Two fibroblasts can look almost identical under a microscope, yet one may still carry a molecular record of the body region it came from—and that record can remain visible in cancer. Fibroblasts help build and support human tissues, and they interact closely with other cells.

They also take part in wound healing, scarring, inflammation, and organ disease. When fibroblasts do not repair tissue properly, wounds can become chronic or scars can become excessive, including hypertrophic or keloid scars.

That makes their identity important: the same kind of support cell can help restore tissue in one setting, but contribute to disease in another. The central question was whether adult fibroblasts still remember their developmental origin.

In other words, do cells made during early development keep a biological record of where they began? The researchers compared fibroblasts from the face, linked to ectomesenchyme, with fibroblasts from the forearm, linked to mesoderm, to examine differences in their HOX gene expression after birth.

They then examined cancer-associated fibroblasts from tumours in several parts of the body, including the face and brain, as well as other body regions. They also asked whether disease erased the developmental pattern or whether fibroblasts retained it in their gene expression under pathological conditions.

The face-derived and forearm-derived fibroblasts showed significantly different overall gene-activity patterns, with nine hundred fifty-nine genes differing between them in the analysis. The differences were especially connected with development and morphogenesis, the biological processes involved in building and shaping body structures during development.

The location pattern also helped distinguish fibroblasts from soft connective tissue beneath the scalp. Those cells showed activity in a different set of HOX genes than fibroblasts from the face and forearm. The researchers tested whether a fibroblast’s HOX gene expression pattern could help identify its developmental origin across the collected samples.

That HOX activity pattern differed strikingly between dermal fibroblasts isolated from the viscerocranium and fibroblasts from the forearm in the comparison. The adult facial and forearm fibroblasts looked very similar, but their activity in homeobox genes differed.

Facial fibroblasts had almost no HOX gene activity. By contrast, HOX genes were active in all the adult fibroblasts of mesodermal origin. Appearance alone therefore missed a distinction that their gene activity preserved.

Fibroblasts from different diseases retain a molecular memory of where they came from: cells with a body-derived origin carry distinct HOX activity, while those from head regions with an ectomesenchymal origin are largely silent. That pattern helps explain why tumour-supporting fibroblasts may arise from different starting cells.

Tumour-associated fibroblasts from areas dependent on ectomesenchyme had almost no HOX gene expression, with only rare exceptions. The same pattern appeared in cells from primary and secondary brain tumours. The study found that cancer-associated fibroblasts from ectomesenchyme-dependent tumours, along with mesenchymal cells from glioblastomas and brain metastases, were devoid of HOX gene expression.

Fibroblasts prepared from epileptogenic brain regions were also reported to be devoid of HOX gene activity in the study’s analysis. There was one important complication: fibroblasts from some highly malignant brain tumours showed different amounts of HOX gene activity. This varied both in how many HOX genes were active and in how strongly they were active.

That contrasted sharply with fibroblasts from epilepsy regions, where HOX gene activity was generally silent, as expected for an ectomesenchymal origin. The glioblastoma samples therefore stood apart from epilepsy controls: their cancer-associated fibroblasts showed variable numbers and intensities of HOX genes, whereas the controls were generally silent.

The study found that adult fibroblasts retain location-linked developmental patterns, even in disease. That could eventually help researchers identify where tumour-supporting cells came from and understand how position shapes treatment.