Our research: Lars-Gunnar Larsson Group
Our research focuses on the function and regulation of the MYC oncoprotein. Our aim is to utilize this knowledge to find ways to target MYC directly or indirectly in tumor cells.
Function, Regulation and Targeting of the Myc Protein
Our research focuses on the function, regulation and targeting of the MYC oncoprotein. The MYC oncogene family encodes transcription factors that regulate a vast number of genes involved in cell growth, apoptosis, metabolism, differentiation, senescence, stemness and other cellular functions. Deregulated expression of MYC contributes to the development of over half of all human cancers, and often correlates with advanced stages of disease, resistance to therapy and poor prognosis. Our research addresses questions on how MYC cooperates and interacts with other factors to regulate gene transcription and how this affects biological processes of relevance for tumor development. We are also interested in how MYC’s function, activity and stability is regulated through interaction with such factors. Finally, we are utilizing these insights into strategies to target MYC directly or indirectly in tumor cells. For these purposes we are utilizes a toolbox of different methodologies and tumor systems based on cell culture and mouse models.
MYC is modified at several sites by phosphorylation, acetylation and ubiquitylation, and these modifications affect MYC function, including its interaction with cofactors and its rapid turnover via the ubiquitin/proteasome pathway. We are trying to dissect the functional role of these modifications and interactions, and how they affect MYC-driven tumor development.
It has recently become clear that MYC interacts with hundreds of proteins in the nucleus, and these interactions probably affect MYC’s function and activity, for instance with respect to chromatin structure, the different phases of the transcription cycle, RNA processing, DNA repair, replication and functions. However, this has only been explored for a handful of interactions, and we are particularly interested in the role of interactions with kinases and their inhibitors, in particular CDK2 and p27, chromatin modifiers like EZH2, BMI1 and SIRT1, as well as E3 ubiquitin ligases like SKP2, FBXW7 and FBXO28. We have evidence that yet other E3 ligases participate in MYC ubiquitylation and are dissecting the specific roles of each of them play and their relation to each other.
To study and possibly target MYC-cofactor interactions, we have established several cell-based protein-protein interactions assays, such as Bimolecular Fluorescence Complementation (BiFC), split Gaussia luciferase assays (GLuc), in situ Proximity Ligation Assay (isPLA), where such interactions can be visualized in living or fixed cells and tissues.
The role of MYC during tumor development
While MYC is involved in many cellular processes, we have during recent years become interested in MYC’s role in the regulation of cellular senescence, one of the main barriers of tumor development. We found that MYC suppresses senescence induced by oncogenes like RAS and BRAF, and that this is an important part of the cooperation between these genes during oncogenic transformation. Further, we discovered that the cell cycle kinase CDK2 plays an important role during MYC-mediated repression of senescence, and that this requires phosphorylation of MYC at Ser-62 by CDK2. Importantly, inhibition of CDK2 by small molecule inhibitors induced senescence in MYC-driven tumor cells in culture and in vivo in mouse tumor models.
To study the importance of senescence suppression for tumor development in vivo we have established conditional, transgenic, immunocompetent mouse lung and melanoma tumor models driven by MYC and BRAFV600E as well as acute myeloid leukemia (AML) mouse models driven by MYC and BCL-XL and MYCN-driven neuroblastoma. At present we are studying the impact of CDK2 depletion/inhibition on senescence and tumor development in these models as “pro-senescence therapy”.
One important aspect of the senescent cell state is the senescence-associated secretory phenotype (SASP), which involves production and secretion of cytokines and chemokines that communicate with cells of the adaptive and innate immune systems with the purpose to eliminate the senescent cells. We are currently using the lung, melanoma and neuroblastoma model systems to dissect the interaction between senescent tumor cells and immune cells with the aim of exploring potential synergies between senescence and immune therapies for cancer treatment.
Despite the urgent need to target MYC in cancer, MYC has been considered “undruggable” due to its intrinsically disordered structure and lack of enzymatic activity, and for this reason there are no specific MYC drugs available in the clinic for cancer treatment at present. There are several potential ways of targeting MYC directly and indirectly. As mentioned above, MYC is dependent on interactions with different cofactors. We have identified and characterized several potent and selective small molecule inhibitors of the interaction between MYC and the obligatory cofactor MAX. These bind directly to MYC and inhibit MYC-dependent gene regulation, tumor cell growth and tumor development in vivo in mouse models while sparing normal cells, and improved analogues of these molecules are developed currently. The protein interaction assay systems we have developed can also be used to identify inhibitors of other MYC-cofactor interactions. The long-term aim of this work is the development of new drugs for cancer treatment.