Anita Göndör

Reproductive dysfunction is frequent in women with hyperandrogenism and obesity, like polycystic ovary syndrome (PCOS). On the other hand, hyperandrogenism can be beneficial for physical performance and is common among female athletes. Differences of sex development (DSD) and androgen receptor (AR) dysfunction are rare disorders of reproductive failure. There is a need for improved diagnostics and treatment.The aim is to:elucidate the role of androgens in female athletic performance and reproduction, and the impact on the steroid profile for anti-doping testingdevelop a technique for the assessment of AR sensitivity in vivoexplore perturbed circadian genome organization as a novel mechanism and therapeutic target in PCOScompare semaglutide and metformin in improving reproductive and metabolic health in PCOS.The effect of testosterone on physical performance and reproduction, and the influence on the steroid profile is evaluated in a randomized clinical trial (RCT). A method for quantification of AR activity in vivo is developed to characterize different genetic variants leading to hyperandrogenism and DSD. Transcriptional circadian rhythms in blood and in target tissues in PCOS are investigated by qRT-PCRs and qPCR. Semaglutide and metformin are compared in a RCT to identify the most effective insulin-sensitizing therapy in PCOS. The overall anticipated outcome is improved fertility and metabolic health in women with common and rare reproductive disorders.

Cancer can be described as a disease of abnormal cells with a so-called plastic phenotype that can undergo rapid microevolution under fluctuating selection pressure. The consequence of this is that the cancer cells outcompete their normal counterparts and develop strategies to survive treatment with chemotherapy. Immature properties, similar to those found in embryonic stem cells and which have the potential to mature into many different cell types found in the adult, characterize cancer stem cells (CSCs) that drive cancer survivability. My work plan is therefore based on the principle that cancer-specific changes in the architecture of the cell nucleus change the 3D structure of the genome and how this phenomenon cooperates with cancer genes to upset the synchronization of circadian gene activity and thus create conditions for phenotypic plasticity. Paired with world-unique methods that enable the identification of key properties in the 3D structure and function of the genome in individual cells, I therefore ask the questions when, where and how circadian regulation is disturbed during the cancer process with a particular focus on CSC and how this affects the properties of the cancer cell. Although I use model systems, the focus of the application is on tissue samples from breast cancer patients. The aim is to seek to understand how a subpopulation of these cells can acquire properties that increase their survival. The point of attack is my discovery that cancer genes traffic the structures of the cell nucleus to increase their pathological activity. All in all, I expect that the results will lead to a paradigm shift in how we look not only at breast cancer but also at cancer in general and how this insight can further be introduced into clinical applications in order to increase the chances of being able to cure cancer.

Breast cancer is the leading cause of death among women, while the early stages are overtreated due to a lack of prognostic markers. Epidemiological studies linked breast cancer to the circadian clock - a system that provides adaptive advantages in a changing environment. It remains an enigma how the circadian clock modulates the phenotypic plasticity of the tumor, a property that drives its adaptability and resistance to therapy. This proposal explores whether deregulation of the circadian 3D epigenome organization fuels the phenotypic plasticity of breast cancer cells. I hypothesize that increased stochastic epigenetic variation in cancer is promoted by altered gene migration between nuclear subdivisions that instruct chromatin states. The resulting increased epigenetic variation is translated into fluctuations in the composition of the transcriptome/proteome of the tumor cells to drive cellular heterogeneity that may explain this condition. I have discovered that timing signals coordinate rhythmic gene migration between the transcriptionally permissive nuclear interior and the repressive lamina, via the nuclear pore. The goal is therefore to uncover cause-and-effect relationships between deregulation of repressive nuclear compartments in breast cancer and circadian disturbances in the trafficking of genes that regulate phenotypic plasticity, in order to uncover early prognostic markers and therapeutic targets.

