Published: 2021-07-09 13:57 | Updated: 2021-07-09 13:57

“We need to prevent the development of Polycystic Ovary Syndrome”

Illustration of POS
POS Photo: N/A

In a recently published review article in Nature Reviews Endocrinology, two researchers at the Department of Physiology and Pharmacology at KI, concludes where the field of research is today regarding causes behind and development of, Polycystic Ovary Syndrome (PCOS) and how epigenetic processes can contribute to the development of the syndrome.

Polycystic Ovary Syndrome (PCOS) affects over 10% of the women in reproductive age and is the most common cause of impaired fertility and the development of insulin resistance and type-2 diabetes, mental illness, and endometrial cancer.

Even though it is so common and has significant consequences, both for the women and economically for the society, we don’t know the underlying causes to the syndrome and the treatment is therefore focused on relieving symptoms.

” Today we know that women with PCOS have high levels of male sex hormone, and that there is a strong heredity. We have shown that daughters to women with PCOS have five times increased risk to develop PCOS and that it can be brought on to future generations (Nature Medicine 20191). But how PCOS is brought on to future generations is still unclear”, says Elisabet Stener-Victorin, professor and group leader at the Department of Physiology and Pharmacology at KI, and one of the authors of the article.

Genome-wide association scan (GWAS) studies only explains about 10% of the heredity. Even other factors that the genetic ones, for example the epigenetic processes, can lead to corresponding heredity through modification of cellular processes and whole body physiology without affecting the DNA sequence.

The pregnant PCOS women have continued high levels of male sex hormone the entire pregnancy and is also gaining more weight, which leads to increased risk of developing gestational diabetes.

”The placenta plays an important role in protecting the growing fetus, and we and others have shown that women with PCOS have disturbances in the function of the placenta which can affect the fetus and it’s germ cells, and thereby theoretically contribute to the development of PCOS in the offspring through epigenetic processes”, explains Elisabet Stener-Victorin.

Studies has also shown that newborn daughters has an increased so called anogenital distance, a sign of fetus exposure for male sex hormone in utero during pregnancy. Even sons to women with PCOS and their brothers has metabolic disorders.

“This is only shown in small clinical trials and if also men can be passed on the syndrome and associated diseases to future generations is something we need to study further”, says Qiaolin Deng, co- author and PhD, lecturer and group leader at the Department of Physiology and Pharmacology at KI.

”We discuss the possibility to develop new therapies that aims to prevent the development rather than only relieve symptoms. This is also what our research aims at. To publish a review article in the field of PCOS in Nature Reviews Endocrinology is a very important step to increase the knowledge and the understanding of the syndrome”, concludes Elisabet Stener-Victorin.

 

Read the article in Nature Reviews Endocrinology here

The article in Nature Reviews Endocrinology is written by Elisabet Stener-Victorin together with colleague Qiaolin Deng at the Department of Physiology and Pharmacology at KI

<a href="https://staff.ki.se/people/elisabet-stener-victorin">Elisabet Stener-Victorin</a>

  • Title: Professor
  • Phone: +46-(0)8-524 872 00
  • Unit: C3 Department of Physiology and Pharmacology
  • Email: elisabet.stener-victorin@ki.se
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<a href="https://staff.ki.se/people/qiaolin-deng">Qiaolin Deng</a>

  • Title: Researcher
  • Phone: +46-(0)8-524 839 33
  • Unit: C3 Department of Physiology and Pharmacology
  • Email: qiaolin.deng@ki.se
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Published: 2021-07-08 10:31 | Updated: 2021-07-08 12:43

Seeing is believing – a snapshot of an active Frizzled renews hope for finding new drugs

New results presented by the Schulte lab at Karolinska Institutet in collaboration with researchers in Shanghai and Montréal, help us understand how the cell surface receptor FZD7 is activated and provides a platform for drug discovery to inhibit this process for therapeutic purposes.

Gunnar Schulte, professor at the Department of Physiology and Pharmacology
Gunnar Schulte, professor at the Department of Physiology and Pharmacology. Photo: Stefan Zimmerman

FZD7 is a cell surface receptor that mediates signaling through transducer proteins known as G proteins. Both proteins have been linked to diverse forms of human cancer (i.e. intestinal cancer, breast cancer and glioma, etc.).

“Our hope is that the development of compounds that revert the process of FZD activation and G protein coupling that we discovered here, will be useful for the treatment of FZD7-dependent tumors. In addition, we think that all FZDs behave in a similar manner when coupling to G proteins and that our findings have bearings for all FZD subtypes, which are relevant in diverse forms of cancer like FZD5 in pancreatic cancer and FZD10 in synovial carcinoma among others”, says Gunnar Schulte, Professor in receptor pharmacology and research group leader for the section Receptor Biology and Signaling at the Department of Physiology and Pharmacology.

The Schulte lab and especially postdoctoral fellows Hannes Schihada, Shane Wright (currently postdoc with Michel Bouvier, University of Montreal and Volker Lauschke, KI), Ainoleena Turku, Pawel Kozielewicz, Maria Kowalski-Jahn and the PhD student Carl-Fredrik Bowin provided functional data and in silico support for the activation process of FZDs, which now open the path towards drug discovery. This work complemented the structural biology approach of the lab of Dr Fei Xu at the ShanghaiTech University.

The Schulte lab will now continue working on integrating the new findings on the role of FZD7 for intestinal tumors with the hope that the new data will lead to a mechanism-based and structure-guided therapy of FZD-dependent cancer.

