CAFs and cross-talk – a recipe to close the gap on pancreatic cancer?

Cancer associated fibroblasts (CAFs) have garnered a lot of interest over their potential as a therapeutic target. And while pre-clinical studies have been promising, there has been little success in human clinical trials.

However, for Giulia Biffi, a Junior Group leader at the CRUK Cambridge Institute, this is even more reason to dig into the complexity of the tumour stroma. Not least of all because she works on pancreatic cancer, a disease characterised by tumours with an extensive non-malignant stroma microenvironment.

And Giulia’s team at Cambridge have certainly created a shift in how we now think about these fibroblasts in pancreatic cancer – a disease recognised as one of the six cancers of unmet need by Cancer Research UK.

And it’s the tackling of the complexity of cancer head on that is so key to improving patient outcomes in a disease that has five-year survival figures below 10% says Giulia.

“We think that by deconvoluting the complexity of this cancer, we will be able to design tailored combinational therapies and diagnostic strategies for patients. Our lab’s goal is to tackle this heterogenous and complex cancer. To do so, we must start considering it, modelling it and treating it as multiple cancers.”

It’s clear that early on in her research career Giulia is making her mark in this field. “Importantly, our initial work in CAF heterogeneity in pancreatic cancer has boosted interest from academia and industry,” she says. Already this year her lab is revealing new discoveries and reinforcing the fact that deeper understanding of CAF complexity is crucial.

“We demonstrated that a subset of myofibroblast CAFs considered to be tumour-restricting, can also be metastasis-promoting.”

Another advancement Giulia and her team are making relates to cell-stroma cross talk and therapeutic susceptibility. “We are particularly excited about a growing area in the lab focusing on how co-operation of distinct mutations in pancreatic malignant cells profoundly impact malignant cell-stroma crosstalk and therapeutic sensitivities,” she says. “We have recently found that loss of SMAD4, which occurs in about a third of patients, differently impacts pancreatic tumours based on the type of KRAS mutation they carry.”

Sheer passion and ambition

So, why dedicate a career to pancreatic cancer research? “I want to make a diagnosis of pancreatic cancer less scary than it is today. I want to give patients options that, at the moment, they don’t have.”

“I went to university and studied Biology to become an ethologist – the study of animal behaviour. Sadly, cancer touched my life during my second year when someone close was diagnosed with cancer and passed away. The cancer took away her love for life before taking her life, and I still struggle thinking about that,” she says.

“I was thus faced with the choice to either continue my path or dedicate my passion and life to cancer research. I chose the latter.”

Giulia carried out her PhD at the CRUK Cambridge Institute, although in a very different field from the one she is in now. But it is that difference, that multi-disciplinary nature of her career which she says has been pivotal to her current work. “I think being in a chemistry-based lab influenced me to become interested in understanding cell-cell interactions and signalling mechanisms almost at the molecular level. So, from my PhD to post-doc was when I chose pancreatic cancer as my focus.”

As her research on the cross talk between pancreatic malignant cells and fibroblasts develops, Giulia also stresses the importance of moving from a map to a manual.

“It has been incredibly rewarding to observe how our initial work on CAF heterogeneity has initiated an expanding excitement and hype for this area. However, to get there, it is now important for the field to go beyond the description of this heterogeneity and move towards its functional understanding.”

“Indeed, discrimination between ‘’drivers’’ of the disease and ‘’passengers’’ reprogrammed by the malignant cells will be key, and we are working on this” she says.

So, what’s next?

Giulia knows that to get benefits to patients will mean translation of her work into some form of clinical intervention. However, she also knows that deep understanding needs to come first.

“Unless we fully understand the impact of targeting specific signalling pathways both intra-tumoral and systemically, we will not be able to design effective therapeutic strategies,” she says.

“While there may be the desire to rush through translational development, I think we are yet to fully understand the cell-cell interactions within the tumours, beyond malignant cell-fibroblast crosstalk, and how they affect the host and vice versa. And, importantly, the role therapies play to shape this balance.”

With pancreatic cancer being such a complex and heterogeneous disease, it brings with it unique challenges. Challenges which she thinks could yield with a wide array of expertise focused on them. “Since, naturally, we cannot all be experts in everything, successful targeting will require cross-lab, multi-collaborative efforts to tackle this,” she says.

“My goal is to be able to arrive at a point where we can predict how tumours will respond to a treatment in order to counteract the potential negative effects of that treatment from the start.”