This proposal explores the molecular mechanisms by which deregulation of circadian 3D epigenome organisation fuels phenotypic plasticity and adaptability of breast cancer cells. It builds on my recent hypothesis that increased stochastic epigenetic variation in cancer is promoted by altered gene mobility between different nuclear sub-compartments that have instructive functions on chromatin states. I coin here this principle as “gene trafficking” to highlight the regulated migration of genes between sub-nuclear compartments. The resulting increased stochastic epigenetic variation is hypothesised to be translated into fluctuations in the composition of the transcriptome/proteome of the tumor cells to facilitate switches between cell states with increased or decreased developmental potential, typical of phenotypic plasticity. I also propose that the stochastic reactivation of the cellular machinery that unleashes phenotypic plasticity is facilitated by the peripheral localisation of their normally repressed genes in somatic progenitor cells/mature cell states. Since gene trafficking to nuclear pores is under circadian control, the research plan aims to establish cause-and-effect relationships between the frequent deregulation of the 3D nuclear architecture and circadian perturbations in tumors. Aim1: To dissect the mechanisms of cancer cell-specific gene trafficking in the 3D nucleusAim2: To explore cell-to-cell heterogeneity in gene trafficking as a driver of cancer evolution

Cancer can be described as a disease of abnormal cells with a so-called plastic phenotype that can undergo rapid microevolution under fluctuating selection pressure. The consequence of this is that the cancer cells outcompete their normal counterparts and develop strategies to survive treatment with chemotherapy. Immature properties, similar to those found in embryonic stem cells and which have the potential to mature into many different cell types found in the adult, characterize cancer stem cells (CSCs) that drive cancer survivability. My work plan is therefore based on the principle that cancer-specific changes in the architecture of the cell nucleus change the 3D structure of the genome and how this phenomenon cooperates with cancer genes to upset the synchronization of circadian gene activity and thus create conditions for phenotypic plasticity. Paired with world-unique methods that enable the identification of key properties in the 3D structure and function of the genome in individual cells, I therefore ask the questions when, where and how circadian regulation is disturbed during the cancer process with a particular focus on CSC and how this affects the properties of the cancer cell. Although I use model systems, the focus of the application is on tissue samples from breast cancer patients. The aim is to seek to understand how a subpopulation of these cells can acquire properties that increase their survival. The point of attack is my discovery that cancer genes traffic the structures of the cell nucleus to increase their pathological activity. All in all, I expect that the results will lead to a paradigm shift in how we look not only at breast cancer but also at cancer in general and how this insight can further be introduced into clinical applications in order to increase the chances of being able to cure cancer.

Immature traits, similar to those found in embryonic stem cells and having the potential to mature into many different cell types found in the adult human, characterize cancer stem cells (CSCs) that are the driving force behind the cancer's viability. Despite the knowledge that cancer cells often show pathological changes in the cell architecture's 3D architecture and thus changes in the distribution between active and inactive genetic predispositions, no one has yet systematically characterized the cell nucleus' architecture, the genome's 3D folding and how these changes can be related to disorders in the cell's homeostasis. the bike. My application is based on my discovery that the architecture of the cell nucleus regulates the synchronization of circadian gene activity. The circadian cycle plays a crucial role in the cell's homeostasis and thus phenotypic stability - its disorder thus has a strong predisposition to cancer. My work plan is therefore based on the premise that cancer-specific changes in the architecture of the cell nucleus change the 3D structure of the genome to disrupt the synchronization of circadian gene activity. Specifically, I ask the question how circadian regulation is disturbed during the cancer process with a special focus on CSC and how this affects the plastic properties of the cancer cell. A key issue in our ambition to fight cancer is therefore how CSC can acquire a plastic phenotype. My long-term ambition is thus to identify and create new avenues of therapy that eliminate the plasticity of CSC. Overall, I expect that the results will lead to a paradigm shift in how we view not only breast cancer but also cancer in general and how this insight can later be introduced in clinical applications to increase the conditions for curing cancer.

Immature traits, similar to those found in embryonic stem cells and having the potential to mature into many different cell types found in the adult human, characterize cancer stem cells (CSCs) that are the driving force behind the cancer's viability. Despite the knowledge that cancer cells often show pathological changes in the cell architecture's 3D architecture and thus changes in the distribution between active and inactive genetic predispositions, no one has yet systematically characterized the cell nucleus' architecture, the genome's 3D folding and how these changes can be related to disorders in the cell's homeostasis. the bike. My application is based on my discovery that the architecture of the cell nucleus regulates the synchronization of circadian gene activity. The circadian cycle plays a crucial role in the cell's homeostasis and thus phenotypic stability - its disorder thus has a strong predisposition to cancer. My work plan is therefore based on the premise that cancer-specific changes in the architecture of the cell nucleus change the 3D structure of the genome to disrupt the synchronization of circadian gene activity. Specifically, I ask the question how circadian regulation is disturbed during the cancer process with a special focus on CSC and how this affects the plastic properties of the cancer cell. A key issue in our ambition to fight cancer is therefore how CSC can acquire a plastic phenotype. My long-term ambition is thus to identify and create new avenues of therapy that eliminate the plasticity of CSC. Overall, I expect that the results will lead to a paradigm shift in how we view not only breast cancer but also cancer in general and how this insight can later be introduced in clinical applications to increase the conditions for curing cancer.

