Boris Zhivotovsky

Lung cancer (LC) is the most common cause of morbidity and mortality among all cancer types. Lung adenocarcinoma (ADC) is increasing the most and is now the most common (40%) form of LC in both men and women. Many factors are responsible for tumor progression, but the main way to kill tumor cells is to activate the cell death machinery. Previously, we have shown that crosstalk between different cell death mechanisms is crucial for successful killing of tumor cells. However, the exact search for specific markers, which can be targeted against tumor cells, is still a very important task. This study is devoted to the search for new lung ADC markers. The main goal is an identification of new targets and mechanisms that coordinate different cell death types to overcome the resistance of lung ADC cells to treatment. Specifically, we will study the role of Tudor staphylococcal nuclease target proteins, PDCD4 and DRAM1, in sensitivity/resistance of lung ADC cells to therapy, uncover mitochondrial mechanisms that integrate apoptosis and ferroptosis signaling as therapeutic targets, and study the effect of mitochondrial quality control proteins and phenotypic factors on lung ADC patients survival probability. An interdisciplinary approach will be used to find biomarkers for targeting lung ADCs. Despite improved diagnostics, and new radiation, chemotherapy and immunotherapy methods, mortality in lung ADC patients is still very high. Within the project, we plan to identify new targets and mechanisms that integrate different cell death modalities to overcome the resistance of lung ADC cells to treatment. We showed that crosstalk between different cell death mechanisms is crucial for successful killing of tumor cells. Therefore, obtained data from new targets that activate this crosstalk together with complex phenotypic factors will help to build a map to predict the outcome of anticancer therapy for patients with lung ADC.

According to the 2018 Cancer Foundation annual report, lung cancer (LC) in Sweden is one of the most common tumor diseases, and the most common in terms of the number of deaths. About 80% of new LC patients were older than 65 years, but 90 of them were younger than 50 years, which is a new trend. Many factors are responsible for tumor progression, but the most important way to kill tumor cells (in addition to surgery) is to activate the cell death machines. Previously, we show that the right relationship between different cell death mechanisms is crucial for the happy killing of tumor cells. However, the search for specific markers, which can be targeted to tumor cells, is still a very important task. The aim of this project is to understand how Bcl-2 family proteins affect the relationship between different cell death mechanisms and how it can realize the sensitivity of lung adenocarcinoma (LA) cells to treatment. Therefore, we plan to identify the role of BNIP3 in regulating the movement and development of metastasis of LA cells, analyze the role of BNIP3 in mitochondrial regulation of an interaction between metabolic pathways that determine the mode of tumor cell death and finally) target Mcl-1 to influence response of LA cells for treatment. We plan to use several modern techniques to find biomarkers, which will target LA treatment. Despite improved diagnostics, surgery and new radiation, chemo and immunotherapy methods, mortality in lung adenocarcinoma (LA) patients is still very high. In the project, we will study basic mechanisms for the involvement of Bcl-2 family proteins in the relationship between different cell death mechanisms to influence the response of LA to treatment. Preliminary results support the idea that one can specifically target pro- and anti-apoptotic Bcl-2 family proteins and activate cell death machines. This knowledge will provide a valuable background for identifying specific "target molecules" and designing "target therapy" for the treatment of LA.

According to the 2018 Cancer Foundation annual report, lung cancer (LC) in Sweden is one of the most common tumor diseases, and the most common in terms of the number of deaths. About 80% of new LC patients were older than 65 years, but 90 of them were younger than 50 years, which is a new trend. Many factors are responsible for tumor progression, but the most important way to kill tumor cells (in addition to surgery) is to activate the cell death machines. Previously, we show that the right relationship between different cell death mechanisms is crucial for the happy killing of tumor cells. However, the search for specific markers, which can be targeted to tumor cells, is still a very important task. The aim of this project is to understand how Bcl-2 family proteins affect the relationship between different cell death mechanisms and how it can realize the sensitivity of lung adenocarcinoma (LA) cells to treatment. Therefore, we plan to identify the role of BNIP3 in regulating the movement and development of metastasis of LA cells, analyze the role of BNIP3 in mitochondrial regulation of an interaction between metabolic pathways that determine the mode of tumor cell death and finally) target Mcl-1 to influence response of LA cells for treatment. We plan to use several modern techniques to find biomarkers, which will target LA treatment. Despite improved diagnostics, surgery and new radiation, chemo and immunotherapy methods, mortality in lung adenocarcinoma (LA) patients is still very high. In the project, we will study basic mechanisms for the involvement of Bcl-2 family proteins in the relationship between different cell death mechanisms to influence the response of LA to treatment. Preliminary results support the idea that one can specifically target pro- and anti-apoptotic Bcl-2 family proteins and activate cell death machines. This knowledge will provide a valuable background for identifying specific "target molecules" and designing "target therapy" for the treatment of LA.

