Information about our current SARS-CoV-2 research below under research topics
MYC-dependent metabolic vulnerabilities
We study different possibilities to exploit synthetic lethal interactions in drug discovery and recently, we have focused on MYC-dependent metabolic vulnerabilities. This particularly interesting cancer vulnerability is tightly linked to a conserved cellular energy sensing pathway controlled by a protein kinase AMPK. Another line of enquiry is related to the role of limited proteolysis in regulation of epithelial integrity-dependent survival of breast epithelial cells. In these studies, we focus on the type II transmembrane serine protease hepsin.
We study cells in three-dimensional (3D) context using different extracellular matrices as scaffolds for reconstruction of mammary gland specific structures. In these 3D culture studies, we use epithelial cell lines and ex vivo primary epithelial cells. In addition, we have established a 3D culture platform for patient-derived breast cancer explants (PDEX) using specific scaffolds that preserve breast tumor cell function and identity. For in vivo validation, we use different immunocompetent in vivo models of breast cancer, including GEMMs and syngraft models. In addition, we study drug responses in patient-derived xenograft (PDX) models of breast cancer.
Cancer therapeutic strategies
We are currently testing several lead therapeutic intervention strategies related to cancer cell metabolism and apoptosis in our collection of preclinical in vitro, ex vivo and in vivo models of breast cancer, hoping to translate soon our scientific discoveries to clinical investigation and ultimately, to benefit of a cancer patient.
For more information contact the lab head Juha Klefstrom. For open positions in the lab, click here.
Pharmacological intervention of SARS-CoV-2 entry mechanisms by blockade of TMPRSS activity
“Hepsin/TMPRSS family members do not only promote cancer invasion, but they also help the coronavirus SARS-CoV-2 to infect cells”
Normally, epithelial cells are separated from neighboring tissues by a blanket- or sheet-like basement membrane. However, when cancer arises the overactive cell surface serine proteases damage the basement membrane. This enables cancerous epithelial cells to invade neighboring tissues, and ultimately metastasize to distant sites. Many cancer-promoting cell surface serine proteases belong to the Hepsin/TMPRSS family.
Interestingly, recent evidence suggests that the hepsin/TMPRSS family members not only promote cancer invasion, but they also help the coronavirus SARS-CoV-2 to infect cells. This may lead to the life-threatening COVID-19 coronavirus disease. The Klefström laboratory has been identifying and developing chemical and pharmacological inhibitors against hepsin/TMPRSS family members for a long time with the goal of preventing cancer invasion. Some of our drugs or drug-like molecules could be repurposed to prevent SARS-CoV-2 entry to the cells, potentially offering a fast-track treatment option for the COVID-19 disease. We are currently testing a number of hepsin/TMPRSS family-targeting drug-like molecules and drugs as potential antivirals as weapons in the battle against coronavirus.
Damalanka VC, Han Z, Karmakar P, O’Donoghue AJ, La Greca F, Kim T, Pant SM, Helander J, Klefström J, Craik CS, Janetka JW.
J Med Chem. 2019 Jan 24;62(2):480-490. doi: 10.1021/acs.jmedchem.8b01536. Epub 2019 Jan 4.
Pant SM, Mukonoweshuro A, Desai B, Ramjee MK, Selway CN, Tarver GJ, Wright AG, Birchall K, Chapman TM, Tervonen TA, Klefström J.
J Med Chem. 2018 May 24;61(10):4335-4347. doi: 10.1021/acs.jmedchem.7b01698. Epub 2018 May 14.
Pant SM, Belitskin D, Ala-Hongisto H, Klefström J, Tervonen TA.
Methods Mol Biol. 2018;1731:169-178. doi: 10.1007/978-1-4939-7595-2_16.
Tervonen TA, Belitškin D, Pant SM, Englund JI, Marques E, Ala-Hongisto H, Nevalaita L, Sihto H, Heikkilä P, Leidenius M, Hewitson K, Ramachandra M, Moilanen A, Joensuu H, Kovanen PE, Poso A, Klefström J.
Oncogene. 2016 Apr 7;35(14):1832-46. doi: 10.1038/onc.2015.248. Epub 2015 Jul 13.
Immunogenic Cell Death (ICD) in Breast Cancer
Immune checkpoint (IC) inhibitors have revolutionized cancer treatment by offering treatment options for previously incurable forms of cancer. However, IC inhibitor monotherapy is not effective against so-called ‘non-immunogenic’ cancers, such as breast cancer. Thus, a clear unmet medical need exists to increase effectiveness of immunotherapy in such cancers. One way to trigger an immune reaction against “non-immunogenic” tumours is induction of immunogenic cell death (ICD), which activates the innate immune system through release of danger-associated molecular patterns (DAMPS). For example, some types of chemotherapy induce ICD through cytotoxic effects, which elicits an immune response that is subsequentially often dampened through upregulation of checkpoint ligands. However, chemotherapy often has quite severe adverse effects that negatively impact quality of life. Therefore, a major opportunity in cancer treatment is to identify more cancer-specific, less toxic alternatives to induce ICD, which is the aim of this project.
