We really need to further unpick the complexity of cancer-associated fibroblasts if we want to improve radiotherapy outcomes says Anna Wilkins. Here she talks about the hope and the challenges of taking on this component of the tumour microenvironment in bladder cancer.
In patient tumours, we see a striking association between enrichment in cancer-associated fibroblasts (CAFs) pre-radiotherapy and poor outcomes.
This has been a consistent observation using both AI approaches to analyse routine H&E samples in rectal cancer and transcriptomic analysis in bladder cancer. To me, it’s a fascinating association because we’ve known for decades that radiation generates dose-limiting fibrosis in many normal tissues, but the biology of tumour fibrosis and radiation hasn’t been unravelled in detail.
To begin to gain this understanding, I think there are two important questions: Firstly, how do CAFs in the tumour microenvironment before radiation contribute to the poor outcomes we see after radiation; Secondly, how are CAFs reprogrammed during radiation – in the context of the wider tumour microenvironment – to impact radiotherapy responses?
It looks as though CAFs contribute to both immune and non-immune mechanisms of tumour cell survival during radiation.
It’s an exciting time to be addressing these questions as CAF heterogeneity is a rapidly advancing field, in part because of recent technical advances in highly multiplex immunofluorescence and spatial transcriptomics. These powerful technologies mean we can, with single cell resolution, specifically address which CAF subtypes are most relevant to radiotherapy responses and how they are signalling in the wider tumour microenvironment.
We have clues from previous work that direct CAF-tumour cell crosstalk involving the MAP kinase pathway, as well as signalling via focal adhesion kinase/β1 integrin, may be important. There’s also a detailed literature pointing to a radiation-induced increase in transforming growth factor beta (TGFβ). This TGFβ can drive increased extracellular matrix production by CAFs and the trapping and suppression of effector immune cells away from tumour cells.
So, it looks as though CAFs contribute to both immune and non-immune mechanisms of tumour cell survival during radiation. Only a deeper mechanistic understanding of this will provide targets to combine with radiation in the clinic.
And that is what I am hoping to achieve – in my case in the context of bladder cancer, a tumour type that has historically been somewhat neglected in research. The UK has been a global leader in the development of curative bladder radiotherapy so there are mature clinical trials with samples we are able to interrogate. The particular benefit of radiotherapy in this context is that it enables patients to avoid radical cystectomy i.e. surgical removal of their bladder, a major operation with life-changing consequences.
Credit: Dr Anna Wilkins |Cancer Research UK