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Studying adult stem cells during cancer initiation

For the vast majority of cancers, the cell at the origin of tumor initiation is still unknown. We are using novel genetic approach to identify the cell lineage at the origin of the most frequent epithelial cancers in humans.

 

 

Identification of basal cell carcinoma initiating cells

Stem cells (SCs) have been hypothesized to be the cells at the origin of cancer as SCs reside and self-renew in tissues for extended period of time, increasing their lifetime risk of accumulating the oncogenic mutations required for cancer formation. However, for the vast majority of cancers, the cell at the origin of tumour initiation is still unknown.

img01The skin epidermis is composed of different discrete histologically and biochemically identifiable compartments containing a HF, a sebaceous gland (SG) and its surrounding interfollicular epidermis (IFE). Multipotent SCs residing in the specialized part of the HF called the bulge are responsible for HF regeneration during homeostasis, but also contribute to IFE repair during wound healing. While bulge SCs represent a reservoir of multipotent SCs able to differentiate into all epidermal lineages, the maintenance of the IFE, the infundibulum (the part of the epidermis that connects the HF to the IFE), as well as the SG is ensured, independently of bulge SCs, by the presence of different resident SCs.

Two epithelial skin cancers are frequent in human populations: the squamous cell carcinoma and the basal cell carcinoma (BCC). The identification of the cells at the origin of these two frequent human cancers still remains elusive.

We have recently used mouse genetics to identify cells at the origin of basal cell carcinoma (BCC), which is one of the most frequent types of cancer in human and results from the activation of hedgehog signalling pathway. Using mice conditionally expressing constitutively active Smoothened mutant (SmoM2), we activated hedgehog signalling in different cellular compartments of the skin epidermis, and determined in which epidermal compartments hedgehog activation induces BCC formation. Activation of SmoM2 in hair follicle bulge stem cells (SCs) and their transient amplifying progenies did not induce cancer formation, demonstrating that BCC do not originate from bulge SC as previously thought.

img02Using for the first time clonal analysis during cancer development, we found that BCC arise from long-term resident progenitor cells of the interfollicular epidermis and the upper infundibulum. SmoM2 expressing cells progressively stopped differentiating and were maintained as dysplastic lesions adopting a placode-like shape. The progressive block of differentiation coincides with the expression of follicular markers, explaining why it was previously thought that BCC arise from HF.

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Our studies uncover the cells at the origin of BCC in mice and demonstrate that expression of differentiation markers in tumour cells is not necessary predictive of the cancer initiating cells.

 

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Our study has been published and makes the cover of the March issue 2010 of Nature Cell Biology.

Kass Youseff K., Van Keymeulen A., Lapouge G., Beck B., Achouri Y., Michaux C., Sotiropoulou P. and Blanpain C. (2010).
Identification of the cell lineage at the origin of basocellular carcinoma.
Nature Cell Biology, 2010 Mar;12(3):299-305. Epub 2010 Feb 14.
PubMed | PDF | F1000 Biology | F1000 Medicine

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Identification of squamous cell carcinoma initiating cells

Squamous skin tumors are the second most frequent skin cancer in human, which affects several hundred thousand of new patients every year in the world.

Squamous cell carcinoma was thought to arise from cells residing in the interfollicular epidermis cells, the part of the skin in between hair follicles, due to its morphological and biochemical resemblance with the normal differentiation of these cells. Using a genetic approach in mice that accurately model how cancers naturally arise in human, we found that squamous tumors arise not only from interfollicular epidermis but also from hair follicle stem cells.

To precisely identify the cells responsible for the development of this skin tumor, we used a genetic method allowing the expression of the mutated oncogene in different cell types of the skin epidermis, and follow the fate of oncogene targeted cells overtime. We found that squamous tumors arise not only from interfollicular epidermis cells, the part of the skin between hair follicles, but also from hair follicle stem cells. We also demonstrated that oncogene targeted cells required a second genetics event to progress into malignant invasive squamous cell carcinoma.

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In conclusion, our studies uncover the cells at the origin of squamous cell carcinoma, one of the most frequent cancers in humans and open new avenues to better understand the mechanism underlying cancer progression. This finding is of particular importance for other cancers as well as it clearly demonstrates that the biochemical and morphological characteristics of tumor cells can be misleading in identifying their cellular origin.

This study was published in Proc Natl Acad Sci U S A (2011), back to back with another paper from the Lowry’s group (UCLA) reporting similar findings and was highlighted by a preview in Nature Medicine.

Lapouge G, Youssef KK, Vokaer B, Achouri Y, Michaux C, Sotiropoulou PA, Blanpain C.
Identifying the cellular origin of squamous skin tumors.
Proc Natl Acad Sci U S A. 2011 May 3;108(18):7431-6. Epub 2011 Apr 18.
PubMed | PDF | Preview

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