“Interestingly, there are several signaling branches downstream of FZDs, which have diverse function in physiology and diseases. While the G protein-independent pathway through b-catenin-dependent transcriptional regulation is heavily linked to tumor proliferation, it remains unclear what aspects of tumor growth are affected by the FZD7-Gs axis”, Gunnar Schulte says.

“With a better structural resolution of these processes, it will become possible to design better assays for drug screening and to develop drugs that affect structural rearrangements to promote or inhibit receptor activation”, Gunnar Schulte concludes.

 

Read the article in Cell Research here

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Published: 2021-06-24 15:37 | Updated: 2021-06-24 17:38

Andrea Carmine Belin voted to join the International Headache Society’s Board of Trustees

headache
Huvudvärk Foto: Pixabay,Mohamed Hassan

Andrea Carmine Belin, researcher at the Department of Neuroscience, has been nominated and elected to the International Headache Society's Board of Directors for a two-year period (2021-2023), which will also be announced in conjunction with the Members' Annual Meeting on September 9, 2021.

Close-up portrait of a smiling Andrea Carmine Belin
Andrea Carmine Belin. Photo: Michael Belin

Congratulations Andrea! Could you tell me a little more about IHS?

"The International Headache Society is the world's leading membership organization for those with a professional commitment to helping people affected by headache disorders."

"As a charity, the purpose of IHS is to advance headache science, education, and management, and promote headache awareness worldwide."

What does this imply for you personally?

"As a headache researcher, it is first and foremost a great honor to have been selected to be part of the IHS board."

"Current and former board members are all leading players in the headache research field as well as clinical work and an inspiration for young researchers and clinicians. The headache field is currently undergoing a revolution on the treatment front as several new drugs targeting the neuropeptide CGPR are launched on the market. It is therefore an extra exciting time to be part of developing IHS's future work areas."

And for your research?

"This position will give me more opportunities to highlight the primary headache disorder my group is focusing on, i.e. Cluster headache, and what is particularly close to my heart, namely the heredity around various headache disorders."

"This will also enable me to reach out with all the important headache research currently done in Sweden, both nationally and internationally."

Published: 2021-06-23 18:06 | Updated: 2021-06-23 18:13

Platinum-chemotherapy can enhance the treatment resistance of ovarian cancer cells

Researchers from Karolinska Institutet have discovered how platinum-chemotherapy can enhance the treatment resistance of ovarian cancer cells, by progressively changing the cancer cell-intrinsic adhesion signaling and cell-surrounding microenvironment.

Ovarian cancer cells
Ovarian cancer cells Photo: N/A

Platinum chemotherapy is standard treatment in ovarian cancers, but treatment resistance commonly develops. The extracellular matrix (ECM)-derived biochemical and mechanical cues in the tumor microenvironment are known to contribute to the ability of cancer cells to metastasize and resist treatment. However, how the dynamic communication between the cancer cells and the ECM is affected by, or influences the disease progression and chemotherapy, have remained elusive.

A new study led by Kaisa Lehti, researcher at the Department of Microbiology, Tumor and Cell Biology at KI, and published in Nature Communications, shows that the ECM microenvironment is modulated in metastasis and following chemotherapy. Changes in the ECM proteins variably altered the cell death response of the tumour cells.

“Particularly in the most aggressive solid tumor tissues, cancer cells are surrounded by a prominent fibrotic network of proteins like collagens, known as the extracellular matrix (ECM) and also defined as the matrisome when considered with various associated factors including cytokines and chemokines. The ECM/matrisome is produced largely by stromal cells, but sensed and remodeled collectively by the cancer cells and the cells of the fibrotic tumor stroma. In tumor cells, specific ECM signaling in stiff microenvironment critically increased their resistance against platinum-mediated, apoptosis-inducing DNA damage”, Kaisa Lehti explains.

Read the full article in Nature Communications

The study included key clinical collaboration with University of Turku and Turku University Hospital as well as Karolinska University Hospital and was completed in collaboration with Norwegian University of Science and Technology, NTNU. It was funded by the KI Strategic Research Program in Cancer (KI Cancer Research), the Swedish Cancer Society, the Swedish Research Council, Sigrid Juselius Foundation, the Finnish Cancer Foundation, Orion Research Foundation, K. Albin Johanssons Foundation, Emil Aaltonen Foundation, the European Union’s Horizon 2020 research and innovation program (under grant agreement HERCULES) as well as the Doctoral Program in Integrative Life Sciences, University of Helsinki.

<a href="https://staff.ki.se/people/kaisa-lehti">Kaisa Lehti</a>

  • Title: Researcher
  • Phone: +46-(0)8-524 852 54
  • Unit: C1 Department of Microbiology, Tumor and Cell Biology
  • Email: kaisa.lehti@ki.se
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Nick Lane Biography
Nick Lane is an evolutionary biochemist and writer in the Department of Genetics, Evolution and Environment, University College London. He was awarded the inaugural Provost's Venture Research Prize for his research on evolutionary biochemistry and bioenergetics in 2009. His work focuses on the origin of life, and the origin and evolution of eukaryotes. He was a founding member of the UCL Consortium for Mitochondrial Research, and is leading the UCL Research Frontiers Origins of Life programme. He is the author of four critically acclaimed books on evolutionary biochemistry. Life Ascending won the 2010 Royal Society Prize for Science Books, while The Vital Question was praised by Bill Gates as 'an amazing inquiry into the origins of life'. His work has been recognized by the Biochemical Society Award in 2015 and the Royal Society Michael Faraday Prize in 2016.

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