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Status |
Public on Aug 29, 2023 |
Title |
ECM composition dictates the mode of cell competition and competence for tumor initiation |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
The skin epidermis is constantly renewed throughout life. Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumor initiation. Basal cell carcinoma (BCC) is the most frequent cancer in human. Cell competition is a biological process that leads to the elimination of cells by winner cells, which have been proposed to be important for tumour initiation. Recent studies identified somatic mutations in cancer drivers in normal tissues that get colonized by clones carrying oncogenic mutations. However, how the different oncogenic mutations impact the balance between renewal and differentiation and lead to clonal expansion, cell competition, tissue colonization and tumor development is currently unknown. Here, using multidisciplinary approaches combining in vivo clonal analysis using intra-vital microscopy, single cell analysis, and functional analysis, we defined at a single cell resolution in living animals how mutations associated with BCC development (SmoM2) affect clonal competition and tumor initiation in real time. We found that SmoM2 expression in the ear epidermis induces a stereotypical pattern of cell competition with clonal expansion leading tumor initiation and invasion. In contrast, SmoM2 expression in the back skin epidermis led to a similar clonal expansion that induces lateral cell competition but without inducing dermal invasion and tumor formation. Single cell analysis showed that oncogene expression is associated with a cellular reprogramming of adult interfollicular cells into embryonic hair follicle progenitor (EHFP) state in the ear but not in the back skin. Comparison between ear and back skin epidermis revealed a very different composition of the dermis with increased stiffness and a denser collagen 1 network in the back skin. Decreasing Collagen 1 expression in the back skin overcame the natural resistance of these cells to undergo EHFP reprogramming and tumor initiation following SmoM2 expression. Altogether our study demonstrates that ECM composition controls the mode of clonal competition and competence to undergo oncogenic transformation upon oncogene expression.
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Overall design |
FACS isolated keratinocyte CD34- YFP+ cells from K14CreER/Rosa-SmoM2-YFP mouse; FACS isolated keratinocyte CD34- Alpha6+ cells from CD1 mouse (Epidermis) / Separation of dermis by mechanical process from epidermis(Dermis)
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Contributor(s) |
Blanpain C, Bansaccal N, Song Y, Sarate R |
Citation(s) |
37968399 |
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Submission date |
Mar 23, 2023 |
Last update date |
Nov 24, 2023 |
Contact name |
Yura Song |
E-mail(s) |
yura.song@ulb.be
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Organization name |
Université Libre de Bruxelles
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Lab |
Laboratory of Stem Cells and Cancer
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Street address |
808, route de Lennik
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City |
Bruxelles |
ZIP/Postal code |
1070 |
Country |
Belgium |
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Platforms (1) |
GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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Samples (8)
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GSM7113240 |
BackSkin Wildtype with GEX library |
GSM7113241 |
BackSkin Wildtype with CellPlex library |
GSM7113242 |
BackSkin SmoM2 induced 3weeks keratinocytes |
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Relations |
BioProject |
PRJNA947920 |