammation of the gut and other body parts. Other common bacteria included Fusobacterium nucleatum, which is associated with colorectal cancer, and Clostridioides difficile, a gut pathogen that has been linked to pancreas disease. 

Poor survival

In tumors, bacteria were predominantly located within cancer cells, and their presence correlated with activities — including cell motility and immune signaling — that are associated with cancer. These observations, the researchers say, “consistently associate microbiota with key cancer-related cellular processes in individual cell types in the tumor microenvironment.” 

The presence of tumor-associated microbes was also predictive of aggressive cancer progression and poor survival, the researchers found.

What’s more, the team discovered that tumors with cell-associated bacteria have activated immune cells. However, modeling results suggested that the immune cells present within the tumor were responding mostly to the microbes rather than the cancer cells. 

“Our results provide evidence that intra-tumoral bacteria reflect or influence the trajectory of tumor growth; either possibility has clinical utility,” the authors say.

What this research adds
Researchers screened bacterial metabolites in mice with pancreatic tumors and assessed how they affected the success of immunotherapy. They found that a molecule called trimethylamine N-oxide (TMAO) and its precursor trimethylamine (TMA) boosted anti-tumor effects. Giving TMAO or TMA to mice with pancreatic cancer delayed tumor growth by activating specific immune responses. TMAO also improved immunotherapy’s efficacy in those mice. Bacteria that produce an enzyme that generates TMA were present at higher levels in people who survived for a long period of time after pancreatic cancer compared to those who survived for only a short period of time.

Conclusions
The findings suggest that TMAO is a driver of anti-tumor immunity. Targeting TMAO may help improve the efficacy of immunotherapy in people with pancreatic cancer.

Immunotherapy has proved effective in many cancer types, but it’s not yet successful in treating other types of cancer, such as pancreatic tumors. Now, researchers have found that a gut microbial metabolite called trimethylamine N-oxide, or TMAO, could improve immunotherapy success in pancreatic cancer.

The findings, published in Science Immunology, suggest that TMAO is a driver of anti-tumor immunity. Targeting TMAO may help improve the efficacy of immunotherapy in people with pancreatic cancer.

Several studies have suggested that gut microbes can sway a person’s response to immunotherapy. However, how the microbiota may contribute to the failure of immunotherapy to treat pancreatic tumors is unclear.

Since the pancreas facilitates digestion in the gut, which hosts gut bacteria, Rahul Shinde at the Wistar Institute and his colleagues set out to explore new ways to harness gut microbes to improve immunotherapy’s efficacy in pancreatic cancer.

Anti-cancer effect

The researchers screened gut bacteria’s metabolites in mice with pancreatic tumors. Then, they investigated how these metabolites affected the success of immunotherapy.

They found that TMAO and its precursor trimethylamine (TMA) boosted anti-tumor effects. Scientists have known that dietary choline or L-carnitine, which are found in foods such as meat and eggs, are metabolized by the gut microbiota into TMA in the intestine. Then, TMA enters the blood circulation and is transformed into TMAO in the liver. 

Giving TMAO or TMA to mice with pancreatic tumors delayed tumor growth, the researchers found. This is likely because TMAO and TMA activate specific immune cells such as macrophages and CD8 T cells, which can kill cancer cells. TMAO and TMA also appeared to decrease the levels of immunosuppressive markers in the tumor environment.

Improving immunotherapy

Next, the team combined TMAO administration with immunotherapy in mice with pancreatic cancer. TMAO boosted the efficacy of immunotherapy in the animals, improving their survival. 

To validate the findings in humans, the researchers examined whether the presence of bacteria producing an enzyme that generates TMA was associated with positive immunotherapy outcomes in people with pancreatic cancer. These bacteria, which include Bacillus and Paenibacillus species, were present at higher levels in people who survived for a long period of time after pancreatic cancer compared to those who survived for only a short period of time, the researchers found. Bacillus bacteria are also abundant in melanoma patients who respond to immunotherapy, the authors say. 

“Together, our study identifies the gut microbial metabolite TMAO as a driver of anti-tumor immunity and lays the groundwork for potential therapeutic strategies targeting TMAO,” they say.

