Among the 28 awardees are two CanCell PIs, Harald Stenmark and Ragnhild Eskeland, a CanCell affiliated PI, Kay Oliver Schink and a CanCell project leader Leonardo Meza Zepeda. In addition, Aurelie Belanger from associate member Phillippe Collas’ group has also received a grant in this cycle. We congratulate all the groups and wish them success.
EPICSARC: Targeting Epigenetic dysregulation in Sarcoma
A discovery based screen for Epigenome-targeted therapy Liposarcoma -
Soft-tissue sarcomas are a group of rare and aggressive tumors with around 500 cases diagnosed in Norway each year. One of the most common soft-tissue sarcomas is Liposarcoma which is a malignant tumor originating in the fat tissue. Patients with LPS have generally a low survival rate and despite some advances in treatment, standard resection followed by chemotherapy/radiation prevails. It is now well established that a combination of genetic and epigenetic events can drive the onset and progression of tumours. A better understanding of these epigenetic aberrations is needed to improve Liposarcoma patient outcomes.
EPICSARC is a basic research project that aims to map these epigenetic aberrations and identify Liposarcoma targets to help identify future therapies and improve treatment responsiveness. EPICSARC's goals include exploring Liposarcoma cell weaknesses by testing responsiveness to epigenetic drugs and conducting a genetic knockdown of epigenetic modulators. EPICSARC is a highly multidisciplinary and collaborative project that will enable development of future personalised cancer treatment.
Simaphagy against cancer
Hyperactive receptor signalling is recognized as one of the hallmarks of cancer, and a wide selection of drugs are used clinically to dampen such hyperactivity. With the advent of precision cancer medicine, the utility of receptor-directed therapies is likely to increase further, but the frequent occurrence of acquired drug resistance calls for additional therapeutic strategies.
Whereas mitogenic receptor signalling was originally thought to be transmitted from the plasma membrane only, more recent research has shown that intracellular signalling from endosomes is equally important. Specifically, as long as activated receptors are situated in the limiting membrane of endosomes, they can transmit mitogenic signals, and signalling terminates when the receptors are removed from the limiting membrane by inclusion into intraluminal vesicles (ILVs) that bud into the endosome. This terminates signalling, and when the resulting multivesicular endosome fuses with a lysosome, which is loaded with hydrolytic enzymes, both the receptor and its ligand become degraded.
Stenmark’s group has previously been characterizing a mechanism for endosomal downregulation of receptor signalling, which involves ligand-induced ubiquitination of the receptor and its recognition by a molecular machinery known as endosomal sorting complex required for transport (ESCRT). The ESCRT machinery, which consists of the four subcomplexes ESCRT-0, -I, -II and -III, recognizes ubiquitinated receptors in the limiting membrane of the endosome, sequesters the receptors into membrane microdomains that contain the coat protein clathrin, and sorts the receptors into ESCRT-triggered ILVs. Thereby, the ESCRT machinery is involved in negative regulation of receptor signalling.
But what happens if ESCRT-mediated receptor silencing fails, as occurs frequently in cancers? The group has recently addressed this issue by identifying proteins that are recruited to endosomes with defective sorting functions. Using proximity based protein biotinylation in conjunction with proteomic analyses, the CanCell scientists have found that two so-called autophagy receptors, SQSTM1 and NBR1, are strongly recruited to endosomes whose only defect is that the ESCRT-0 subunit HRS is mutated so that it does not bind clathrin. Autophagy, self-eating, is a catabolic process used by the cell to degrade harmful or superfluous cytoplasmic content, such as microorganisms, protein aggregates, or non-essential or damaged organelles. Autophagy receptors are cellular proteins that label cytoplasmic objects for autophagy, and recruit the autophagic machinery to such objects. Their recent findings have led Stenmark’s group to propose that autophagy of dysfunctional endosomes, which they term simaphagy (from Greek, sima=signal, phagia=eating) may act as a failsafe mechanism that kicks in once endosomal receptor sorting fails (see Figure). The present proposal is designed to explore the mechanisms of simaphagy, its involvement in cancer, and its potential in precision oncology.
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"Drink or drive" - Regulation of cell invasion and metastasis in micropinocytosis
Almost all cancer-related deaths are not caused by the primary tumor, but by metastases that form from cells that migrate from the primary tumor and colonize other organs where they can form new tumors. Why some cells in a tumor decide to leave and migrate to new organs to form metastases is only poorly understood. In this project, we will investigate what causes a tumor cell to migrate and form metastases. One of the potential triggers for cell migration is the availability of nutrients. Tumors are often poor in nutrients, and many cancer cells often take up additional amino acids by a process called macropinocytosis or "cell drinking". Macropinocytoe also regulate the migration of cells, and cells often "drink" nutrients or migrate ("drive") in a process called "Drink or Drive". In this project, we will investigate why cells decide to migrate and form metastases. We will test whether low nutrients are a triggering factor for cells to switch to invasive cell migration, and how cells sense whether they have enough nutrients. We will identify key proteins that regulate this process and investigate how they function, which will allow us to identify potential drug targets.
GIST risk, improving precision medicine for patients with gastrointestinal cancer
In the era of precision medicine, treatment using a tyrosine kinase receptor inhibitor (TKI) has been very successful in gastrointestinal stromal tumors (GIST). Current therapy for patients with a high risk of relapse and metastatic disease is based on imatinib, a TKI directed against hyperactive KIT or PDGFRA pathways, the oncogenic drivers of the disease. In a localized setting, adjuvant treatment is recommended for three years for high-risk patients. However, 40% of the patients relapse within three years after stopping adjuvant treatment. In a metastatic situation, most patients show an initial treatment response, but then the tumor evolves and develops resistance through diverse mechanisms, some of which are poorly understood. Thus, there is a need to avoid the progression and development of resistance. GIST-Risk aims to improve patient stratification of high-risk GIST to control the disease better and, through investigational studies, reveal novel therapeutic vulnerabilities in GIST undergoing imatinib treatment. We will validate chromosomal instability as a prognostic biomarker for localized high-risk GIST to provide a better stratification of high-risk GIST that may benefit from additional therapy (WP1) and, through biological studies, reveal novel dependencies for progression and resistance in GIST (WP2 and WP3). These will be essential for the better management and treatment of GIST patients.
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Investigating the role and prognostic value of core lamin isoforms in breast cancer
Breast cancer is the second deadliest form of cancer in women. Breast cancer consists of abnormal cells that grow and divide permanently instead of dying over a period of time, as normal cells usually do. The cells contain a nucleus, which is a small egg-shaped structure that acts as the brain of the cell and contains our genes. The nucleus is protected by a shell containing components called lamin. There are different families of lamins, which can protect the nucleus and genes, but also participate in transmitting messages from inside and outside the cell. In many cancers, lamin no longer fulfills its function correctly, and we already know that this can be due to a change in the number or molecular variant of lamin. Because lamin family members are not sufficiently identified today, it can be difficult to measure the number and variant. In this research project, we will identify all the family members of lamin and count them in breast cancer tumors. We will also decide which family members protect the core. Finally, we will identify which family members contribute to malignant breast cancer.