Wistar Scientists Identify Esophageal Cancer Biomarkers

Dr. Noam Auslander and authors trained a neural network to identify cancer risk from microbes.

PHILADELPHIA—(Dec. 5, 2023)—Wistar scientists have developed a new tool that can help identify cancer-associated microbes by using machine learning technology. Under the leadership of Dr. Noam Auslander — assistant professor in the Ellen and Ronald Caplan Cancer Center’s Molecular & Cellular Oncogenesis Program — the group has analyzed short read RNA-sequencing data to detect biomarkers for esophageal carcinoma, or ESCA. Their paper, “Microbial gene expression analysis of healthy and cancerous esophagus uncovers bacterial biomarkers of clinical outcomes,” was published in International Society for Microbial Ecology Communications.

Tumor microenvironments are often analyzed using RNA sequencing, or RNAseq, which identifies mRNA in a population of cells to find which genes are being expressed. Theoretically, RNAseq data can reveal the expression of microbial genes in cancerous tissue, which could help to identify microbiome shifts that might be playing a role in the cancer’s development. But RNAseq “reads” — the physical lengths of genetic data that correspond with gene expression — are often quite short, posing a challenge for classifying them into diverse microbial genetic origins. Assembling the short RNAseq reads into longer contiguous segments that can be associated with a vast array of potential origins — be they human, viral, or bacterial — to identify specific microbes whose expression correlates with ESCA is computationally challenging.

That’s where Dr. Auslander and her group decided to intervene by training a convolutional neural network, a type of machine-learning technology that can be taught to train itself to accurately assess large quantities of data. The team, using large publicly available datasets of characterized short-read data, trained the network to sort short-read RNAseq data by its likely origin: human, viral, or bacterial. Their model sought to pare down the number of short reads that would need to be assembled for identification, which would reduce the computational load of screening for microbial influences in cancer tissue.

Once the model was trained, its sorting capabilities allowed the group to selectively analyze ESCA tissue for reads of microbial origin and compare those data with apparently healthy esophageal tissue. Auslander’s team found several instances of microbial expression present in ESCA with significantly less incidence in apparently healthy esophageal tissue.

In particular, they found that nearly half of the microbial genes over-expressed in cancer originated from bacteriophages, which are viruses that infect bacteria; this finding may indicate that viruses infecting microorganisms within the tumor microenvironment facilitate ongoing cancerous gene expression.

The team also identified patient outcome predictors amid the data. Bacterial iron-sulfur proteins were found to impact human genes involved in ferroptosis — a type of cell death pathway that’s modulated by iron — which predicted poor prognosis in ESCA patients. Microbial genes involved in mitochondrial reprogramming were also found to predict ESCA patient prognosis.

“By building on our previous work, our team has successfully leveraged machine learning to dive deeper into what’s going on inside cancer,” said Dr. Auslander. “While it’s always important to remember that correlation does not equal causation, the associations we’ve been able to find between certain microbial genes and ESCA will allow scientists to further understand the mechanics of esophageal cancer — which is the first step in stopping it.”

Co-authors: Daniel E. Schäffer of Carnegie Mellon University, The Wistar Institute, and the Massachusetts Institute of Technology; Wenrui Li of The University of Pennsylvania; Abdurrahman Elbasir and Dario C. Altieri of The Wistar Institute; Qi Long of The University of Pennsylvania; and Noam Auslander of The Wistar Institute.

Work supported by: National Cancer Institute grant numbers R00CA252025 and P30-CA016520 and National Institute on Aging grant number RF1-AG063481.

Publication information: “Microbial gene expression analysis of healthy and cancerous esophagus uncovers bacterial biomarkers of clinical outcomes,” published in International Society for Microbial Ecology Communications.

###

The Wistar Institute is the nation’s first independent nonprofit institution devoted exclusively to foundational biomedical research and training. Since 1972, the Institute has held National Cancer Institute (NCI)-designated Cancer Center status. Through a culture and commitment to biomedical collaboration and innovation, Wistar science leads to breakthrough early-stage discoveries and life science sector start-ups. Wistar scientists are dedicated to solving some of the world’s most challenging problems in the field of cancer and immunology, advancing human health through early-stage discovery and training the next generation of biomedical researchers. wistar.org