2D cancer cell line models have historically facilitated drug discovery efforts in cancer chemotherapies, but these systems often poorly model drug responses in patients. 3D culture models, such as multicellular tumour spheroids and patient-derived organoids, more accurately reflect the tumour microenvironment, with spatially distinct cell phenotypes reflective of differentiation, nutrient, drug and oxygen gradients, and the presence of hypoxia and necrosis. These make more representative models, with the drawback that they are less accessible to conventional screening techniques. Incorporating elements of the TME in these models, such as cancer-associated fibroblasts (CAFs), represents a step forward for modelling of cancer-TME interactions and enables more realistic simulation of drug responses in patients.

As part of the Innovation for Translation Research Group (ITRG) under Prof Tim Underwood and Dr Zoe Walters, I studied interactions between the cancer cells and their tumour microenvironment in oesophageal adenocarcinoma (OAC) and built complex 3D cancer models containing OAC organoids and CAFs. I have designed wholemount immunofluorescence methodology to non-destructively image these interactions in 3D (Figure 1) (1). Next-generation models of the TME will improve our understanding of TME-driven mechanisms of resistance and could be used to design new treatment regimes that target the TME in addition to the cancer cells, improving chemotherapy efficacy.

Going forwards, I am looking to set this system up with collaborators in order to model other diseases, including HPV-infected tonsils modelling early squamous cell neoplasia, and soft tissue cancers of the gastrointestinal tract.

References

1. Patient-Derived Tumor Organoid and Fibroblast Assembloid Models for interrogation of the tumor microenvironment in Esophageal Adenocarcinoma. Benjamin P. Sharpe, Liliya A. Nazlamova, Carmen Tse, David A. Johnston, Rhianna Blyth, Oliver J. Pickering, Ben Grace, Jack Harrington, Rushda Rajak, Matthew Rose-Zerilli, Zoe S. Walters, Tim J. Underwood. bioRxiv 2024.01.02.572565; doi: https://doi.org/10.1101/2024.01.02.572565