Desenvolvimento de um modelo ex vivo de cancro de mama triplo negativo num chip: uma ferramenta para explorar novas vias de intervenção terapêutica

The BeMIC project, a consortium between the i3S and IPO-Porto, addresses the critical need for innovative treatment strategies and personalized medicine approaches in triple-negative breast cancer (TNBC), a subtype associated with poorer prognosis and limited treatment options. Leveraging advanced ex vivo preclinical models, the project aims to develop a cutting-edge alginate-based vascularized organoid-on-a-chip platform tailored to the unique characteristics of TNBC. We hypothesize that personalized and well-defined cancer models can improve the accuracy of predicting patient-specific responses to breast cancer treatment, potentially leading to more effective and targeted therapies. Advanced ex vivo preclinical models better replicate the in vivo tumor biology and their microenvironments, offering a promising approach for developing and testing new therapies. The primary objective of the project is threefold: 1. Development of Patient-Derived TNBC Organoids in Tunable Alginate Matrices: The project aims to create patient-derived TNBC organoids within a precisely controlled and adaptable alginate 3D matrix, developed in collaboration with i3S and IPO. By biofunctionalizing hydrogels to dynamically adjust mechanical properties, the objective is to mimic the evolving extracellular matrix (ECM) conditions during tumor progression. This approach will enable the transition of cell-laden constructs from stiffness levels resembling healthy breast tissue to those characteristic of tumor-like environments, facilitating a more accurate representation of TNBC biology. 2. Establishment of a Vascularized Microfluidic Device: The project intends to establish a microfluidic device featuring vessel-like channels that can be perfused with customizable flow rates. This innovative platform will enhance the physiological relevance of TNBC organoid models by enabling the establishment of vascular networks essential for long-term organoid viability and functionality. 3. Generation of Vascularized TNBC Organoids for Personalized Cancer Models: By combining patient-derived TNBC organoids with the vascularized microfluidic device, the project aims to overcome the limitations of traditional organoid models, particularly the absence of vasculature. The resulting vascularized TNBC organoids will offer a more physiologically relevant platform for studying tumor-tumor microenvironment (TME) interactions and exploring personalized cancer treatments. Once established, this model will enable comprehensive investigations into the tumor cell response to various therapies, particularly focusing on the impact of radiation therapy (RT) alone or in combination with immunotherapy (IT). The project objectives include examining how different radiation schemes influence tumor immune profiles and exploring the synergistic effects of radiotherapy and immunotherapy. Furthermore, the project aims to develop personalized cancer models with enhanced predictive capabilities. Leveraging advanced organoid models, the project will evaluate patient-specific responses to treatment, potentially optimizing individualized regimens to improve cancer management and patient care, especially in cases of treatment-resistant malignancies. The collaborative efforts between i3S and IPO will ensure the translation of scientific discoveries into innovative clinical applications, ultimately benefiting TNBC patients.