eprintid: 30736
rev_number: 17
eprint_status: archive
userid: 6288
dir: disk0/00/03/07/36
datestamp: 2021-11-17 10:21:02
lastmod: 2022-11-14 17:30:34
status_changed: 2021-11-17 10:21:02
type: doctoralThesis
metadata_visibility: show
creators_name: Solé Boldo, Llorenç
title: Epigenomic characterization of human keratinocyte cancers and their cellular origin
subjects: ddc-500
subjects: ddc-570
subjects: ddc-610
divisions: i-140001
adv_faculty: af-14
keywords: DNA methylation, Keratinocyte cancers, Skin aging, Fibroblasts
abstract: Keratinocyte cancers (KC) are the most common malignancy in fair-skinned populations, with millions of cases diagnosed yearly. Although historically overlooked by cancer registries, their continuously rising incidence and the economic burden they pose on health systems have put KC in the spotlight. KC arise from epidermal keratinocytes and comprise two main tumor types: basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). The latter mostly originates from pre-cancerous dysplasias named actinic keratosis (AK) or in situ carcinomas known as Bowen’s disease (BD). Two subclasses of AK/cSCC were previously identified based on their DNA methylation profiles, reflecting two distinct cells-of-origin.
This notion was further explored in this thesis by epigenomically characterizing 102 epidermal samples using Infinium MethylationEPIC BeadChips. This cohort included healthy controls, AK, cSCC, BD, BCC, and non-cancerous senile warts (seborrheic keratosis; SK), thus comprising the full range of malignancy in epidermal tumors. Methylation patterns at keratinocyte-specific enhancers stratified the samples into two subclasses with epidermal stem cell-like or keratinocyte-like profiles. While SK and BCC samples predominantly displayed keratinocyte-like profiles, cSCC and its precursors displayed both, indicating potential clinical implications. Further analyses indicated distinct cell division rates and invasive features between cell-of-origin subclasses. Lastly, single-cell methylomics and transcriptomics validated the cell-of-origin-based stratification of epidermal tumors.
Dermal fibroblasts are a heterogeneous cell population with essential roles in maintaining skin architecture and function. However, their diversity in human skin and its functional significance are still relatively unclear. In this work, fibroblast heterogeneity was systematically analyzed using the single-cell transcriptomes of more than 5,000 fibroblasts from sun-protected healthy human skin. Four distinct subpopulations with specific localization and primed to exert differential secretory, mesenchymal, and pro-inflammatory roles were identified. Importantly, this priming was substantially reduced upon intrinsic aging.
Collectively, this work provides important insight into the cellular origin of KC, establishes new opportunities for robust patient risk assessment, and represents a detailed analysis of human dermal fibroblast heterogeneity and their intrinsic aging.
date: 2022
id_scheme: DOI
id_number: 10.11588/heidok.00030736
ppn_swb: 1822371716
own_urn: urn:nbn:de:bsz:16-heidok-307368
date_accepted: 2021-09-15
advisor: HASH(0x55fc36be5c08)
language: eng
bibsort: SOLEBOLDOLEPIGENOMIC2022
full_text_status: public
place_of_pub: Heidelberg
citation:   Solé Boldo, Llorenç  (2022) Epigenomic characterization of human keratinocyte cancers and their cellular origin.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/30736/1/PhDThesis_LSB.pdf