Identifying the cellular origin of squamous skin tumors

Abstract

Squamous cell carcinoma (SCC) is the second most frequent skin cancer. The cellular origin of SCC remains controversial. Here, we used mouse genetics to determine the epidermal cell lineages at the origin of SCC. Using mice conditionally expressing a constitutively active KRas mutant (G12D) and an inducible CRE recombinase in different epidermal lineages, we activated Ras signaling in different cellular compartments of the skin epidermis and determined from which epidermal compartments Ras activation induces squamous tumor formation. Expression of mutant KRas in hair follicle bulge stem cells (SCs) and their immediate progeny (hair germ and outer root sheath), but not in their transient amplifying matrix cells, led to benign squamous skin tumor (papilloma). Expression of KRas G12D in interfollicular epidermis also led to papilloma formation, demonstrating that squamous tumor initiation is not restricted to the hair follicle lineages. Whereas no malignant tumor was observed after KRas G12D expression alone, expression of KRas G12D combined with the loss of p53 induced invasive SCC. Our studies demonstrate that different epidermal lineages including bulge SC are competent to initiate papilloma formation and that multiple genetic hits in the context of oncogenic KRas are required for the development of invasive SCC.

Development and Homeostasis of the Skin Epidermis

“…Mosaic activation of a constitutively active mutant of KRas (KRas LSL-G12D ) mimicking the natural occurrence of sporadic tumors in different compartments of the skin epidermis revealed the SCC-initiating cells (Fig. 5) (Lapouge et al 2011;White et al 2011). Papilloma formation was observed upon KRas G12D expression in bulge SCs and their progeny, but not in HF transit-amplifying cells.…”

“…Although SG arises during morphogenesis from HF progenitors that may be common to bulge SCs, it is unclear whether bulge SCs participate in the normal renewal of the gland in the absence of pathological conditions. Lineage tracing using K15CREPR mice showed labeling of rare SG cells (Morris et al 2004), whereas Lgr5 (Jaks et al 2008) and K19CREER failed to label the SG during homeostasis Lapouge et al 2011). In contrast, during pathological conditions that stimulate SG proliferation such as oncogenic Ras expression (Lapouge et al 2011) or Blimp1 deletion (Horsley et al 2006), bulge SCs can contribute to the expansion of SG.…”

“…Lineage tracing using K15CREPR mice showed labeling of rare SG cells (Morris et al 2004), whereas Lgr5 (Jaks et al 2008) and K19CREER failed to label the SG during homeostasis Lapouge et al 2011). In contrast, during pathological conditions that stimulate SG proliferation such as oncogenic Ras expression (Lapouge et al 2011) or Blimp1 deletion (Horsley et al 2006), bulge SCs can contribute to the expansion of SG. Under physiological conditions, the SG contains its own unipotent progenitors that ensure its high cellular turnover.…”

“…Papilloma formation was observed upon KRas G12D expression in bulge SCs and their progeny, but not in HF transit-amplifying cells. KRas G12D expression in the IFE-induced hyperproliferation and hyperplasia, sometimes progressing into papillomas, indicating that cells of the IFE are competent to develop papillomas (Lapouge et al 2011). The cellular origin of DMBA/TPA-induced papilloma and SCC has not been determined yet, but the absence of tumors in DMBA/ TPA-treated CD34-null mice (Trempus et al 2007) and the resistance to DMBA/TPA-induced tumor formation in mice with Stat3 deletion in bulge SCs and their progeny (Chan et al 2004;Kim et al 2009a) indicate that bulge SCs probably participate in papilloma formation.…”

The propensity for epithelial-mesenchymal transitions is dictated by chromatin states in the cancer cell of origin

“…Previous studies showed that the expression of oncogenic KRas G12D coupled with genetic deletion of p53 deletion in interfollicular epidermal (IEF) cells was sufficient to elicit SCC with well-differentiated morphology; however, recapitulating these same genetic events in hair follicle (HF) cells resulted in SCC bearing multiple morphologies, including well-differentiated SCC, spindle cell SCC, and mixed morphology SCC (18,19). Such findings suggest that cell of origin and its unique genetic makeup ultimately determines the tumorigenic fate of distinct cell types to identical genetic events.…”