1)Jarid2 regulates mouse epidermal stem cell activation and differentiation ; 2)Tumor heterogeneity and metastasis-initiation in human squamous cell carcinoma
Jarid2 is required for the genomic recruitment of the polycomb repressive complex-2 (PRC2) in embryonic stem cells. However, its specific role during late development and adult tissues remains largely uncharacterized. In this first part of my thesis, we show that deletion of Jarid2 in mouse epidermi...
| Autor: | |
|---|---|
| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2013 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/283482 |
| Acceso en línea: | http://hdl.handle.net/10803/283482 |
| Access Level: | acceso abierto |
| Palabra clave: | Epidermal homeostasis Epidermal stem cells Jarid2 Polycomb group proteins Chromatin Cancer stem cells Metastasis Squamous cell carcinoma Quiescence Chemotherapy Homeostasis epithelial Células madre epidermicas Proteínas Polycomb Cromatina Células madre cancerosa Metástasis Carcinomas escamos Quiescencia Tratamiento farmacológico 577 |
| Sumario: | Jarid2 is required for the genomic recruitment of the polycomb repressive complex-2 (PRC2) in embryonic stem cells. However, its specific role during late development and adult tissues remains largely uncharacterized. In this first part of my thesis, we show that deletion of Jarid2 in mouse epidermis reduces the proliferation and potentiates the differentiation of postnatal epidermal progenitors, without affecting epidermal development. In neonatal epidermis, Jarid2 deficiency reduces H3K27 trimethylation, a chromatin repressive mark, in epidermal differentiation genes previously shown to be targets of the PRC2. However, in adult epidermis Jarid2 depletion does not affect interfollicular epidermal differentiation but results in delayed hair follicle (HF) cycling as a consequence of decreased proliferation of HF stem cells and their progeny. We conclude that Jarid2 is required for the scheduled proliferation of epidermal stem and progenitor cells necessary to maintain epidermal homeostasis. Several human and mouse solid tumors, including squamous cell carcinomas (SCC), contain a population of Cancer Stem Cells (CSCs). CSCs are characterized by their unique ability to initiate and propagate the tumor; however, very little is known about their capacity to disseminate to distant organs and give rise to metastasis. CSCs display a great functional and molecular heterogeneity, and it has been proposed that different CSC subclones might exist to either maintain the primary tumor or to metastasize in distant sites. However, the identity of these heterogeneous populations of CSCs, as well as their molecular and functional characteristics for most type of tumors remains to be elucidated. Using a novel xenograft system that we have developed to study human head and neck squamous cell carcinoma, we have identified a labelretaining (LRC) population inside the cancer stem cell pool defined by the high expression of CD44 and high activity of Aldh1. Unexpectedly, tumor LRC harbor poor initiating potential, and are more sensitive to chemotherapy than their proliferating counterparts. Intriguingly, tumor LRCs are defined by a unique transcriptome signature previously linked with bone and lung identity, two major sites of SCC metastasis, suggesting they might be involved in the colonization of distant tissues by SCC tumors. We have also identified surface molecules, including CD36 and CD37, that are uniquely expressed by tumor LRCs, that can be used as surrogate markers to isolate and characterize them from primary human SCCs. Based on this signature, we could demonstrate that the presence or absence of this population in the primary tumor of a large cohort of patients with cutaneous SCC is highly predictive of the metastatic occurrence. In addition, several markers exclusively expressed by tumor LRCs can be targeted with drugs currently in clinical trials for the treatment of other diseases. We are testing whether some of these therapeutical strategies are effective to preventing or reducing the metastatic potential of SCC tumors. |
|---|