Now we will screen a library of candidate cancer drugs in several breast cancer ICD-reporter cell lines we created. To shorten the time to clinical application, a chemical libraries containing approved and emerging investigational drugs will be used. The most promising candidates will be studied in vitro (in cell lines and in monocyte-derived dendritic cells (MDDCs)), ex vivo (in PDEC) and in vivo.
Targeting MYC-dependent metabolic vulnerabilities
MYC is an oncogene and a transcription factor that is overexpressed in over 40% of breast cancers (Haikala et al., 2017). MYC supports cancer cell division by promoting cell cycle progression, and by switching cell metabolism to serve growth-promoting metabolism. MYC activation induces a metabolic switch characterized by enhanced glucose and glutamine utilization as well as by instructing the normally ATP- generating citric acid cycle to serve biosynthetic reactions. We found that the metabolic changes induced by MYC lead to decreased production of ATP and the consequent activation of a key cellular energy sensor protein AMP-activated kinase (AMPK) (Nieminen et al., 2013). We also found, that MYC-induced AMPK activity makes the cells more sensitive to apoptotic cell death, providing important new insight into the close connections between the MYC oncogene, cell death sensitivity and cancer metabolism.
Furthermore, we study how the altered metabolism-derived sensitivity to apoptosis could be exploited as a potential therapeutic strategy to kill cancer cells. We have discovered novel synthetic lethal and combination therapy- based approaches to harness MYC’s full apoptotic potential to pharmacologically activate apoptotic cell death in cancer cells (Haikala et al., 2016, Haikala et al., 2017).
How loss of epithelial Integrity promotes cancer?
In order to properly perform their function, epithelial tissues need to maintain a pre-defined architecture. This structure is built via the localization and polarized orientation of the cells that constitute the tissue. Classical examples of epithelial tissues include skin with important barrier function and secretion glands, for example, milk producing mammary gland.
If the structurally organized epithelial cells lose contact with the rest of the structure or polarized orientation, this will affect to their ability control proliferation or cell death regulation. These defects in epithelial integrity can lead to tissue malfunction and development of epithelial pre-cancerous lesions or full-blown cancer.
Specific cell signaling circuitries are responsible for providing cues that help epithelial cells to organize into tissue structures. We aim to understand how cancer gene mutations affect to these signaling pathways in a way that predisposes the epithelial tissues to development of breast cancer.
For more information about this resaerach line, see
Microenvironmental management of mammary cell fate determination
Cancer cell lines have been proven to be a valuable source of information for drug discovery process, but their limitations have been increasingly recognized. Culturing cells in 2D conditions will cause a lack of original complexity and heterogeneity of the tumor in situ. Chemicophysical cues from the surrounding stroma and cell- cell /cell- ECM interactions are also lacking from 2D cultures. This tumor-stroma interaction is particularly important since it affects cell signaling, proliferation, cell survival, and therefore has an impact on drug sensitivity and responses. For these reasons there has been an increasing interest in creating artificial models by implanting malignant tissues in three-dimensional culture systems and bioreactors. The advantage of these systems (patient derived ex vivo, pdex) is that the conditions are more controllable, they allow higher throughput studies, shorter time to achieve results with lower costs, and free of experimental animal use. In the past several years, a tremendous effort has been put into a development of 3D culture systems and adopting them in drug discovery, cancer cell biology, and stem cell studies. The biggest challenges of 3D models are to maintain the viability of tumor samples in long term cultures and preventing them for changing their cellular identity, and the overall heterogeneity of the original tumor during culture period. We have developed in collaboration with molecular material specialists from Aalto University a novel cellular identity preserving 3D model, which we are using to reveal those fundamental molecular mechanisms regulating cellular identity in mammary gland and in breast cancer. Realizing both the chemical and mechanical properties of microenvironment, which are constantly been altered through tissue remodeling (proliferation, apoptosis, migration), affects directly gene expression profiles, opens up new research directions to design new approaches in cancer research but also for regenerative medicine, developmental, and cell biology.
Targeting protelytic activity that alters tumor microenvironment and cell autonomously promotes tumor growth
Our recent investigations have exposed a role for tumor suppressor LKB1 in maintenance of cell junction integrity in mammary epithelial cells. Loss of LKB1 damages tight junctions and desmosomes, which leads to redistribution of proteins that normally reside in desmosomes, including a transmembrane serine protease hepsin. The redistributed hepsin inflicts damage to basement membranes, thus paving a way to dissemination of cancerous cells (Partanen et al PNAS 2012).
Type II transmembrane serine protease hepsin is overexpressed and redistributed in clinical breast cancer samples, although the HPN gene is not a frequent target of cancer-specific genetic alterations. Our aim is to identify cancer relevant upstream factors responsible for oncogenic deregulation of hepsin and cancer promoting downstream consequences of uninhibited hepsin action. We are also currently investigating different therapeutic approaches to inhibit hepsin as a possible strategy to limit cancer growth and invasion (Tervonen et al. Adv. Cancer Res 2011; Partanen et al. Philos Trans R Soc Lond B Biol Sci 2013; Tervonen et al. Oncogene 2016).