We microdissected and sequenced the actinic keratosis and squamous cell carcinoma areas. Remarkably, in most cases, they shared no somatic mutations, indicating that they collided – i.e. unrelated tumors that happen to occur in close proximity.

But we found some squamous cell carcinomas that clearly evolved from the neighboring actinic keratosis. In these, SWI/SNF mutations or MAPK mutations recurrently drove the transition from pre-malignant to malignant tumors.

Lymphocytes surrounded both AKs and SCCs. The main difference is that the SCCs express checkpoint ligands, whereas the AK cells do not. Are checkpoint ligands expressed as a result of new driver mutations? Larger studies will confirm.

In summary, we report the key events that occur during the evolution of keratinocytes to cutaneous squamous cell carcinomas.

Huge thanks to co-authors, especially Bishal Tandukar, Delahny Vineisha Deivendran. Supported by National Cancer Institute, Melanoma Research, NIAMS, CDMRP, LEO Foundation - LEO Fondet, Tracy and Guy Jaquier. Feedback encouraged!

Found Bishal Tandukar and Meng Wang. On our way to Society For Melanoma Research congress in New Orleans

Happy to share the latest preprint from our lab, “Somatic mutations distinguish melanocyte subpopulations in human skin”. biorxiv.org/content/10.110… [1]

We genotyped ~300 skin cells from over 50 different donors (available in cBioPortal and dbgap). Their mutation burdens vary from person to person, site to site within each person, and cell to cell within each site. Here, we explore the latter source of variability. [2]

Most melanocytes in heavily sun exposed skin have high mutation burdens, but we were stunned to see that there is a subpopulation of melanocytes with virtually no mutational damage. [3]

How is it possible for melanocytes from the same site, ostensibly exposed to the same dosages of UV radiation, to have 30-fold differences in mutation burdens? [4]

First, we explored mutational signatures, indicating that low mutation burden melanocytes evade the worst of UV-radiation-induced mutagenesis. [5]

Second, we explored gene expression profiles, indicating that low mutation burden melanocytes occupy a more stem-like state [6]

Third, we explored morphologic features, indicating that low mutation burden melanocytes are smaller with fewer dendrites. Others have noted that melanocyte stem cells in the hair bulge share similar morphologic features [7]

All of these traits suggest that low mutation burden melanocytes come from the hair bulge, a reservoir of stem cells that is somewhat protected from UV radiation. To test this theory, we performed spatial transcriptomics on the @10XGenomics Xenium platform [8]

Indeed, melanocytes that express LowMut gene expression profiles were enriched in the hair bulge. They could also be found in the interfollicular epidermis, where they were somewhat more abundant near the opening of the hair shaft. [9]

In summary, we believe that UV radiation will, over decades, damage interfollicular melanocytes, killing off some cells. These cells are replenished from stem cells in the hair bulge. It is a clever adaptation to rejuvenate damaged skin. [10]

Special thanks to Bishal Tandukar for leading this work and to fantastic collaborators, Robert Judson-Torres and iwei yeh @Yeh_lab

Also thanks to other authors… Delahny Vineisha Deivendran Aravind Kumar Bandari Rojina Nekoonam limin chen Neda Bahrani Harsh Sharma. Not on X Beatrice Weier, Noel Cruz Pacheco, Min Hu, Kayla Marks, Rebecca Zitnay

Thanks to supporters. @NCIHTAN National Cancer Institute @cdMRP NIAMS Melanoma Research LEO Foundation - LEO Fondet University of Utah Department of Dermatology at UCSF @UCSFcancer

Check out this awesome paper from the Shain Lab! Melanocyte migration and localization patterns using Xenium suggests mechanism for repairing damaged skin cells.