What is already known on this topic
Pancreatic ductal adenocarcinoma is an aggressive form of cancer that kills most people within two years of diagnosis. Previous studies have shown that the bacterial component of the microbiome is often altered in this cancer. But little is known about the role of the community of fungal species, known as the mycobiome.

What this research adds
By analyzing mice and people with pancreatic cancer, researchers found that some fungi travel from the gut to the pancreas, where they trigger changes in an immune system protein that promotes inflammation and cancer development. Mice treated with a wide-spectrum antifungal drug had tumor weight reduced by up to 30% over 30 weeks.

Conclusion
Although more work is needed before the new findings can be applied in treating people with cancer, the study suggests that the mycobiome may be a new target for therapeutic agents.

Certain fungi move from the gut to the pancreas, where they can trigger pancreatic cancer growth, according to new research. The study, published in Nature, is the first to show that the community of fungal species in the pancreas – known as the mycobiome – can influence the development of pancreatic ductal adenocarcinoma.

Most people with pancreatic ductal adenocarcinoma usually die within two years of diagnosis, and only about 1 in 10 live longer than five years. And while several studies showed that the bacterial component of the microbiome is often altered in this type of cancer, little is known about the role of the mycobiome.

Berk Aykut and Smruti Pushalkar at New York University School of Medicine and their colleagues set out to assess whether fungi could colonize the pancreas and promote cancer growth.

Fungal migration

The researchers analyzed tumor samples from mice and people with pancreatic cancer to search for fungi-specific DNA markers. The team found that both people and mice had an increased fungal colonization of the pancreas compared to their healthy counterparts.

To find the source of these fungi, the researchers introduced a fungal strain tagged with a fluorescent molecule into the guts of mice. As early as 30 minutes later, the team could detect those fluorescent fungi in the rodents’ pancreas.

Yeast culprit

In mice engineered to express a cancer-causing protein only in the pancreas, the pancreas mycobiome was different from the gut mycobiome. In particular, the yeast Malassezia was more prevalent in pancreatic tumors than in the guts of the engineered mice or the pancreas of healthy rodents. The same yeast strain was also common in pancreatic ductal adenocarcinoma samples from people. What’s more, in pancreatic tumors the team detected increased levels of Parastagonospora, Saccharomyces, and Septoriella fungi.

Mice treated with a wide-spectrum antifungal drug had tumor weight reduced by up to 30% over 30 weeks. The anti-fungal also increased the anti-cancer effect of a common chemotherapy drug. However, if the animals were colonized with Malassezia after the treatment, their pancreatic ductal adenocarcinoma started to grow again, up to 20% faster.

Triggering inflammation

In people, pancreatic ductal adenocarcinoma is associated with the expression of a protein called mannose-binding lectin, which binds carbohydrates on the surface of microorganisms and triggers inflammation, which has been linked to tumor development.

In mice engineered to lack mannose-binding lectin, cancer progression in the pancreas was delayed, even in the presence of Malassezia. This suggests that Malassezia promotes cancer progression by triggering pancreatic inflammation.

Although more work is needed before the new findings can be applied in treating people with cancer, the study suggests that the mycobiome may be a new target for therapeutic agents.

What is already known on this topic
About 91% of people with pancreatic ductal adenocarcinoma, which is the most common form of pancreatic cancer, survive less than 5 years. Even for individuals who undergo surgery to remove early-stage pancreatic tumors, the survival rate is 24 to 30 months. Only a few pancreatic cancer patients are still alive more than 5 years after surgery, but what determines such long-term survival is unclear.

What this research adds
A key difference between people with pancreatic cancer who survive long-term and those who die within 5 years is the overall diversity and the type of bacteria that live on their tumors. Transferring gut microbes from long-term survivors into a mouse model of pancreatic cancer changed the rodents’ tumor microbiota and helped to reduce cancer growth.

Conclusions
The findings show that the tumor microbiota of people with pancreatic cancer could be a useful prognostic tool. The results also suggest that it may be possible to target the bacteria on tumors as a therapeutic approach against pancreatic cancer.

The composition of the tumor microbiota could influence the survival of people with pancreatic cancer. That’s the conclusion of the first report to explore the effect of tumor bacteria on clinical outcomes.

