“The tumor microenvironment enormously affects cancer cells”

“We are a university and conduct research in the pursuit of knowledge.” It is important to URPP co-director Maries van den Broek to adhere to this maxim. That’s why the primary contribution by UZH researchers in the URPP Translational Cancer Research consists of gaining a “really good understanding of what happens in cancer,” she says. Many aspects of cancer pathogenesis are still not understood, she explains, such as why cancer cells migrate and form metastases in some people but not in others.

Bridge between basic research and clinical practice
“When we conceptualized the URPP 12 years ago, there was hardly any dialogue between those conducting basic research at UZH and the clinics at University Hospital Zurich that treat cancer patients,” van den Broek recounts. Each domain worked on its own behalf, indeed very well, but not in an interconnected way. “We searched specifically for people who were interested in engaging in close cooperation to gain a better understanding of the different processes involved in oncogenesis and cancer progression,” van den Broek relates. A fruitful collaboration was established together with the departments of dermatology, hematology, oncology, pathology and neurology at University Hospital Zurich.

Successfully invested in postdocs
To put together the network, the URPP consortium invested the funds it received from UZH mainly in postdoc positions, a biobank and an mRNA platform. The postdoctoral researchers were supervised and mentored in their work by basic researchers at UZH and by clinical researchers, which paid off in spades. “That enabled us to achieve our goal of building a bridge between basic research and clinical practice,” van den Broek says with evident pleasure and pride. “A network made up of a wide array of basic researchers at UZH and specialists at the clinics at University Hospital Zurich exists today.” Van den Broek is confident that this network will continue to launch joint research projects even after the URPP winds down.

One particularly successful achievement from the collaboration between clinical practitioners and researchers is a new therapeutic strategy that was further developed and refined in the URPP. It will undergo safety testing in a Phase 1 clinical trial this year. That is a “a great accomplishment for a medical URPP,” co-director Van den Broek stresses.

Numerous publications
The URPP Translational Cancer Research brought forth 184 publications jointly authored by basic researchers and clinical practitioners. “That’s really very many, and none of them would have come into being without the URPP,” van den Broek says. But “it naturally takes a very, very long time” before approaches to how to personalize and improve chemotherapies, immunotherapies or targeting therapies against cancer begin to take shape from that research.

How cancer cells infiltrate tissue
During the course of the URPP, the researchers, for example, employed different methods in an attempt to gain a better understanding of the cancer cell metastasis process. Using C. elegans (a species of nematode) as a model organism, for instance, they looked into the question of how cells are able at all to break loose from their cluster and invade other tissue. And by means of in vitro screening, they examined biobank samples to ascertain which features of a cancer cell are predictive of response to therapy. A fundamental understanding of which types of cancer cells tend to metastasize and how they do that is needed in order to eventually be capable of manufacturing inhibitor molecules that block the spread of metastasizing cancer cells, van den Broek explains.

What during the last 12 years surprised the co-director of the URPP Translational Cancer Research? “How heterogeneous cancer is,” van den Broek replies. It, of course, is known today that cancer can vary from person to person, she says. “But cancer cells in tumors, for example, are also very heterogeneous within a single person. That’s surprising, and it makes it a tough challenge to understand the various processes that occur inside a tumor.”

Van den Broek was also surprised by how much the tumor microenvironment affects how well a therapy works or how rapidly cancer cells grow or spread. Besides cancer cells, the tumor microenvironment also consists of healthy cells such as blood vessel cells, immune cells, and fibroblasts and is tremendously dynamic, which is why its appearance constantly changes. “We still know very little about the factors that affect the composition of the tumor microenvironment,” van den Broek says.

Van den Broek feels certain that cancer research in the Zurich area would not have advanced into the premier league without the URPP. “We’re a player on the international stage and are a sought-after collaboration partner,” co-director van den Broek says, adding that it’s a remarkable accomplishment for a university in tiny Switzerland, where for many studies too few patients are available and data protection regulations are strict.

The interlinkage of basic research and clinical practice will remain in place after the URPP Translational Cancer Research ends. Alongside the motivation roused in cancer researchers in a broad sense by the URPP, the following three continuations will contribute to perpetuating that cooperation.

Comprehensive Cancer Center Zurich
The URPP Translational Cancer Research gave birth to the Comprehensive Cancer Center Zurich (CCCZ), a patient-oriented oncology center of excellence jointly operated by the University of Zurich, University Hospital Zurich, Balgrist University Hospital and University Children’s Hospital Zurich. The CCCZ pools expertise in cancer medicine and cancer research in Zurich, enabling it to provide top-notch holistic, interdisciplinary cancer patient care that incorporates the latest research findings. The CCCZ will also conduct clinical trials and develop new technologies with the goal of providing improved therapy concepts to fight cancer. Its research priority is on precision medicine that makes it possible to diagnose cancer more precisely and provide personalized patient treatment.

Biobank with clinical samples
During the course of the URPP, a group of researchers led by cancer biologist Mitchell Levesque and pathologist Holger Moch created a live tumor cell biobank that uses a proprietary protocol to collect a wide array of live tumor cells and preserves them in liquid nitrogen and archives the corresponding molecular and clinical data (such as the therapy history). In addition, all of the cancer samples in the biobank undergo genome sequencing; their genetic mutations are thus known. “A biobank of such high quality is unique,” van den Broek says. The samples can be used to propagate primary cell lines for research purposes. Thousands of samples are sent to scientists around the world each year. Van den Broek says, “The demand is huge. The biobank has given us international visibility.”

Messenger RNA (mRNA) platform
In addition, a group of researchers led by immunologist Steve Pascolo built an mRNA platform that will continue to operate after the URPP ends. The desired mRNA can be produced quickly and inexpensively in the laboratory. Once it is introduced into cells (in vitro or in vivo), it can be used to manufacture therapeutic proteins against cancer (cytokines, antibodies, etc.) or to make CAR-T cells.

Steve Pascolo has been researching mRNA since 1998 with the goal of developing innovative therapies to treat cancer and other diseases. The mRNA platform cooperates with a variety of national and international research groups that wish to obtain specific mRNA molecules for research purposes.