Benchmarking human tissue culture systems that mimic the tumor microenvironment

Grant number: 2021/41/B/NZ7/03786 Funded by:

National Science Centre

Project description:

Personalized cancer medicine (PCM) is one of the most active fields of biomedical research. The potential is immense: Experimental models for ex vivo chemotherapy testing could allow better informed, evidence-based and more effective cancer therapy decisions, improving the often poor outcome especially of advanced cancer patients. This would contribute to reducing patients┬┤ quality of life, by avoiding ineffective therapies with systemic side effects, or help discover novel drugs as anti-cancer therapies. It might be expected that the most representative in vitro models for PCM might provide the highest predictive potential for clinical purposes. However, overly complex model systems may hamper the development of informative, reproducible assay formats in practice. It remains unclear which of the currently available in vitro model systems faithfully represents the nature of the original tumor tissue, its intra-tumor heterogeneity, cellular composition, histology and genetic complexity. Only some of these components may be required to provide maximally informative, predictive readout. As a result of our incomplete knowledge, no in vitro assays are currently established or officially recommended for clinical practice. Their true predictive value remains poorly validated. This collaborative, inter-disciplinary project will fill this gap of fundamental knowledge. We will thoroughly characterize and compare the cellular and genetic composition of various tumor models with each other, and with the original tumor. We will focus simultaneously on cancer cells and non-transformed components the tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs), endothelial cells and immune cells. We will use single-cell sequencing, combined with microfluidics technologies developed at University of Warsaw (UW) and a bioinformatics analysis pipelines performed by ICHF PAN; and a selection of relevant ex vivo model systems developed at the Medical University of Lublin (UMLUB). The models under scrutiny include patient-derived organoids (PDO), patient-derived explants (PDE), zebrafish avatars, and engineered microtissues. At a later stage, we will further include selected Organ-on-a-chip approaches (OoC) and microfluidics devices, which may gain broader use in upcoming years. We will also use droplet microfluidics to develop well-characterized model systems, based on detailed knowledge concerning the tumor heterogeneity. The duration of this project (4 years) will allow us to retrospectively compare chemotherapeutic responses in the models with clinical patient outcome; and evaluate the true predictive value of our models for clinical needs. We will focus on head and neck squamous cell carcinomas (HNSCC); a frequently aggressive tumor type with poor response to chemo- and radiotherapies. This results in early relapse, progression, formation of local and/or distant metastasis, and death of approx. 50% of the cancer patients within 2-5 years after diagnosis. HNSCC is further characterized by a limited spectrum of clinically approved therapies, which severely restricts options for patients and clinicians. Identifying novel, efficient therapies is an outstanding, unmet clinical need.