The biology of upper GI cancers

Focus of research

As a PhD candidate at the University of Amsterdam, I studied cell motility and Hedgehog signaling in developmental contexts, but also in cardiovascular disease. Landmark contributions from this work include the proof that the inhibitory sterol-transporting capacity of the receptor Patched1 regulates Hedgehog pathway activity (Bijlsma et al. PLoS Biology 2006). In addition, we were first to establish the functional uncoupling of the transcriptional and the chemotactic Hedgehog signaling, as was known for the Wnt pathway (Bijlsma et al. Stem Cells 2008). My postdoctoral work at UC Berkeley resulted in the discovery of previously unrecognized Hedgehog signaling events that mediate axon guidance in advanced models for neuronal development (Bijlsma et al. Science Signaling 2012). Also, we developed a species-specific RNA-Seq analysis on mixed-species tumor cocultures which allowed us to untangle tumor-stroma crosstalk events critical to tumor growth (Damhofer et al. Mol Oncol 2013).

This training has allowed a smooth transition to cancer biology upon taking up my position as a group leader at the AMC. Ongoing research in my group focuses on the tumor cell biology that drives the aggressive growth of pancreatic, esophagogastric, and colon cancer with the ultimate aim to improve their treatment. Specifically, topics studied are:

 1) How the non-epithelial fraction, or stroma, in gastrointestinal cancer contributes to aggressive tumor cell behavior, and whether this tumor-stroma interaction can be monitored non-invasively and be targeted (Ebbing et al. PNAS 2019). We aim to identify which signals mediate critical tumor-stroma crosstalk, and whether we can use this to target tumor growth and drug resistance. In addition, we develop blood-borne markers to stratify patients for stroma-targeting treatments.

2) It is known that mesenchymal cell and tissue states in cancer contribute to poor outcome, and my group has identified and functionally addressed the vulnerabilities of these mesenchymal subtypes in gastrointestinal cancer tissue, as well as in patient-derived experimental models for these malignancies (Ebbing et al. Gastroenterology 2017).

3) Furthermore, my team has delineated the mechanisms that drive transient mesenchymal cell states in gastrointestinal cancers, most notably in esophageal cancer. These topics are highly interconnected with each other, but also with my previous graduate and postdoctoral work. I am currently expanding this work to study how metabolic reprogramming pertains to the topics currently covered in my group. Related to this are our studies on cellular plasticity in healthy, premalignant, and cancerous pancreas.

4) The lethality of pancreatic cancer relies on the presence of so called cancer stem cells. Current tools to identify these cells have serious shortcomings. Together with the Vermeulen group, we have adapted tracing methods to trace the offspring of a single cell in tumors grown from these cells. These allow us to study the population of cancer stem cells that are thought to contribute to pancreatic cancer growth (Lenos et al. Nat Cell Biol 2018)

Models used in my group range from cell culture systems, mouse experiments, biobanking and the analysis of predictive and prognostic markers and profiles in large cohorts. Most of these have been generated through our live biobanking. I have founded the AMC biobank pancreatic carcinoma – BioPAN and co-coordinate the esophageal BiOES biobank. For these biobanks we accrue and store blood samples, tissue, and clinical data. Analyses on these materials include expression profiling and measurements of serum markers. BioPAN closely collaborates with the nation-wide PancreasParel biobank of which I am the coordinator, and the AMC-VUmc Liquid Biopsy Center that I co-head. Our expression profiling efforts have enabled us to identify subgroups of patients that differ in their clinical outcome and other clinically important parameters. 

A long-standing strength of our hospital has been to effectively bring biomedical knowledge to the clinic, most notably in the field of gastroenterology. Our aims align perfectly with this; to put fundamental science to work and actually improve patient outcomes. Importantly, the above efforts are now also coming to fruition beyond the typical dissemination through publications, and findings from my group are currently being developed into investigator-initiated trials (BASALT trial).