The findings, published in Cell, suggest that it may be possible to target the bacteria on tumors as a therapeutic approach against pancreatic cancer.

Effective therapies for this type of cancer are very much needed. About 91% of people with pancreatic ductal adenocarcinoma, which is the most common form of pancreatic cancer, survive less than 5 years. Even for individuals who undergo surgery to remove early-stage pancreatic tumors, the survival rate is 24 to 30 months.

Only a few pancreatic cancer patients are still alive more than 5 years after surgery, but what determines such long-term survival is unclear. Previous studies in skin cancer have suggested that gut bacteria can influence responses to different therapies.

So Erick Riquelme and Yu Zhang at the University of Texas M. D. Anderson Cancer Center and their colleagues set out to test whether modulating the gut or the tumor microbiota could help fight off pancreatic cancer.

Microbial differences

The researchers compared the microbiota of pancreatic tumor samples from long-term survivors, who had survived on average 10 years after surgery, and short-term survivors, who had survived an average of 1.6 years.

People whose tumor microbiota was highly diverse survived about 9.66 years, while those with a less diverse tumor microbiota survived nearly 1.7 years.

The tumor microbiota of long-term survivors had high levels of Pseudoxanthomonas, Saccharropolyspora, and Streptomyces bacteria.

Immune response

Next, the researchers analyzed whether tumor bacteria could shape the immune response to pancreatic cancer. The tumors of long-term survivors had higher numbers of immune cells, including cancer cell-killing CD8+ T cells, than the tumors of short-term survivors.

Samples with a high abundance of activated immune cells had increased levels of the three bacterial types identified in the tumor microbiota of long-term survivors. This suggests that these bacteria could contribute to the anti-tumor immune response by favoring recruitment and activation of CD8+ T cells, the researchers say.

Fecal transplant

Transferring gut microbes from long-term survivors into a mouse model of pancreatic cancer changed the rodents’ tumor microbiota within a few weeks. What’s more, the tumors of mice that received fecal transplants from long-term survivors had more activated immune cells and were 70% smaller on average than the tumors of rodents that received tumor bacteria from short-term survivors.

The findings suggest that the tumor microbiota of people with pancreatic cancer can be used as both a prognostic tool and a therapeutic approach against pancreatic cancer.

• What is already known on this topic
  Pancreatic cancer is the seventh most common cancer in Europe, killing more than 95,000 people every year. In the European Union, the incidence of deaths caused by pancreatic cancer has increased by 5% between 1990 and 2016, according to a recent report. However, despite the rise in death rates, research on effective treatments is lagging behind.

• What this research adds
  The study sheds light on the impact of the microbiota on pancreatic cancer progression, showing that the bacteria in a cancerous pancreas are distinct and significantly more abundant than those in a non-cancerous pancreas, in both mice and humans. In mice, removing bacteria from the gut and pancreas slowed cancer growth and triggered immune cells to react against cancer cells.

• Conclusions
  The study offers an insight into how microbes could promote pancreatic cancer. Its results suggest that modulating the microbiota could help to treat pancreatic cancer by increasing the efficacy of some cancer therapies and slowing tumor growth.

The microbiota of a cancerous pancreas is significantly different and larger than that of a non-cancerous pancreas, according to a study published in Cancer Discovery. Smruti Pushalkar and her colleagues at the New York University (NYU) College of Dentistry and NYU School of Medicine have shown that removing bacteria from the gut and pancreas slows cancer growth and triggers immune cells to react against cancer cells in mice.

Pancreatic cancer is the seventh most common cancer in Europe and kills more than 95,000 people every year. Life expectancy at the time of diagnosis is less than 5 months and only 3% of patients survive for 5 years. A recent report by United European Gastroenterology shows that, in the European Union, the incidence of deaths caused by pancreatic cancer has increased by 5% between 1990 and 2016.

However, despite the rise in death rates, research on effective treatments is lagging behind. Pancreatic cancers are resistant to both chemo- and immuno-therapies, and currently the only curative approach is resection of the pancreas, which is technically challenging. Because microbial dysbiosis has been associated with the development of several cancers, including stomach, colon and liver cancers, the researchers examined the role of gut and pancreas bacteria in the development and progression of pancreatic cancer.

