Colon adenoma mapping links GDF15 to cells that support tissue renewal and to lower CD8-cell density
Colon adenoma mapping links GDF15 to cells that support tissue renewal and to lower CD8-cell density
An August 7 preprint examined human colon adenomas, which are polyps composed of altered glandular cells, some of which develop into cancer. The authors compared spatial RNA and protein measurements from 22 adenomas with an analysis of 101 samples of normal tissue, adenomas, and carcinomas from 16 patients. This allowed them to identify which cellular states and immune cells occur near one another within the tissue.
Between 5–10% of adenomas develop into cancer. The arrangement of cells within a polyp may help explain this transition by showing which cells are neighbors and what signals they send to one another.
Conventional analysis breaks tissue apart and erases this spatial information. Spatial multiomics examines a tissue section while preserving the locations of its cells. It shows which genes and proteins are active in each region. The authors used this approach to locate senescence, a prolonged arrest of cell division, within specific parts of the polyps.
Two groups of altered cells occurred near one another in these regions. One had a senescence program, while the other had a program that supports tissue renewal. The first method measured several cells at once. The second method resolved individual cells and showed that the two programs belonged to distinct cell groups within the same adenoma niche.
The authors compared advanced and early adenomas, regions with high and low stemness, and senescent regions of adenomas and normal epithelium. Six proteins secreted by cells were common to all these comparisons. Of these, the authors selected GDF15, a stress response protein. Its RNA was more abundant in the samples than the RNA of the other candidates, and it could link the neighboring cellular states. When the researchers statistically accounted for GDF15, the association between senescence and stemness in advanced adenomas became weaker. GDF15 therefore remains a candidate local mediator.
Regions of mucosa with high GDF15 levels contained fewer CD8 cells, which are immune cells capable of killing cells with tumor-like features. The authors observed this local pattern in human adenomas using both protein markers and RNA measurements.
This study continues an existing line of research on GDF15. In 2019, some members of the same group showed that senescent fibroblasts, which are connective tissue cells, secrete GDF15 and support adenoma cell growth in organoids and cell systems. The new preprint examines this question within the adenoma itself by asking which cells are associated with this signal before carcinoma develops.
A subsequent experiment in an adenoma model could test whether suppressing GDF15 changes the proximity of cells with senescence and renewal programs.