Work in recent years has shown that the genetic material can establish interactions both within and between chromosomes that affect its function via coordination of the genetic material's activities with significance for phenotypic variation and adaptive responses to a changing microenvironment. An example of such a principle consists of circadian regulation created by cell-autonomous "clocks" which are continuously affected by light and food intake. Circularly regulated heredity is strongly linked to metabolic processes and, when their activity is disrupted, can contribute to cancer formation. However, the molecular mechanisms behind these principles are largely unknown I have discovered that circadian regulated genes "migrate" from the interior of the cell nucleus to its periphery to become inactivated. Furthermore, I have discovered new factors that control these processes by manipulating the central "clock". In the research program, projects are described that describe completely new principles for how these factors work together and how their work can create conditions for cancer in connection with structural changes in the cell nucleus architecture in cancer stem cells. The application includes a project aimed at trying to restore the cell nucleus architecture and thus normal circadian regulation. If the submitted research plan receives support from the Cancer Foundation and can thus be implemented, it is my expectation that my work will create an increased understanding of how the function of the genetic material is influenced by the cell's exposure to circadian factors and how this function can when it is disrupted increase the risk of the occurrence of cancer stem cells. . Although circadian regulation of gene expression is an internationally highly recognized research area, this connection is almost unknown. The application also contains a project that seeks to recreate normal circadian regulation in cancer stem cells and thereby accelerate their maturation.

Work in recent years has shown that the genetic material can establish interactions both within and between chromosomes that affect its function via coordination of the genetic material's activities with significance for phenotypic variation and adaptive responses to a changing microenvironment. An example of such a principle consists of circadian regulation created by cell-autonomous "clocks" which are continuously affected by light and food intake. Circularly regulated heredity is strongly linked to metabolic processes and, when their activity is disrupted, can contribute to cancer formation. However, the molecular mechanisms behind these principles are largely unknown I have discovered that circadian regulated genes "migrate" from the interior of the cell nucleus to its periphery to become inactivated. Furthermore, I have discovered new factors that control these processes by manipulating the central "clock". In the research program, projects are described that describe completely new principles for how these factors work together and how their work can create conditions for cancer in connection with structural changes in the cell nucleus architecture in cancer stem cells. The application includes a project aimed at trying to restore the cell nucleus architecture and thus normal circadian regulation. If the submitted research plan receives support from the Cancer Foundation and can thus be implemented, it is my expectation that my work will create an increased understanding of how the function of the genetic material is influenced by the cell's exposure to circadian factors and how this function can when it is disrupted increase the risk of the occurrence of cancer stem cells. . Although circadian regulation of gene expression is an internationally highly recognized research area, this connection is almost unknown. The application also contains a project that seeks to recreate normal circadian regulation in cancer stem cells and thereby accelerate their maturation.

Work in recent years has shown that the genetic material can establish interactions both within and between chromosomes that affect its function via coordination of the genetic material's activities with significance for phenotypic variation and adaptive responses to a changing microenvironment. An example of such a principle consists of circadian regulation created by cell-autonomous "clocks" which are continuously affected by light and food intake. Circularly regulated heredity is strongly linked to metabolic processes and, when their activity is disrupted, can contribute to cancer formation. However, the molecular mechanisms behind these principles are largely unknown I have discovered that circadian regulated genes "migrate" from the interior of the cell nucleus to its periphery to become inactivated. Furthermore, I have discovered new factors that control these processes by manipulating the central "clock". In the research program, projects are described that describe completely new principles for how these factors work together and how their work can create conditions for cancer in connection with structural changes in the cell nucleus architecture in cancer stem cells. The application includes a project aimed at trying to restore the cell nucleus architecture and thus normal circadian regulation. If the submitted research plan receives support from the Cancer Foundation and can thus be implemented, it is my expectation that my work will create an increased understanding of how the function of the genetic material is influenced by the cell's exposure to circadian factors and how this function can when it is disrupted increase the risk of the occurrence of cancer stem cells. . Although circadian regulation of gene expression is an internationally highly recognized research area, this connection is almost unknown. The application also contains a project that seeks to recreate normal circadian regulation in cancer stem cells and thereby accelerate their maturation.