A slow cycling Lgr5 tumour population mediates basal cell carcinoma relapse after therapy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE117458 | GEO | 2018/10/11
REPOSITORIES: GEO
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Project description:Basal cell carcinoma (BCC) is the most frequent cancer in humans and results from constitutive activation of the Hedgehog pathway1. Several Smoothened inhibitors are used to treat Hedgehog-mediated malignancies, including BCC and medulloblastoma2. Vismodegib, a Smoothened inhibitor, leads to BCC shrinkage in the majority of patients with BCC3, but the mechanism by which it mediates BCC regression is unknown. Here we used two genetically engineered mouse models of BCC4 to investigate the mechanisms by which inhibition of Smoothened mediates tumour regression. We found that vismodegib mediates BCC regression by inhibiting a hair follicle-like fate and promoting the differentiation of tumour cells. However, a small population of tumour cells persists and is responsible for tumour relapse following treatment discontinuation, mimicking the situation found in humans5. In both mouse and human BCC, this persisting, slow-cycling tumour population expresses LGR5 and is characterized by active Wnt signalling. Combining Lgr5 lineage ablation or inhibition of Wnt signalling with vismodegib treatment leads to eradication of BCC. Our results show that vismodegib induces tumour regression by promoting tumour differentiation, and demonstrates that the synergy between Wnt and Smoothened inhibitors is a clinically relevant strategy for overcoming tumour relapse in BCC.
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Project description:A slow cycling Lgr5 tumour population mediates basal cell carcinoma relapse after therapy
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Project description:Recent studies have demonstrated that ablative fractional laser (AFL) can inhibit the hedgehog pathway, enhance immune infiltration, and clear basal cell carcinomas (BCCs) in murine models. In this study, we applied RNA sequencing to further characterize the impact of AFL on the transcriptome of murine skin containing early-stage microscopic BCCs, contrasting it with the effects of the FDA approved hedgehog inhibitor vismodegib. Our results showed that BCC induction in murine skin was primarily linked to gene upregulation. Both AFL and vismodegib treatments were able to reverse this upregulation with vismodegib demonstrating superior performance by reversing the most genes (AFL: 59/277; vismodegib 180/277). Surprisingly, Ingenuity Pathway Analysis revealed that both treatments also caused considerable immune cell infiltration. Based on gene set enrichment analysis and cell type deconvolution, AFL treatment resulted in the largest immune cell recruitment, which for both treatments primarily consisted of infiltrating neutrophils, macrophages, and monocytes. In conclusion, the distinct effects observed in BCC skin following AFL and vismodegib treatment highlight key differences between the two interventions. Future applications of AFL or vismodegib treatments could leverage their individual effects, for example by combining AFL’s effects on the immune system with other topical treatments.
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Project description:Here, we report a discrete population of keratinocytes, marked by Thy1, in the basal layer of the IFE. We find that basal keratinocytes expressing differential levels of Thy1 display distinct transcriptional signatures. Thy1+ keratinocytes do not express T cell markers, express a unique transcriptional profile, cycle significantly slower than epidermal progenitors and display significant expansion potential in vitro. Collectively, these results reveal a distinct stem cell population that plays a critical role in epidermal homeostasis and repair.
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Project description:Phenotypic heterogeneity within a population of genetically identical cells is emerging as a common theme in multiple biological systems, including human cell biology and cancer. Using live-cell imaging, flow cytometry, and kinetic modeling, we showed that two states--quiescence and cell cycling--can coexist within an isogenic population of human cells and resulted from low basal expression levels of p21, a Cyclin-dependent kinase (CDK) inhibitor (CKI). We attribute the p21-dependent heterogeneity in cell cycle activity to double-negative feedback regulation involving CDK2, p21, and E3 ubiquitin ligases. In support of this mechanism, analysis of cells at a point before cell cycle entry (i.e., before the G1/S transition) revealed a p21-CDK2 axis that determines quiescent and cycling cell states. Our findings suggest a mechanistic role for p21 in generating heterogeneity in both normal tissues and tumors.
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Project description:The presence of distinct stem cells that maintain the interfollicular epidermis is highly debated. Here, we report a population of keratinocytes, marked by Thy1, in the basal layer of the interfollicular epidermis. We find that epidermal cells expressing differential levels of Thy1 display distinct transcriptional signatures. Thy1+ keratinocytes do not express T cell markers, express a unique transcriptional profile, cycle significantly slower than basal epidermal progenitors and display significant expansion potential in vitro. Multicolor lineage tracing analyses and mathematical modeling reveal that Thy1+ basal keratinocytes do not compete neutrally alike interfollicular progenitors and contribute long-term to both epidermal replenishment and wound repair. Importantly, ablation of Thy1+ cells strongly impairs these processes, thus indicating the non-redundant function of Thy1+ stem cells in the epidermis. Collectively, these results reveal a distinct stem cell population that plays a critical role in epidermal homeostasis and repair.
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Project description:Smoothened inhibitors are currently being investigated for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). The majority of BCC patients treated with vismodegib experience significant clinical benefit, however, a small number of patients develop resistance. Knowledge of resistance mechanisms can generate predictive biomarkers and is critical for the design of additional therapeutic strategies aimed at circumventing resistance. To investigate mechanisms of resistance to vismodegib in BCC we sequenced and profiled biopsies from patients who initially responded to treatment and subsequently progressed on drug. We find that resistance is associated with re-activation of the Hedgehog (Hh) pathway through diverse mechanisms, including concurrent copy number alterations in the downstream Hh pathway components SUFU and GLI2, as well as novel SMO mutations that reduce sensitivity to vismodegib. The latter fall into two classes: those that activate SMO and those that directly affect the vismodegib-binding pocket. Additionally, we observe evidence of clonal selection of SMO mutations and intra-tumor heterogeneity of resistance mechanisms, which implies diverse and combinatorial strategies are required to overcome resistance.
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Project description:We identified slow-cycling cells (SCCs) in Ewing sarcoma using a label retention assay with CFSE. We labeled cells of SK-ES-1, an Ewing sarcoma cell line, with CFSE. After 5 days culture, we isolated cells retaining strong fluorescence (upper, ~10%) as SCCs and other cells (lower, ~90%) as non-slow-cycling cells (non-SCCs) using FACS AriaTM Ⅲ cell sorter.
2022-10-17 | GSE204671 | GEO
Project description:Transcriptomic analysis of early-stage basal cell carcinomas in murine skin following ablative fractional laser and vismodegib treatment
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