Comparing pediatric and adult cancer progression and therapy response

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Developing 3D in vitro models of basal cell carcinoma

Publication . Pacheco, Maria Ana Grade Simões; Sánchez-Danés, Adriana

Abstract Basal cell carcinoma (BCC) is the most common human cancer. It is a skin cancer that accounts for more than 5 million new cases each year. BCC is caused by either Smoothened (Smo) or Patched1 (Ptch1) loss of function which constitutively activate the Hedgehog signalling (Hh) pathway. Even though this malignancy is predominant in adulthood, Gorlin Syndrome is characterised by the early onset of multiple BCC lesions at puberty because patients carry a germline mutation in Ptch1 gene. Since BCC mostly affects adults but can also impact children, it was considered the ideal model for comparing paediatric and adult cancer, which is one of the main lines of interest of the Sánchez-Danés laboratory. Despite remarkable progress in BCC treatment, the lack of effective treatments for paediatric patients, who often experience severe long-term side effects when subjected to adult therapies, underscores the need for an in vitro model that can faithfully mimic both paediatric and adult BCC and could be used as drug screening platform. To date, there were no currently available 3D in vitro models for BCC that enabled the study of paediatric and adult cancers underlying biology and response to therapy, due to the difficulty of maintaining BCC cells in culture. This thesis aimed to address this gap by developing a suitable model for studying the differences between paediatric and adult BCC. To this end, we used two complementary strategies: (1) development and characterization of BCC-derived organoids and (2) development and characterization of a murine-derived 3D BCC skin reconstruct model. Our results showed that BCC-derived organoids from juvenile and adult mice successfully recapitulated the BCCs in situ. Specifically, juvenile BCC tumours and the corresponding organoids were bigger and less differentiated, when compared to their adult counterparts. Despite the successful generation and characterization of the BCC organoids, we decided to take our research a step further and developed a 3D skin model to study dermal-epidermal interactions within the context of BCC. Notably, this model provided valuable insights, as it demonstrated that BCC cells could be maintained in a 3D structure and exhibit key characteristics of in vivo BCC tumours, including invasion into a dermis-like layer, cluster formation, limited differentiation, and active proliferation. Nevertheless, these promising findings, it is essential to validate these models further with larger sample sizes to enhance the reliability of our conclusions. These two innovative models developed in this project represent not only valuable tools for studying the differences between paediatric and adult BCC, but also hold great potential as drug screening platforms, offering hope for improved therapeutic strategies for Gorlin syndrome patients

2023-12-05Dissertação de mestrado

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Entidade financiadora

Fundação para a Ciência e a Tecnologia

Programa de financiamento

3599-PPCDT

Número da atribuição

PTDC/MED-ONC/5553/2020