TGen Study Leverages Advanced Genomics to Map Lung Tissue Changes

Significant alterations in the structure and cellular composition of the distal lung are a defining characteristic of pulmonary fibrosis (PF); however, the specific spatial contexts that play a role in the disease’s development have yet to been clearly identified.

Nick Banovich, Ph.D.

“We’ve been using advanced genomics approaches to study PF for the past seven years,” Nicholas Banovich, Ph.D, an associate professor and director of the Division of Bioinnovation and Genome Sciences at Translational Genomics Research Institute (TGen), told MHE. “This began with studies that leveraged emerging single-cell RNA sequencing technologies. These studies were really impactful, enabling us to explore molecular dysregulation at cell type resolution, so we knew which types of cells were actually undergoing changes in individuals with PF.”

TGen, which is headquartered in Phoenix, Arizona, is a nonprofit research center that is affiliated with City of Hope, a hospital and research center in Southern California that focuses primarily on cancer.

As part of TGen’s research, a new study looked at spatial approaches that could localize changes not only to individual types of cells but actually to where those cells are within the tissue.

“In a way, you can think of this as marrying traditional pathology but overlying genomics on top of it,” Banovich explained. “It’s really a big change from how we’ve done genomics research in the past, and it provides a much more detailed picture of how the disease moves through the tissue and what the molecular drivers and consequences are.”

The findings from the latest study, published on Feb. 3, 2025, in Nature Genetics, identify molecularly defined spatial niches in both healthy and fibrotic lungs.

“We believe these niche analyses provide a really powerful way to look at a disease like PF,” Banovich said. “The idea is you can use this technology to divide the tissue into regions of molecular and cellular similarity. The concept arises from the idea that it’s really impractical to comprehensively annotate the tissue using traditional pathology approaches. Instead, we can look at regions that have the same types of cells or mRNA transcripts appearing in the same region and then assign every cell into one of these niches.”

By sing the analysis, the researchers are able to compare a molecular-driven approach to traditional pathology annotations and enable them to find many instances of concordance but also places where the genomics pushed past what was possible with visual annotation.

One finding was that in relatively preserved regions of fibrotic lungs, the molecular signature of “normal alveoli” was virtually absent. Banovich called this a great example of how niche analysis helped to identify something really interesting.

“We could examine regions of the lung from individuals with pulmonary fibrosis that appear normal based on histology,” he said. “However, our niche analysis found that these regions already have a change undergone profound molecular and cellular changes. It’s important to remember that these are still tissue samples from individuals who received a lung transplant. So even though a particular region looked normal, by definition these individuals were at the latest stages of disease. It’s still difficult to draw a direct line to the work from this study to what may be the earliest molecular changes in disease.”

The study also highlights the role of KRT5−/KRT17+ cells and their detachment in pulmonary fibrosis.

“In 2020, our group and another group published two studies in tandem which first described these KRT5-/KRT17+ cells. We found them to be present nearly exclusively in individuals with fibrotic lung disease, and our study proposed that they were likely to arise from improper alveolar type 2 (AT2) cell differentiation,” Banovich said. “AT2 cells act as stem cell in the alveolus and differentiate into AT1 cells after alveolar damage. Using spatial transcriptomics, we could for the first time really profile these cells in their ‘habitat’ if you will. Amazingly through our niche analysis, we found these cells tend to sit at regions of alveolar epithelium that are in near direct contact with activated fibroblasts.”

While somewhat speculative, the study suggests these cells start as normal alveolar cells then are receiving signals from activated fibroblasts that are causing them to “abandon ship.”

“Cells in the alveolus do have the ability to migrate during injury so it’s not clear if these cells are trying to migrate to a better location, or if they are just sloughing off and dying,” Banovich said. “We know in more remodeled regions of tissue that normal alveolar cells are basically gone, so this could be a key part of the process driving alveolar loss. A lot of work still needs to be done to confirm these hypotheses, but this study has created the foundation for us to answer these questions.”

The goal, he said, is really to understand the foundational process driving disease, validating potentially relevant targets, and enabling drug developers to use the information to build new therapeutics that push towards a cure for PF.