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SOX2 confers tumour permissiveness in a specific skin progenitor population

ABSTRACT: The skin’s continuous renewal relies on stem and progenitor cells, yet their differential susceptibility to oncogenic mutations in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. Rapid cSCC development occurs in melanoma patients treated with BRAF inhibitors, driven by paradoxical MAPK activation. To model this in mice, we use two complementary approaches: HRASG12V with BRAFi to mimic paradoxical MAPK activation, and BRAFV600E, which drives MAPK hyperactivation without further treatment. We target these mutations to the interfollicular stem and differentiation-committed progenitors of the basal epidermis. While stem cells rapidly form tumours, progenitors exhibit long-latency resistance despite retaining mutations and repopulating the basal layer. Ultimately, both populations produce similar tumours, revealing a shared transformation programme. However, SOX2 is uniquely upregulated in tumours from the progenitor population. SOX2 is expressed in 20% of human cSCC, suggesting that it could mark tumours originating from committed progenitors. Here, we show that SOX2 overexpression in progenitors induces a stem-like state and renders this otherwise resistant population permissive to transformation.

ORGANISM(S): Mus musculus

PROVIDER: GSE303703 | GEO | 2025/10/20

REPOSITORIES: GEO

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Similar Datasets

SOX2 confers tumour permissiveness in a specific skin progenitor population.

Project description:The skin’s continuous renewal relies on stem and progenitor cells, yet their differential susceptibility to oncogenic mutations in cutaneous squamous cell carcinoma (cSCC) remains poorly understood. Rapid cSCC development occurs in melanoma patients treated with BRAF inhibitors, driven by paradoxical MAPK activation. To model this in mice, we use two complementary approaches: HRASG12V with BRAFi to mimic paradoxical MAPK activation, and BRAFV600E, which drives MAPK hyperactivation without further treatment. We target these mutations to the interfollicular stem and differentiation-committed progenitors of the basal epidermis. While stem cells rapidly form tumours, progenitors exhibit long-latency resistance despite retaining mutations and repopulating the basal layer. Ultimately, both populations produce similar tumours, revealing a shared transformation programme. However, SOX2 is uniquely upregulated in tumours from the progenitor population. SOX2 is expressed in 20% of human cSCC, suggesting that it could mark tumours originating from committed progenitors. Here, we show that SOX2 overexpression in progenitors induces a stem-like state and renders this otherwise resistant population permissive to transformation.

2025-10-20 | GSE280236 | GEO

Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma - 30 whole exomes

Project description:Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF/MAPK pathway activation. Here, we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFβ Smad signaling which is localised to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BrafV600E or KrasG12D knockin) and TGFβ signaling ablation (through Tgfbr1 deletion) in LGR5+ve stem cells enables rapid cSCC development in the mouse. Mutation of Tp53 (which is commonly mutated in sporadic cSCC) coupled with Tgfbr1 deletion in LGR5+ve cells also results in cSCC development. These findings indicate that LGR5+ve stem cells can act as cells of origin for cSCC and that RAS/RAF/MAPK pathway hyperactivation or Tp53 mutation, coupled with loss of TGFβ signaling, are driving events of skin tumorigenesis.

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Disruption of the Wnt-antagonist APC in the pituitary stem cells drives adamantinomatous craniopharyngioma

Project description:Adamantinomatous craniopharyngioma (aPCs) are complex intracranial neoplasms that arise in the sellar or parasellar region affecting the endocrine system and leading to severe comorbidities. Activating mutations resulting in degradation resistant from of b-Catenin (CTNNB1 gene) have been shown to be the main driver for a large proportion of these neoplasms. However, the underlying genetic driver for a proportion of these tumours is still unknown. Using murine transgenic models, we show that genetic deletion of the Wnt-antagonist and tumour suppressor, Adenomatous Polyposis Coli (Apc) within the pituitary progenitors/stem cells leads to pituitary tumours that closely resemble human aCPs. These tumours present classical histopathological hallmarks of aCPs such as clusters of accumulating nuclear b-catenin that are slow dividing and undergo secretory phenotype. These tumours present wet keratin, stellar-reticular-like structures and cystic components. We show that a hypomorphic allele of Apc is sufficient for tumour development indicating that disruption of Apc function can lead to aCP formation independent of b-Catenin mutations. Moreover, we identify that bi-allelic loss of Apc in the Sox2+ve pituitary stem cells is sufficient to initiate tumour formation, indicating that Sox2+ve stem cells are the cell origin of these Apc-driven tumours. Transcriptomic analyses of early tumour-initiating cells reveal that clusters of accumulating b-Catenin, undergo p21-mediated cellular senescence and that the secretory phenotype is composed of inflammasome, angiosome and developmental growth factors which are different from the b-Catenin-driven aCP tumours. Our data, unequivocally shows, that disruption of the tumour suppressor Apc in the pituitary progenitors/stem cells is a main driver of aCPs independent of mutations in b-Catenin. We provide two novel murine models that represents a genetic subtype of aCPs which helps to further understand aCP pathogenesis.

