Boosting Innovative Organoid Co-Culture Models to Identify Therapeutic Targets in Pancreatic Ductal Adenocarcinoma

• Grant number: 25/02899-8
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2025
• End date: August 31, 2027
• Field of knowledge: Biological Sciences - Biology
• Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
• Principal Investigator: Pedro Luiz Porfirio Xavier
• Grantee: Pedro Luiz Porfirio Xavier
• Principal researcher abroad: Daniel Öhlund
• Institution abroad: Umeå University, Sweden
• Host Institution: Faculdade de Zootecnia e Engenharia de Alimentos (FZEA). Universidade de São Paulo (USP). Pirassununga , SP, Brazil
• Associated researchers: Fabiana Fernandes Bressan ; Heidge Fukumasu ; Talal Jamil Qazi
• Associated research grant: 22/06305-7 - Identifying new therapeutic targets in Pancreatic Ductal Adenocarcinoma by combining relevant models and approaches, AP.GR

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) remains one of the most challenging types of cancer, largely due to the lack of targetable pathways and the failure of preclinical data to translate into clinical efficacy. To address this, we started an ambitious project to identify new therapeutic targets and develop first steps of an innovative oncolytic virus-based therapy for PDAC, supported by the FAPESP Generation Program (2022/06305-7). This project is based on three major scientific and technical challenges, one of which involves the establishment of sophisticated and physiological cell culture models of PDAC, such as tissue-specific 3D models and organoids. Here, to further enhance our Generation Project, we propose a mobility project (SPRINT) to strengthen the collaboration with Prof. Dr. Daniel Öhlund at Umeå University. This collaboration will enable us to deeply learn and refine PDAC organoid co-culture, besides brainstorming the findings generated in our ongoing assays. This SPRINT project is based on three missions: 1) in the first mission, two researchers will visit the Wallenberg Center for Molecular Medicine at Umeå University to learn and discuss advanced 3D organoid co-culture models developed by Dr. Öhlund's group. We will learn and discuss key aspects for the establishment and characterization of these models, including I) methods for collecting murine tumor tissues; II) protocols for dissociating patient-derived tissues; III) optimizing organoid culture medium composition; IV) assays for characterizing phenotypic effects in organoids. Additionally, we will discuss the initial findings from our collaboration with Dr. Öhlund, on KRAS inhibition in PDAC organoids. 2) In the second mission, Dr. Öhlund will visit the Laboratory of Comparative and Translational Oncology (LOCT-FZEA/USP), to observe our models and experimental approaches. We will present and show how we are developing the High-Content (HCS) three-dimensional (3D) PDAC Screening Platform in our group and allow him to assess how these models could be integrated into the HCS platforms developed by his group. Furthermore, this mission will be fundamental to discuss key points including I) depth strategies to overcome challenges in the implication of these models in HCS platforms and drug development; II) appropriate visualization of 3D structures with automated imaging systems; III) ensure compatibility with liquid handling systems. 3) Finally, in the third mission, two researchers will visit the Wallenberg Center for Molecular Medicine at Umeå University to discuss and establish collaborations on developing stromal cells, including stellate, multiple types of Cancer-Associated Fibroblasts, endothelial, and immune cells through reprogramming human fibroblasts. Some key points will be discussed including I) protocols for reprogramming fibroblasts; II) protocols to induce differentiation; III) protocols to characterize the different types of reprogrammed cells; IV) single cell analysis to define the heterogeneity of Tumor Microenvironment in the organoid co-culture models. Thus, this mission can open new avenues for integrating these co-culture models into our laboratories, enhancing the identification of potential therapeutic targets for PDAC. Thus, we aim for this Brazil-Sweden collaboration to develop state-of-the-art discovery of drug targets and establishment of innovative technologies, substantially contributing to the oncology field in Brazil and worldwide. Moreover, we intend to foster new relevant collaborations to our project, creating opportunities for graduate students to work with Dr. Öhlund and other renowned researchers from Umeå University. (AU)