Universidade do Algarve | 12h00 | Auditorium 1.8.1
Title: “Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts”
Abstract: Cancer is as unique as the person fighting it. With the exception of a few biomarker-driven therapies, patients go through rounds of trial-and-error approaches to find the best treatment. Using patient-derived cell lines, we show that zebrafish larvae xenotransplants constitute a fast and highly sensitive in vivo model for differential therapy response, with resolution to reveal intratumor functional cancer heterogeneity. We screened international colorectal cancer therapeutic guidelines and determined distinct functional tumor behaviors (proliferation, metastasis, and angiogenesis) and differential sensitivities to standard therapy. We observed a general higher sensitivity to FOLFIRI [5-fluorouracil(FU)+irinotecan+folinic acid] than to FOLFOX (5-FU+oxaliplatin+folinic acid), not only between isogenic tumors but also within the same tumor. We directly compared zebrafish xenografts with mouse xenografts and show that relative sensitivities obtained in zebrafish are maintained inthe rodent model. Our data also illustrate how KRAS mutations can provide proliferation advantages in relation to KRASWT and how chemotherapy can unbalance this advantage, selecting for a minor clone resistant to chemotherapy. Zebrafish xenografts provide remarkable resolution to measure Cetuximab sensitivity. Finally, we demonstrate the feasibility of using primary patient samples to generate zebrafish patient-derived xenografts (zPDX) and provide proofof- concept experiments that compare response to chemotherapy and biological therapies between patients and zPDX. Altogether, our results suggest that zebrafish larvae xenografts constitute a promising fast assay for precision medicine, bridging the gap between genotype and phenotype in an in vivo setting.
Short Bio: Rita Fior is Developmental Biologist, fascinated by how cells interact with each other, to deliver instructions, to collaborate, to compete or synchronize their actions. During her PhD, under the supervision of Prof. Domingos Henrique, Rita Fior studied the Notch downstream events that control the balance between neural differentiation and progenitor maintenance (Fior and Henrique, 2005; 2009) and generated an unstable Notch reporter to study Notch signalling in real-time (Fior et al, 2011). For the Pos-doc, the researcher established a collaboration between Leonor Saúde (IMM, PT) and Julian Lewis (FRS, CRUK) and found a transcription based negative feed-back loop that allows the coordination between 3 major events during zebrafish segmentation: differentiation, cell movement and stem cell maintenance (Fior et al, 2012, Cutty, Fior et al, 2011). Recently, became interested in CANCER. This turn in his scientific interest started building up, when she realized that there are several chemotherapy treatments options, but no available test to determine the best therapy for each individual patient. In 2014, Rita teamed up with Miguel Godinho-Ferreira to develop a new in vivo test for personalized medicine using the zebrafish-xenograft model. They challenged the model to test if it could reveal inter- and intra- tumor heterogeneity and screened the CRC international therapy guidelines (Fior et al, 2017). Future work is aimed at validating this model in clinical studies to test predictability of the assay (GI and Breast cancer). In addition, Rita Fior would like to explore the cellular interactions that occur during innate tumor rejection/evasion. During his research career, have been involved in teaching in several PhD editions of the IGC and PGCD (Cape Verde) programs as well as Master programs (FCUL, FML) and a Developmental Biology Master course at the FCT, UNL (2010-2016). Recently, she was invited to design and lecture a new course in Cell and Molecular Biology of Cancer in the Faculty of Science, University of Lisbon (2016- ) where development, evolution and clinical perspectives are mixed together in a series of seminars.