Stem cells and the cancer cell of origin
For the vast majority of cancers, the cancer cell of origin is still unknown. Our lab has been pioneered in using mouse genetics to identify the cancer cell of origin in the most frequent cancers in human.
We used lineage tracing to uncover the cellular origin of the basal cell carcinoma, the most common skin cancers and neoplasia in humans. We found that in contrast to the general thought, basal cell carcinoma did not arise from hair follicle stem cells, but rather originate from long-lived stem cells of the interfollicular epidermis and infundibulum. Nature Cell Biology 2010). We found that upon oncogenic hedgehog signaling, these adult stem cells are reprogrammed into embryonic hair follicle progenitors by a Wnt dependent mechanism before progressing into invasive tumors (Nature Cell Biology 2012).
We found that Sox9 is essential to promote long-term renewal of these oncogene targeted stem cells required for tumor initiation and to induce the extracellular matrix and cytoskeleton remodeling promoting invasion, linking tumor initiation and invasion (Cell Stem Cell 2015). We defined for the first time the quantitative dynamics of tumor initiation at the single cell level from the activation of the oncogene to the development of invasive tumours and demonstrated that the capacity of oncogene expressing cells to induce tumor formation depends on the specific clonal dynamics of the oncogene targeted stem cells at the origin of the cancer (Nature 2016).
Squamous cell carcinoma (SCC) represents the second most frequent skin cancer. Using mice conditionally expressing a constitutively active KRas mutant and an inducible CRE in different epidermal lineages, we demonstrated that different epidermal lineages are competent to initiate SCC (PNAS 2011). We found that SCCs arising from the interfollicular epidermis consisted of well-differentiated tumours, whereas SCCs that arose from hair follicle exhibit epithelial to mesenchymal transition (EMT) features. Using transcriptional and chromatin profiling, we identified distinct set of genes that were epigenetically and transcriptionally primed in the cell of origin to promote EMT during tumorigenesis, demonstrating that the cell of origin in cancers regulates tumor heterogeneity (Cell Stem Cell 2017).
Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours. Pik3ca and p53 are the two most frequently mutated genes in human breast cancers. The cellular origin and the mechanisms leading to Pik3ca-induced tumour heterogeneity remain unknown. Surprisingly, oncogenic Pik3ca expression in basal cells induced the formation of luminal tumours, while its expression in luminal cells gave rise to basal-like tumours. Interestingly, expression of Pik3ca in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that have undergone cell fate transition demonstrate a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures, which correlated with the cell of origin, tumour type and different clinical outcomes in patients with breast cancers (Nature 2015).
We are now studying the cells at the origin of skin and breast cancers induced by other oncogenes and tumor suppressor genes and defining the molecular mechanisms associated with tumor initiation and heterogeneity.
Alexandra Van Keymeulen, permanent FNRS researcher
Adriana Sanchez Danes, postdoctoral fellow
Gaelle Lapouge, postdoctoral fellow
Eugenia Pastushenko, postdoctoral fellow
Marco Fioramonti, postdoctoral fellow
Gaëlle Bouvencourt, technician
Mélanie Liagre, technician
Samuel Scozzaro, technician
Identification of the cell lineage at the origin of basal cell carcinoma. Kass Youseff K, Van Keymeulen A, Lapouge G, Beck B, Achouri Y, Michaux C,, Sotiropoulou P and Blanpain C. Nature Cell Biology 2010 Mar;12(3):299-305. Cover of Nature Cell Biology 2010 accompanied by a preview in Cell Stem Cell.
Identifying the cellular origin of squamous skin tumors. Lapouge G, Kass Youssef K, Vokaer B, Achouri Y, Michaux C, Sotiropoulou PA, Blanpain C. Proc Natl Acad Sci U S A 2011 May 3;108(18):7431-6. Highlighted by a preview in Nature Medicine.
Adult interfollicular tumour-initiating cells are reprogrammed into an embryonic hair follicle progenitor-like fate during basal cell carcinoma initiation. Youssef KK, Lapouge G, Bouvrée K, Rorive S, Brohée S, Appelstein O, Larsimont JC, Sukumaran V, Van de Sande B, Pucci D, Dekoninck S, Berthe JV, Aerts S, Salmon I, Del Marmol V, Blanpain C. Nat Cell Biol. 2012 Dec;14(12):1282-94. Highlighted by a news and views in Nature cell Biology.
Tracing the cellular origin of cancer. Blanpain C.Nat Cell Biol. 2012 Dec 23; 15(2):126-34.
Sox9 controls renewal of oncogene targeted cells and links tumor initiation and invasion. Larsimont JC, Youssef KK, Sánchez-Danés A, Sukumaran V, Defrance M, Delatte B; Liagre M, Marine JC, Lippens S, Guerin C, Del Marmol V, Vanderwinden JM, Fuks F & Blanpain C. Cell Stem Cell. 2015 Jul 2;17(1):60-73.
Reactivation of multipotency by oncogenic PIK3CA induces breast tumor heterogeneity. Van Keymeulen A, Lee MY, Ousset M, Rorive S, Brohée S, Wuidart A, Bouvencourt G, Giraddi R, Dubois C, Salmon I, Sotiriou C, Phillips WA, Blanpain C. Nature 2015 Sep 3;525(7567):119-23. Highlighted by a preview in Cancer Discovery
Defining the clonal dynamics leading to mouse skin tumor initiation Sánchez-Danés A, Hannezo E, Larsimont JC, Liagre M, Youssef KK, Simons B, Blanpain C. Nature. 2016 Aug 18;536(7616):298-303. Highlighted by a preview in Cancer Discovery
Cell-Type-Specific Chromatin States Differentially Prime Squamous Cell Carcinoma Tumor-Initiating Cells for Epithelial to Mesenchymal Transition. Latil M, Nassar D, Beck B, Boumahdi S, Wang L, Brisebarre A, Dubois C, Nkusi E, Lenglez S, Checinska A, Vercauteren Drubbel A, Devos M, Declercq W, Yi R, Blanpain C. Cell Stem Cell. 2017 Feb 2;20(2):191-204.e5. Highlighted by a preview in Cell Stem Cell
Deciphering the cells of origin of Squamous Cell Carcinomas. Sánchez-Danés A and Blanpain C. Nat Rev Cancer. 2018 May 30.