(Disponível em Português)
What do the most common skin cancer and one of the most common pediatric brain tumours have in common? The two may seem unrelated, but in fact, they are both triggered by the same genetic mutations.
Adriana Sánchez Danés, the newest member of the research faculty at Champalimaud, aims to investigate these two types of cancer and understand the differences and commonalities between them, with the ultimate goal of developing novel therapeutic means to treat them.
To learn more about her previous work on this topic and how she plans to pursue it further, we had an online chat with her from her apartment in one of Lisbon’s most charming neighbourhoods, Campo de Ourique.
Before arriving at the Champalimaud Centre for the Unknown, you made a scientific breakthrough by identifying a novel treatment for inoperable Basal Cell Carcinoma. Can you tell us about that?
I did my postdoctoral training at the lab of Cédric Blanpain in Brussels, who is a leading figure in epithelial stem cell and cancer biology research. While I was there, I focused on the most common skin cancer, which also happens to be the most common human cancer – Basal Cell Carcinoma.
Fortunately, most Basal Cell Carcinoma cases are easily treatable because the tumours can be surgically removed. However, some are inoperable, when, for example, the tumour is near the eye, or the nose. Instead of surgery, these patients undergo targeted drug therapy.
However, in the majority of inoperable cases, even though the tumour shrinks upon treatment, when the treatment is stopped the tumour comes back. No one understood why this was happening and so we decided to try to identify the population of cells that were resisting the treatment and causing relapse.
To study this question, we first generated Basal Cell Carcinoma in mice models and then treated them with the same drug patients receive (vismodegib). We observed that there were little groups of cells that persisted throughout the treatment in the skin of these mice. These cells were dormant during the treatment period. However, upon treatment discontinuation, the dormant cells started to proliferate, leading to tumour relapse.
What was special about these dormant cells?
Many of the normal functions of cells happen through chains of molecular interactions called ‘molecular signaling pathways’. These pathways lead to various outcomes, such as cell proliferation. Basal Cell Carcinoma occurs when a specific molecular signaling pathway called Hedgehog, which plays an important role during embryonic development, gets into an uncontrollable ‘hyperdrive’. In fact, vismodegib, the drug that inoperable Basal Cell Carcinoma patients receive, specifically blocks the Hedgehog pathway.
The dormant tumour cells that we found in our mice models [and later on also in patients suffering from advanced basal cell carcinoma treated with vismodegib], had another signalling pathway that was abnormally active: the Wnt pathway. This pathway is known to govern numerous normal cellular and developmental processes such as cell fate determination, cell proliferation, and migration.
We decided to target these dormant tumour cells using a Wnt inhibitor, and found that by combining Wnt and Hedgehog inhibition we were able to eliminate the persisting tumour lesions in our mice models. This combined approach led to tumour eradication in the majority of the cases, indicating that these dormant cells were responsible for relapse in Basal Cell Carcinoma. I must say that it was really exciting to identify a combination of drugs that was already available in clinics that led to the eradication of resisting tumour cells and avoid tumour relapse in the most frequent human cancer.
Do you think this discovery could be used to treat patients in the near future?
Yes, I think so. Actually, the two drugs that block the Hedgehog and Wnt pathways have already been developed. Vismodegib has been used to treat cancer patients for around a decade. The Wnt inhibitor we used was initially developed to treat other types of cancers. Our study demonstrated that it could also be used for something they didn’t originally think about – to treat Basal Cell Carcinoma patients.
The pharmaceutical company that developed the Wnt inhibitor is currently working on formulating it as a cream to be topically applied in the skin of patients. In our body, various cells require the activation of the Wnt pathway for normal function, for example, in the intestine. So when this drug is taken orally, it leads to many adverse secondary effects, such as intestinal problems. Topical application would overcome some of the side effects observed upon systemic Wnt inhibition.
Will you continue with this line of research at your new lab at the Champalimaud Centre for the Unknown?
Yes, I will keep on working on Basal Cell Carcinoma and open another line of research on Medulloblastoma, a pediatric brain tumour. I found it extremely interesting that the same genetic mutations [in the Hedgehog pathway] lead to the formation of the most common adult cancer [Basal Cell Carcinoma] and to the formation of one of the most common pediatric brain tumours [Medulloblastoma]. In the lab we aim to uncover how these two tumour types differ from each other or resemble each other in terms of tumour initiation, progression and response to therapy.
More specifically, one arm of the lab will identify the different populations of tumour cells present in Basal Cell Carcinoma, with the goal of uncovering the role of these populations in cancer progression and response to treatment. This, in turn, will help us achieve our final goal, which is to promote tumour regression and cure patients. I believe that our collaboration with Ana Fidalgo, who is the Head of the Dermatology Unit at the Champalimaud Clinical Centre, will be key to successfully develop this research.
The second arm will be dedicated to Medulloblastoma. Here too we will be studying the mechanisms that drive Medulloblastoma initiation,progression and response to therapy. The establishment of this line of research happened naturally as a synergy between the knowledge in neurobiology I acquired during my PhD, paired with the expertise in cancer biology that I had developed during my postdoc. [During my PhD I developed an in vitro model that was able to recapitulate the neurodegeneration that occurs in the brain of Parkinson’s Disease patients]. This research venue will immensely benefit from collaborating with the well-recognised neuroscientists of Champalimaud Research, such as the teams of Megan Carey and Leopoldo Petreanu, as well as with medical specialists such as José Maria Bravo Marques, who is a Clinical Neurologist at the Champalimaud Clinical Centre.
We intend to pursue these projects by combining methods such as genetic lineage tracing, clonal analysis, imaging and functional experiments in vivo and in vitro in genetic mouse models. We also plan to grow tumour organoid cultures derived from both mice and human tumour cells, which can be used for faster drug screening platforms and genetic manipulation.
You were recruited under a European Commission Horizon 2020 project called QuantOCancer, can you tell us about that?
QuantOCancer is a project that has several pillars. One of them is to recruit the “ERA Chair Holder”, a principal investigator that will establish a new lab at the Champalimaud, that’s me. The other parts focus on helping the institution to grow in different aspects, such as human resources and data management. Another goal is to implement cancer research that bridges fundamental and applied approaches at the institution. The Champalimaud Centre for the Unknown is an excellent setting for this goal since we work in close proximity to the clinicians of the Champalimaud Clinical Centre, which is a clinical facility for the treatment of oncologic and neuropsychiatric diseases, translational research activities and advanced educational programmes.
It has been great to be the ERA chair holder because it helped me set the lab much faster. For one, it allows you to have a critical mass of people already when you start the lab. Also, the support of Laura Ward, who is the QuantOCancer project manager, and Raquel Gonçalves, who provides lab administrative support, has made a big difference. They have been extremely helpful, as were all Champalimaud faculty members. To name a few, Henrique Veiga-Fernandes, Eduardo Moreno, Christa Rhiner, Bruno Costa-Silva and Celso Matos [who is also responsible for the QuantOCancer Project].
I arrived quite recently, in October 2019. Things have been advancing slowly, especially now with the pandemic. Still, it wasn’t too bad because, during the lockdown, I ended up being very proficient. I wrote a couple of grants, ethics protocols, and more. But of course, I am looking forward to returning full time to the Champalimaud Centre for the Unknown to continue building my lab and pursuing my research questions.
Edited by: Catarina Ramos, CCU Communication Team.