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Common and overlapping oncogenic pathways contribute to the evolution of acute myeloid leukemias

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2011-06-27 | GSE24797 | GEO

Mll-AF9 induced changes in gene expression in various hematopoietic cells

Project description:The pathways by which oncogenes, such as MLL-AF9, initiate transformation and leukemia in humans and mice are incompletely defined. In a study of target cells and oncogene dosage, we found that Mll-AF9, when under endogenous regulatory control, efficiently transformed LSK (Lin- Sca1+ c-kit+) stem cells while committed granulocyte-monocyte progenitors (GMPs) were transformation-resistant and did not cause leukemia. Mll-AF9 was expressed at higher levels in hematopoietic stem (HSC) than GMP cells. Mll- AF9 gene dosage effects were directly shown in experiments where GMPs were efficiently transformed by the high dosage of Mll-AF9 resulting from retroviral transduction. Mll-AF9 up-regulated expression of 196 genes in both LSK and progenitor cells, but to higher levels in LSKs than in committed myeloid progenitors. Keywords: mutant hematopoietic cells

2008-02-25 | GSE10627 | GEO

Transcription profiling of mouse hematopoietic cells (GMP, CMP, CLP and HSC), FACS sorted from wild type and Mll-AF9 knock-ins

2008-04-07 | E-GEOD-10627 | biostudies-arrayexpress

Pax3 loss of function delays tumor progression in kRAS-induced zebrafish rhabdomyosarcoma models

Project description:Rhabdomyosarcoma is a soft tissue cancer that arises in skeletal muscle due to mutations in myogenic progenitors that lead to ineffective differentiation and malignant transformation. The transcription factors Pax3 and Pax7 and their down-stream target genes are tightly linked with the fusion positive alveolar subtype, whereas the RAS pathway is usually involved in the embryonic, non-fusion variant. Here, we analyse the role of Pax3 in a non-fusion context, by linking alterations in gene expression in pax3a/pax3b double mutant zebrafish with tumour progression in kRAS-induced rhabdomyosarcoma tumours. Several genes in the RAS signalling pathway, including MAPK signalling pathway, were significantly down-regulated in pax3a/pax3b double mutant zebrafish. Onset and progression of rhabdomyosarcoma tumours were also delayed in the pax3a/pax3b double mutant zebrafish indicating that Pax3 transcription factors have an unappreciated role in mediating malignancy also in non-fusion rhabdomyosarcoma.

2022-10-19 | GSE208266 | GEO

Key differences identified between actinic keratosis and cutaneous squamous cell carcinoma by transcriptome profiling

Project description:Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair skinned populations worldwide and its incidence is increasing. Despite previous observations of multiple genetic abnormalities in cSCC, the oncogenic process remains elusive. The purpose of this study was to investigate the transcriptomes of cSCC and actinic keratoses (AK), to elucidate key differences between precursor AK lesions and invasive carcinoma. This study identified 196 genes that are differentially expressed between AK and cSCC, with enrichment for processes including epidermal differentiation, cell migration, cell cycle regulation and metabolism. Gene set enrichment analysis highlighted a key role for the MAPK pathway in the transition from AK to cSCC. Furthermore, the differentiation status of the tumor influenced the gene expression profile, which may have implications for drug sensitivity and response in clinical trials. These data indicate that progression to cSCC is associated with a complex pattern of molecular changes. We have identified relevant pathways involved in this process, in particular that the MAPK pathway may be pivotal to the transition from AK and may represent a potential therapeutic target. RNA was extracted by laser capture microdissection from 10 AK and 30 cSCC, for analysis using the Affymetrix HG U133 Plus 2.0 microarrays. The cSCC samples included a range of histological diagnoses (well differentiated through to poorly differentiatied) from both immunocompetent and immunosuppressed patients.

2014-01-21 | E-GEOD-45216 | biostudies-arrayexpress

Ultraviolet radiation shapes dendritic cell leukaemia transformation in the skin

Project description:Tumours most often arise from progression of precursor clones within a single anatomical niche. In the bone marrow, clonal progenitors can undergo malignant transformation to acute leukaemia, or differentiate into immune cells that contribute to disease pathology in peripheral tissues. Outside the marrow, these clones are potentially exposed to a variety of tissue-specific mutational processes, although the consequences of this are unclear. Here we investigate the development of blastic plasmacytoid dendritic cell neoplasm (BPDCN)-an unusual form of acute leukaemia that often presents with malignant cells isolated to the skin. Using tumour phylogenomics and single-cell transcriptomics with genotyping, we find that BPDCN arises from clonal (premalignant) haematopoietic precursors in the bone marrow. We observe that BPDCN skin tumours first develop at sun-exposed anatomical sites and are distinguished by clonally expanded mutations induced by ultraviolet (UV) radiation. A reconstruction of tumour phylogenies reveals that UV damage can precede the acquisition of alterations associated with malignant transformation, implicating sun exposure of plasmacytoid dendritic cells or committed precursors during BPDCN pathogenesis. Functionally, we find that loss-of-function mutations in Tet2, the most common premalignant alteration in BPDCN, confer resistance to UV-induced cell death in plasmacytoid, but not conventional, dendritic cells, suggesting a context-dependent tumour-suppressive role for TET2. These findings demonstrate how tissue-specific environmental exposures at distant anatomical sites can shape the evolution of premalignant clones to disseminated cancer.

2023-03-27 | GSE227690 | GEO

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