According to the Cancer Fund's annual report 2016, lung cancer (LC) is one of the five most common tumor diseases in Sweden in 2014 and the most common in terms of the number of deaths. Despite treatment success in recent years, it is unclear why non-small cell LC (NSCLC) is so resistant to therapy and cell death. We found a Tudor-SN-S100A11-PLA2 shaft that regulates apoptosis triggered by platinum-based drugs. Down regulation of autophagy (the mechanism of cell survival) makes LC cells more susceptible to apoptosis in response to therapeutic drugs. But how the relationship between cell survival and death mechanisms can affect the response of NSCLC cells in therapy is still unclear. The aim of the project is to understand how relationship between cell survival mechanisms and cell death can affect the response of NSCLC cells to treatment. Therefore, we plan to investigate the role of Tudor-SN target proteins, BNIP3 and IGFBP 2, in the sensitivity of NSCLC cells to chemotherapy

identify unknown pathways in NSCLC cells under conditions of suppressed autophagy responsible for sensitivity of LC to therapeutic drugs. Finally, we will examine the relationship between diet, degree of autophagy and the risk of developing NSCLC. We plan to use techniques to find biomarkers that will be targeted for treatment by NSCLC. Despite improved diagnostics, surgery and new chemo and radiation treatment methods, mortality in lung cancer patients is still very high. In this project, the basic mechanisms that regulate the balance between cell survival and cell death mechanisms that affect the response of NSCLC cells to treatment are studied. Preliminary data supports our expectations that the ability to regulate this balance will help us make tumor cells more specifically undergo cell death. This knowledge will provide a valuable background for identifying specific "target molecules" and designing "target therapy" for the treatment of NSCLC.

According to the Cancer Fund's annual report 2016, lung cancer (LC) is one of the five most common tumor diseases in Sweden in 2014 and the most common in terms of the number of deaths. Despite treatment success in recent years, it is unclear why non-small cell LC (NSCLC) is so resistant to therapy and cell death. We found a Tudor-SN-S100A11-PLA2 shaft that regulates apoptosis triggered by platinum-based drugs. Down regulation of autophagy (the mechanism of cell survival) makes LC cells more susceptible to apoptosis in response to therapeutic drugs. But how the relationship between cell survival and death mechanisms can affect the response of NSCLC cells in therapy is still unclear. The aim of the project is to understand how relationship between cell survival mechanisms and cell death can affect the response of NSCLC cells to treatment. Therefore, we plan to investigate the role of Tudor-SN target proteins, BNIP3 and IGFBP 2, in the sensitivity of NSCLC cells to chemotherapy

identify unknown pathways in NSCLC cells under conditions of suppressed autophagy responsible for sensitivity of LC to therapeutic drugs. Finally, we will examine the relationship between diet, degree of autophagy and the risk of developing NSCLC. We plan to use techniques to find biomarkers that will be targeted for treatment by NSCLC. Despite improved diagnostics, surgery and new chemo and radiation treatment methods, mortality in lung cancer patients is still very high. In this project, the basic mechanisms that regulate the balance between cell survival and cell death mechanisms that affect the response of NSCLC cells to treatment are studied. Preliminary data supports our expectations that the ability to regulate this balance will help us make tumor cells more specifically undergo cell death. This knowledge will provide a valuable background for identifying specific "target molecules" and designing "target therapy" for the treatment of NSCLC.

