Investigators at Rutgers Cancer Institute of New Jersey and RWJBarnabas Health have used an approach known as single-cell analysis of host-microbiome interactions (SAHMI), to examine the microbiome of pancreatic tumors and identify particular microorganisms, at single-cell resolution, that are associated with inflammation and poor survival. The researchers, headed by Subhajyoti De, PhD, at Rutgers Cancer Institute, suggest that these microorganisms may represent new targets for earlier diagnosis or treatment of pancreatic cancer, which is the fourth leading cause of cancer death for both men and women in the United States. Reporting on their work in Cancer Cell (“Tumor microbiome links cellular programs and immunity in pancreatic cancer,”) senior author De, and colleagues noted, “Our results provide evidence that intra-tumoral bacteria reflect or influence the trajectory of tumor growth; either possibility has clinical utility.”
The microbiome contributes to human health and disease, including oncogenesis, the authors noted. And while it is uncertain whether the healthy pancreas harbors its own microbiome, “emerging evidence indicates that bacteria and fungi can translocate to the pancreas and induce local and systemic changes that promote development of pancreatic ductal adenocarcinoma (PDA).”
Historically, and despite being increasingly implicated in pancreatic cancer, several barriers have limited systematic investigation of the tumor-associated microbiome in patients with PDA, the scientists noted. These include the vast differences in microbiome composition between individuals and the small number of model systems that can recapitulate tumor-microbiome interactions in humans. Many types of intestinal bacteria are also very hard to culture, and there is also a risk of contamination after surgery complicating data interpretation. For their study, De, along with Bassel Ghaddar, a student in the MD/PhD program at Rutgers Robert Wood Johnson Medical School, wanted to investigate microbes residing in pancreatic tumors, and determine if they have consequences for cancer progression or treatment.
The researchers teamed up with Martin Blaser, MD, the Henry Rutgers chair of the human microbiome at Rutgers University, and developed the genomic approach, SAHMI, to identify microorganisms associated with individual human cells. “We recently developed SAHMI, a computational pipeline to recover and denoise microbial signals from single-cell sequencing of host tissues,” they wrote. Sifting through millions of RNA sequences using the sophisticated software, the investigators identified which sequences likely represented human genes, and which were microbial in origin.
“This new technique allowed us to identify tumor-associated microbes and measure the activity of the host cells at the same time, which is a significant technical advance, and the results were stunning,” noted De, who is also an associate professor of cancer systems biology at Rutgers Robert Wood Johnson Medical School.
Studying two independent groups of pancreatic tumors, the team found that some had bacteria that were associated with specific cell types within the tumor, which were essentially absent in normal pancreatic tissues. These bacteria were predominantly located within tumor cells, and their abundance correlated with cancer-related cell activities. The specific signatures of the microbes that were found predicted particularly aggressive cancer progression and poor prognosis.
The microbial footprints within the pancreatic tumors raised the question of whether the immune cells that were present were responding to the cancer or to the microbes. The study findings also suggested that the immune responses were mostly responding to the microbes in the tumor and not to the cancer cells. “Our observations provide a new view about why pancreatic cancers are so difficult to treat,” noted Blaser, who is also a research member at Rutgers Cancer Institute and professor of epidemiology and biostatistics at Rutgers School of Public Health. “But better understanding of these interactions may identify new approaches for therapies.”
Reporting on the work in Cancer Cell, the researchers acknowledged that their results do not establish direct causal relationships, “i.e., whether microbes are oncogenic or pro-inflammatory or whether they represent infection of established tumors …”. Additional studies will be needed to directly test causation, they commented. Regardless, the team concluded, “SAHMI creates opportunities to examine patterns of human-microbiome interactions from single-cell sequencing data without the need for additional experimental modifications, generating testable hypotheses about host-microbiome relationships at multiple levels. This framework is not tumor specific and can be applied to study a variety of tissues and disease states as well as other infectious agents, such as viruses, fungi, or helminths.”