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 polycombrepressive complex-2 (PRC2) in embryonic stem cells. However, itsspecific role during late development and adult tissues remains largelyuncharacterized. In this first part of my thesis, we show that deletion ofJarid2 in mouse epidermis reduces the proliferation and potentiates thedifferentiation of postnatal epidermal progenitors, without affectingepidermal development. In neonatal epidermis, Jarid2 deficiencyreduces H3K27 trimethylation, a chromatin repressive mark, inepidermal differentiation genes previously shown to be targets of thePRC2. However, in adult epidermis Jarid2 depletion does not affectinterfollicular epidermal differentiation but results in delayed hairfollicle (HF) cycling as a consequence of decreased proliferation of HFstem cells and their progeny. We conclude that Jarid2 is required for thescheduled proliferation of epidermal stem and progenitor cellsnecessary to maintain epidermal homeostasis.Several human and mouse solid tumors, including squamous cellcarcinomas (SCC), contain a population of Cancer Stem Cells (CSCs).CSCs are characterized by their unique ability to initiate and propagatethe tumor; however, very little is known about their capacity todisseminate to distant organs and give rise to metastasis. CSCs display agreat functional and molecular heterogeneity, and it has been proposedthat different CSC subclones might exist to either maintain the primarytumor or to metastasize in distant sites. However, the identity of theseheterogeneous populations of CSCs, as well as their molecular andfunctional characteristics for most type of tumors remains to beelucidated.Using a novel xenograft system that we have developed to study humanhead and neck squamous cell carcinoma, we have identified a labelretaining(LRC) population inside the cancer stem cell pool defined bythe high expression of CD44 and high activity of Aldh1. Unexpectedly,tumor LRC harbor poor initiating potential, and are more sensitive tochemotherapy than their proliferating counterparts.Intriguingly, tumor LRCs are defined by a unique transcriptomesignature previously linked with bone and lung identity, two major sitesof SCC metastasis, suggesting they might be involved in thecolonization 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 assurrogate markers to isolate and characterize them from primary humanSCCs.Based on this signature, we could demonstrate that the presence orabsence of this population in the primary tumor of a large cohort ofpatients with cutaneous SCC is highly predictive of the metastaticoccurrence. In addition, several markers exclusively expressed by tumorLRCs can be targeted with drugs currently in clinical trials for thetreatment of other diseases. We are testing whether some of thesetherapeutical strategies are effective to preventing or reducing themetastatic potential of SCC tumors.