Centre for Cancer Cell Reprogramming (CanCell)

CanCell aim to identify the "Achilles' heels" of cancer cells and design methods to target these in a way that the cancer cells will be "reprogrammed" into harmless cells. The center uses advanced methods such as light- and electronmicroscopy, genome- editing and sequencing, cloning, model organisms and cell lines to map what distinguishes the biology of cancer cells from normal cells. The center includes six research groups with different expertise with research activities located at the Institute for Cancer Research and the Institute for Medical Basic Sciences. In addition, the center collaborates closely with national and international experts in other fields. CanCell published 41 articles in 2023 in international journals of high reputation. CanCell MSc/PhD course, Molecular cancer medicine, was completed with good participation and with strong efforts by CanCell junior researchers as teachers. CanCell researchers have achieved several important breakthroughs in 2023, all resulting from collaborations between CanCell groups. One of the centre’s main activities during the first phase has been to conduct large-scale screening of cancer cells to identify their vulnerabilities. One of the strategies is to use combinations of known drugs in order to find synergies that reduce side effects and resistance development. To this end, researcher Robert Hanes in Enserink’s group has developed a bioinformatics tool, “screenwerk”, which helps scientists fo design and implement screens with combinations of drugs (Bioinformatics). This project was a collaboration between Enserink’s group and two of CanCell associated members, bioinformatics expert Eivind Hovig and biostatistics expert Manuela Zucknick. Screenwerk is expected to prove highly useful for both CanCell researchers and other researchers implementing screens with combinations of drugs. In addition to screening for drug sensitivity CanCell researchers also perform genetic screens of cancer cells and map the protein networks of cancer cells. All these types of screens result in lists of proteins or genes that might be of interest for more detailed studies, and part of the challenge is to choose which candidates are most relevant. To address this, CanCell researcher Sigve Nakken in Eivind Hovig’s group, in collaboration with Wesche’s group, has developed a program, oncoEnrichR, which provides a structured and user friendly anslysis report from a list of candidates from any screen with emphasis on cancer relevance (International J. of Cancer). A cellular process known as autophagy (self eating) is important in cancer biology since it protects us against cancer under normal conditions but can also promote cancer progression once a cancer has been initiated. The autophagic process commences with a membrane that encloses parts of the cells’s cytoplasm to form a so-called autophagosome. The autophagosome then fuses with a lysosome, which contains degradative enzymes, and this leads to degradation of the autophagosome’s content. The origin of the autophagosome membrane is still not known, but researcher Viola Nähse in Stenmark’s group has identified an enzyme, DFCP1, which plays an important role in the biogenesis of the autophagosome membrane (Nature Comm.). It turns out that DFCP1 is particularly important for selective autophagy of damaged mitochondria and micronuclei, which contributes to prevent cancer development. This study was a collaboration between Stenmark’s group and the group of CanCell associate member Terje Johansen, an expert in selective autophagy. Lysosomes play an important role in autophagy and other cellular degradative processes, and they are therefore of great importance in cell biology. Because their content is toxic to the cell if released, it is interesting in cancer research to destabilize the lysosome membranes of cancer cells in order to cause cancer cell death. Several drugs are known to have such properties, and it has been shown that cancer cell lysosomes are more vulnerable to damage than the lysosomes of normal cells, suggesting lysosome-induced cell death as a viable strategy in cancer therapy. However, it has turned out that damaged lysosome membranes can be repaired, and researcher Maja Radulovic in Stenmark’s group has uncovered a mechanism for lysosome repair that entails transport of lipids from the endoplasmic reticulum to the damaged lysosome membrane (EMBO). Since this is an enzymatic process, it is possible to inhibit it pharmacologically, which opens new opportunities for enhancing the effect of drugs that cause lysosome-mediated cancer cell death. This study was a CanCell collaboration between Stenmark’s and Simonsen’s groups and involved Jäättelä group in Copenhagen (members of CanCell Scientific Advisory Board). Postdoc Namrita Kaur in Alf Håkon Lystad’s project group has been studying another cellular response to lysosome damage (EMBO). This project was a collaboration between the CanCell groups of Stenmark and Simonsen

A worldwide effort to identify genetic and epigenetic aberrations in cancer has yielded tremendous amounts of information that offer unprecedented opportunities for cancer diagnosis and therapy. A major obstacle to translating this information into clinical benefit is our incomplete understanding of the molecular mechanisms by which irreversible genetic aberrations and reversible epigenetic modifications affect tumour cells, and how the tumour microenvironment and somatic tissues promote cancer progression. CanCell's vision is to form a world-class centre that elucidates changes in cellular pathways which are rewired during cancer development, defined as "cancer cell programmes", including cell signalling, metabolism, membrane dynamics, and genome/chromatin organisation. The centre's unique strategy is to reveal cross-talk between these programmes via close cooperations between leading experts on the individual processes. Due to the complexity of cancer cell programmes, resolving their impact on cancer progression requires the close integration that can only be achieved within a dynamic research centre with tightly interwoven research projects. Innovative methods and collaborations with a strong interdisciplinary team of associate members and world-leading visiting professors will further enhance the impact of CanCell's research. In vitro models with cultured cells and in vivo models with fruit flies, zebrafish and mice will be used to recapitulate cancer progression in individual cells and in organisms, with special emphasis on tumour-microenvironment interactions. These integrated analyses will identify novel oncogene and non-oncogene addiction pathways that cancer cells are particularly dependent on for their growth, spreading and survival, thus exposing "Achilles' heels" of cancer. This will be exploited for "reprogramming" cancer cells into non-malignant cells in vitro and in vivo to pave the way for novel cancer therapies.