In pancreatic ductal adenocarcinoma (PDAC), the most common and deadliest form of pancreatic cancer, pancreatic cancer cells drastically reprogram nearby normal fibroblasts – cells that normally maintain tissue structure and repair – to become cancer‑supporting “cancer‑associated fibroblasts” (CAFs). These CAFs dominate the tumour mass and help fuel growth and metastasis, whilst also probably playing a role in treatment resistance. Understanding how fibroblasts and cancer cells interact is the focus of exciting new research funded by Pancreatic Cancer UK, and led by Dr Giulia Biffi and Professor Richard Gilbertson at Cambridge University:
Fibroblasts in healthy pancreas versus tumour environments
In a healthy pancreas, fibroblasts construct and stabilise the extracellular matrix, producing collagen, glycoproteins, and other scaffolding molecules. They help maintain proper architecture and respond to injury through controlled wound-healing responses.
In contrast, in PDAC, pancreatic cancer cells hijack these fibroblasts – often through secreted signals like TGF‑β, PDGF, IL‑1 and FGF – to transform them into CAFs. These activated cells proliferate, remodel the tumour microenvironment (for example, by secreting collagen-rich stroma), support tumour growth, enable immune evasion, and inhibit drug penetration.
CAFs as both tumour promoters and treatment resistors
CAFs contribute to tumour progression in multiple ways:
- They deposit extracellular matrix proteins that create a physical barrier, restricting chemotherapy delivery and creating hypoxic conditions conducive to tumour aggressiveness.
- They secrete pro‑tumour growth factors (VEGF, FGF, PDGF), inflammatory cytokines, and chemokines that promote angiogenesis, invasion, and immune suppression.
- Some CAF subsets shield cancer stem‑cell populations, help maintain their “stemness,” and protect them from chemotherapy or immunologic attack.
It is precisely this mechanism that makes CAFs a very promising avenue for exploring new therapies for pancreatic cancer.
The challenge: identifying key signalling signals
Cancer cells communicate with CAFs – and with other tumour cells – through cell signalling, using chemical messengers (growth factors, ligands, cytokines). However, the tumour microenvironment is highly complex. Many signals are exchanged, not all are essential drivers. So far, distinguishing the “driver” signals (which promote tumour progression) from “passenger chatter” has proved extremely difficult, making it hard to prioritise which signalling axes should be targeted to really disrupt tumour growth:
Pan‑tumour CAF similarities hint at shared biology
Interestingly, recent studies – including work from Dr Giulia Biffi’s lab – have shown that similar groups of CAFs appear in both pancreatic and lung cancers. This implies that cancer cells in different organs may co‑opt fibroblasts in a similar fashion, using conserved signalling programs to advance disease. This is an important discovery, as if the same fibroblast subtypes and signalling cues appear across tumour types, those shared pathways may be particularly useful therapeutic targets.
Goals and Methods of the New Cambridge Study
Funding awarded in 2025 to Dr Biffi (Biffi Group) and Professor Gilbertson (Gilbertson Group) at Cambridge University supports a study aimed at:
- Profiling cell signalling in:
- Primary pancreatic cancers,
- Primary lung cancers,
- Pancreatic cancer metastases located in the lungs.
- Using advanced computer modelling to sift through large datasets of these three tumour types – identifying which signalling pathways, especially those involving CAFs, are consistently active in cancer progression across all contexts.
- Prioritising conserved fibroblast‑involving signalling cues predicted by the model to be the most critical for tumour growth.
- Experimentally testing the effects of disrupting those signals in a mouse model of pancreatic cancer – aiming to see if blocking them slows tumour progression, reduces metastasis, or improves response to treatment.
What this means for patients with metastatic pancreatic cancer
Pancreatic cancer frequently spreads to the lungs, liver, and other organs, and metastatic PDAC is notoriously difficult to treat. If this study identifies shared CAF‑dependent signalling pathways active in both primary pancreatic tumours and metastases (especially to the lungs), therapies targeting those pathways could potentially be effective even after metastatic spread.
In mouse models, if disrupting such pathways slows tumour growth or improves survival, those signals could become the basis of drug development efforts. Ultimately, the goal is to develop new treatments that target CAF‑tumour interaction, complement standard chemotherapy, and improve outcomes for patients with metastatic PDAC, which at the moment are pretty abysmal.
This new study is an exciting step forward in the ongoing battle against pancreatic cancer. By targeting the tumour ecosystem itself, it offers hope for interventions that may finally make a dent in one of the most devastating cancers.