A cancerous pancreas harbors a larger microbiota than a non-cancerous pancreas

First, the team looked at whether gut bacteria can access the pancreas. After giving mice fluorescently-tagged Enterococcus faecalis and Escherichia coli, the researchers noticed that the bacteria were able to migrate to the pancreas. Further analyses showed that bacteria in both mouse and human pancreatic cancer tissues were significantly more abundant than those in normal pancreas.

Next, the researchers sequenced the bacterial DNA from the pancreatic cancer tissue from 12 patients to characterize their pancreatic microbiota. The microbiota composition of pancreatic cancer tissues was distinct from that of normal human pancreas, and was enriched in species such as Proteobacteria (45%), Bacteroidetes (31%), and Firmicutes (22%).

Bacteria could promote the progression of pancreatic cancer

To assess whether bacteria promote pancreatic cancer progression, the researchers used a mouse model of pancreatic cancer, called KC. Germ-free KC mice were protected against cancer progression compared to KC mice colonized by bacteria. Similarly, mice injected with pancreatic tumor cells developed about 50% less cancer cells after being treated with antibiotics, suggesting that bacteria promote the progression of pancreatic cancer.

Next, the team looked at the gut microbiota composition of KC and wild-type mice over 9 months to identify changes associated with cancer progression. The most abundant bacterial species, Bacteroidetes and Firmicutes, didn’t change over time in the two groups. But Actinobacteria increased by about 60% in KC mice by week 20, whereas they didn’t in wild-type mice. Also Deferribacteres and Bifidobacteria became more abundant in KC mice compared with wild-type mice from weeks 28 to 36 and 13 to 36, respectively.

Similarly, the gut microbiota of patients with pancreatic cancer and healthy people were both dominated by Firmicutes and Bacteroidetes, but Proteobacteria, Synergistetes, and Euryarchaeota were significantly more abundant in patients with pancreatic cancer.

To test whether bacteria trigger the development of pancreatic cancer in genetically predisposed mice, the researchers used antibiotics to remove gut bacteria in KC mice and then transferred into their guts the feces from either wild-type or KC mice. The animals that received feces from KC mice showed increased tumor growth, whereas those that received feces from wild-type mice didn’t.

Bacteria trigger cancer progression by suppressing immune cell function

The researchers hypothesized that the microbiome promotes pancreatic cancer progression by suppressing immune cell function. Indeed, removing bacteria with antibiotics caused a substantial increase of T cells and a reduction of myeloid-derived suppressor cells within the cancer tissue. Antibiotic treatment also increased the CD8:CD4 T-cell ratio within the tumor, which is associated with enhanced immunogenicity, and caused an increased production of pro-inflammatory molecules such as TNFα and IFNγ.

To confirm the protective immune effects associated with the removal of bacteria, the team took T cells from pancreatic tumors in control and antibiotic-treated mice. Then, they transferred the T cells to mice that had been injected with pancreatic tumors. Mice that received of T cells from control mice were not protected from pancreatic cancer, while those that received T cells from antibiotic-treated mice developed about 50% less cancer cells.

The researchers hypothesized that the immune tolerance promoted by the pancreatic tumor-associated microbiota is the result of higher pattern recognition receptor (PRR) activation in the tumor microenvironment. Consistent with this hypothesis, the team found that gut bacterial extracts from KC mice induced higher activation of some PRR reporter cell lines compared with gut extracts from wild-type mice. Pancreatic tumors in antibiotic-treated mice showed a substantially lower expression of PRRs compared with pancreatic tumors in control mice.

In summary, the study found that eliminating bacteria with antibiotics slowed pancreatic tumor progression and reduced the number of cancer cells by about 50% by restoring the ability of immune cells to recognize cancer cells. The authors speculate that the most abundant species found in pancreatic cancers – including proteobacteria and actinobacteria – release cell membrane components such as lipopolysaccharides and proteins such as flagellins, which prevent immune cells from attacking the tumor.

Overall, the results suggest that modulating the microbiota could increase the efficacy of some cancer therapies and slow tumor growth, thus opening new avenues for pancreatic cancer treatment.