eprintid: 33872
rev_number: 15
eprint_status: archive
userid: 6995
dir: disk0/00/03/38/72
datestamp: 2023-10-11 08:07:13
lastmod: 2023-10-11 13:00:51
status_changed: 2023-10-11 08:07:13
type: doctoralThesis
metadata_visibility: show
creators_name: Schütz, Sabrina
title: Characterization of cancer-associated fibroblast heterogeneity in squamous cell carcinoma progression using single-cell RNA sequencing
subjects: ddc-500
subjects: ddc-570
divisions: i-140001
divisions: i-850300
adv_faculty: af-14
cterms_swd: Biologie
cterms_swd: Krebsforschung
abstract: Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte cancer with a rapidly increasing incidence and one of the most common cancer types in the fair-skinned population. Chronic exposure to ultraviolet radiation (UVR) is its main risk factor and can lead to the development of a premalignant skin lesion, actinic keratosis (AK), which might further progress into cSCC. In addition, invasive cSCC can also develop from the in situ carcinoma Bowen’s disease (BD). During this progression, resident dermal fibroblasts are transformed into cancer-associated fibroblasts (CAFs) that are known to promote tumorigenesis. However, a detailed characterization of cSCC-related CAFs with respect to their fibroblast subpopulation-specific origin, heterogeneity, and tumor-promoting functions was still missing. Therefore, in this thesis, more than 115,000 single-cell transcriptomes from healthy human skin, BD and cSCC samples were analyzed. The results revealed two main CAF subpopulations with distinct functions and origins. Inflammatory CAFs (iCAFs) seemed to develop mainly from pro-inflammatory fibroblasts and presented immunoregulatory functions, including cellular interactions with immune cells in the tumor microenvironment (TME). On the other hand, myofibroblastic CAFs (myCAFs) were observed to originate mainly from healthy mesenchymal fibroblasts and were involved in extracellular matrix (ECM) remodeling processes. Furthermore, multiplexed RNA fluorescence in situ hybridization (FISH) assays not only confirmed both CAF subpopulations in human BD and cSCC, but also provided valuable information about the time window of CAF activation, as no CAFs could be observed in AK tissue sections. Interestingly, these findings could not be transferred to basal cell carcinoma (BCC), the second major keratinocyte cancer. Taken together, this thesis provides novel insights into CAF development, stratification, and functions during cSCC initiation and progression.
date: 2023
id_scheme: DOI
id_number: 10.11588/heidok.00033872
ppn_swb: 1861586256
own_urn: urn:nbn:de:bsz:16-heidok-338725
date_accepted: 2023-09-15
advisor: HASH(0x561a6282a828)
language: eng
bibsort: SCHUTZSABRCHARACTERI20230717
full_text_status: public
place_of_pub: Heidelberg
citation:   Schütz, Sabrina  (2023) Characterization of cancer-associated fibroblast heterogeneity in squamous cell carcinoma progression using single-cell RNA sequencing.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/33872/1/Thesis_Sabrina_Schuetz.pdf