In Autumn 2019 Marten Hornsveld (Postdoc at Deptartment of Cell and Chemical Biology, LUMC) visited the Department of Oncology – Pathology at Karolinska Institutet (KI) in Stockholm. During the four-month exchange stay within the framework of Eurolife Early Career Researchers program Marten studied signal transduction pathways in pancreatic cancer associated fibroblasts. The Eurolife grant of 7.500 euro was funded by the Directorate of Research Policy, LUMC.
Both detection and treatment of pancreatic cancer are obstructed by cancer associated fibroblast (CAFs) in the tumor microenvironment. Marten aims to uncover how CAFs support tumor growth and how to target supportive CAFs for therapeutic benefit, using human pancreatic tumor organoid co-culture models in the lab of prof. Peter ten Dijke (dept. CCB, LUMC). The PDGFRβ and TGFβ molecular signal transduction pathways are heavily involved in CAF regulation within the tumor microenvironment. Marten worked with Prof. Arne Östman at the KI and Rudbeck laboratory of the Uppsala University in Sweden to explore promising targeting strategies of PDGFRβ and TGFβ pathway interplay in pancreatic CAFs.
In 2019 I was awarded a Eurolife scholarship by the Directorate of Research Policy, LUMC. This fellowship of 7.500 euro provided me with the opportunity to join forces for 4 months with prof. Arne Östman and dr. Carina Strell at the Dept. of Oncology & Pathology, Karolinska Institutet in Stockholm and the Rudbeck laboratory of the Uppsala University in Sweden. Together with these tumor microenvironment experts, I set out to identify clinically relevant properties of the pancreatic tumor microenvironment.
Pancreatic cancer is difficult to diagnose, hard to treat and only curable when high-risk radical surgery is part of the treatment strategy. 5-year survival is only 9% in The Netherlands and incidence is rising. In contrast to almost all other cancer types, therapy efficiency has marginally improved in recent decades. Hence, there is an urgent need for innovative therapeutic opportunities, either targeting cancer cells, or as we do, by focusing on the tumor microenvironment. Up to 90% of pancreatic tumor-content is the desmoplastic tumor microenvironment known as stroma, which predominantly consists of cancer-associated fibroblasts. This stroma can interfere with therapy by obscuring cancer cells during diagnosis and surgery, obstructing drug delivery, repressing immune infiltration and providing metabolic support to pancreatic cancer cells. An important reason for the lack of clinical advancement is that the molecular and cellular determinants dictating clinically relevant stromal properties are unclear.
To better understand pancreatic tumor stroma, I set up novel 3D organotypic mini-tumor models containing patient derived pancreatic cancer organoids and pancreatic stellate cells, the main source of pancreatic cancer-associated fibroblasts. These models resemble the heterogeneity of pancreatic cancer pathology and provide the complexity required to understand how cancer-associated fibroblasts interact with cancer cells. With this Eurolife scholarship we were able to exchange my experiences with organoid technology and modeling the tumor microenvironment via multiple seminars and lectures at Karolinska Institutet, SciLife and the Uppsala University. On the other hand, I was able to learn about the pathology and histology of pancreatic tumor stroma and familiarize myself with state-of-the-art fluorescent multiplex histological analysis.
During my 4-months visit in Autumn 2019 and Winter 2019/2020, we identified two clinically relevant populations of pancreatic cancer-associated fibroblasts and set up a novel 9-marker Vectra Polaris multiplex histology platform to functionally characterize these fibroblast subtypes in patient cohorts. Back at the LUMC, I now recreate these clinically relevant subtypes of fibroblasts in my pancreatic mini-tumor models to study how these fibroblast subtypes interact with cancer cells. With this we aim to uncover molecular stromal properties which we can exploit for better treatment. This Eurolife scholarship therefore sparked a long-term interdisciplinary collaboration between the LUMC (specifically the research group of Peter ten Dijke), Karolinska Institutet and Uppsala University aiming to provide basis for improved pancreatic cancer therapy. In addition, the exchange further established the collaboration between Peter ten Dijke (LUMC) and Arne Östman (Karolinska Institutet), who jointly organized the Eurolife Summer School entitled ‘Molecular Mechanisms in Cancer – Translating Discoveries into Personalised Therapies’, hosted by LUMC in 2018.