According to the Cancer Fund's annual report 2016, lung cancer (LC) is one of the five most common tumor diseases in Sweden in 2014 and the most common in terms of the number of deaths. Despite treatment success in recent years, it is unclear why non-small cell LC (NSCLC) is so resistant to therapy and cell death. We found a Tudor-SN-S100A11-PLA2 shaft that regulates apoptosis triggered by platinum-based drugs. Down regulation of autophagy (the mechanism of cell survival) makes LC cells more susceptible to apoptosis in response to therapeutic drugs. But how the relationship between cell survival and death mechanisms can affect the response of NSCLC cells in therapy is still unclear. The aim of the project is to understand how relationship between cell survival mechanisms and cell death can affect the response of NSCLC cells to treatment. Therefore, we plan to investigate the role of Tudor-SN target proteins, BNIP3 and IGFBP 2, in the sensitivity of NSCLC cells to chemotherapy

identify unknown pathways in NSCLC cells under conditions of suppressed autophagy responsible for sensitivity of LC to therapeutic drugs. Finally, we will examine the relationship between diet, degree of autophagy and the risk of developing NSCLC. We plan to use techniques to find biomarkers that will be targeted for treatment by NSCLC. Despite improved diagnostics, surgery and new chemo and radiation treatment methods, mortality in lung cancer patients is still very high. In this project, the basic mechanisms that regulate the balance between cell survival and cell death mechanisms that affect the response of NSCLC cells to treatment are studied. Preliminary data supports our expectations that the ability to regulate this balance will help us make tumor cells more specifically undergo cell death. This knowledge will provide a valuable background for identifying specific "target molecules" and designing "target therapy" for the treatment of NSCLC.

According to the Cancer Fund's annual report 2013, lung cancer (LC) is one of the five most common tumor diseases in Sweden in 2011 and the most common in terms of the number of deaths. LC is treated with radiation. chemotherapy that kills tumor cells by activating various cell death programs. Despite treatment success in recent years, it is still unclear why non-small cell LC (NSCLC) is so resistant to treatment and cell death. We have found that the resistance of LC cells to radiation is associated with over-expression of a miRNA and a protein contained in its biosynthesis. By what mechanisms this affects tumor sensitivity to radiation is still unclear. The overall goal of this research project is to understand how miRNA-regulated pathways affect the treatment effect of non-small cell lung cancer. Therefore, we plan to investigate the role of so-called Tudor-staphylococcal nuclease (Tudor-SN) plays in this regard as well as the importance of miRNA-214 for the regulation of cell death and carcinogenesis. Finally, we also want to analyze the expression of Tudor-SN and miRNA-214 in tumor biopsies from patients with NSCLC. We will use microarray and other modern techniques to identify biomarkers that can be used in the treatment of NSCLC. Despite improved diagnostics, surgery and new chemo and radiation treatment methods, mortality in lung cancer patients is still very high. In this project, the basic mechanisms governing the defective cell death machinery in resistant lung cancer cells are studied. Our assumption is that the microRNA and the Tudor SN protein affect the cell death programs, the lack of function of which leads to treatment resistance. This knowledge will provide a valuable background for identifying specific "target molecules" and designing "target therapy" for the treatment of NSCLC.

According to the Cancer Fund's annual report 2013, lung cancer (LC) is one of the five most common tumor diseases in Sweden in 2011 and the most common in terms of the number of deaths. LC is treated with radiation. chemotherapy that kills tumor cells by activating various cell death programs. Despite treatment success in recent years, it is still unclear why non-small cell LC (NSCLC) is so resistant to treatment and cell death. We have found that the resistance of LC cells to radiation is associated with over-expression of a miRNA and a protein contained in its biosynthesis. By what mechanisms this affects tumor sensitivity to radiation is still unclear. The overall goal of this research project is to understand how miRNA-regulated pathways affect the treatment effect of non-small cell lung cancer. Therefore, we plan to investigate the role of so-called Tudor-staphylococcal nuclease (Tudor-SN) plays in this regard as well as the importance of miRNA-214 for the regulation of cell death and carcinogenesis. Finally, we also want to analyze the expression of Tudor-SN and miRNA-214 in tumor biopsies from patients with NSCLC. We will use microarray and other modern techniques to identify biomarkers that can be used in the treatment of NSCLC. Despite improved diagnostics, surgery and new chemo and radiation treatment methods, mortality in lung cancer patients is still very high. In this project, the basic mechanisms governing the defective cell death machinery in resistant lung cancer cells are studied. Our assumption is that the microRNA and the Tudor SN protein affect the cell death programs, the lack of function of which leads to treatment resistance. This knowledge will provide a valuable background for identifying specific "target molecules" and designing "target therapy" for the treatment of NSCLC.