21 Defining the cell populations responsible for skin cancer initiation and relapse following therapy

Abstract

IntroductionThe identification of specific cell type from which cancer arises and the cancer cell population that resists upon therapy leading to tumour relapse constitute the main topics of our research. We use the basal cell carcinoma (BCC), the most frequent cancer in humans, as a cancer model for our studies.Material and methodsWe used lineage tracing approach to elucidate the cell at the origin of BCC and study the cancer cell population responsible for relapse following therapy discontinuation.Results and discussionsTo uncover the cancer cell of origin in BCC and the changes in the cellular dynamics that lead to tumour initiation, we assessed the impact of oncogenic hedgehog signalling activation in distinct cell populations and their capacity to induce BCC. We found that only stem cells, and not progenitors, were competent to initiate tumour formation upon oncogenic hedgehog signalling. Interestingly, this difference was due to the hierarchical organisation of tumour growth in oncogene-targeted stem cells, characterised by an increase of symmetric self-renewing divisions and a higher p53-dependent resistance to apoptosis, leading to rapid clonal expansion and progression into invasive tumours.11 Sánchez-Danés A, Hannezo E, Larsimont JC, Liagre M, Youssef KK, Simons BD, Blanpain C. Defining the clonal dynamics leading to mouse skin tumour initation. Nature. 2016 Jul 8;536(7616):298–303. doi: 10.1038/nature19069To study the cancer cell population that mediates BCC relapse upon therapy, we treated two different genetic BCC mouse models with a Smoothened inhibitor (Smoi), the most commonly drug used to treat locally advanced and metastatic BCC. The mechanism by which Smoi leads BCC regression and emergence of resistant tumour cells are currently unknown. We found that Smoi mediates BCC regression by promoting epidermal differentiation and that during the course of Smoi administration, some BCC become resistant to therapy mimicking the situation found in humans. We identify Lgr5 as a marker expressed in the resistant tumour cell population upon Smoi administration.Finally, we demonstrate that combination of Smoi administration with Lgr5 lineage ablation leads to BCC eradication.ConclusionWe demonstrated that stem cells cells are competent to initiate basal cell carcinoma, whereas, committed progenitors resistant.We demonstrated that Smoi administration in combination with Lgr5 lineage ablation leads to BCC eradication, constituting a clinically promising approach to overcome resistance to therapy and cure BCC.