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Cancer cells face many challenges: their rapid cell division leads to defective proteins in the long run. Their nutritional status and their oxygen supply are often precarious, the toxins of chemotherapy threatening: scientists speak of such a situation of "cellular stress". The different stress stimuli activate the JNK enzyme in the cell as a central stress switch. In cancer cells, this can have many effects. Depending on the environment, the activity of JNK triggers a cell suicide or survival program.
"We wanted to know exactly what is happening in bad cancer cells after JNK activation," says Thordur Oskarsson, stem cell researcher at DKFZ and HI-STEM *. In this study, he and his team discovered a direct link between JNK activation and metastasis formation. The researchers also found that standard chemotherapy treatments administered in bad cancer also activated JNK, which limited the effectiveness of the treatment.
"Drugs are certainly doing their job and destroying cancer cells – but obviously they also have adverse effects that need to be taken into account," says Oskarsson, "but he points out that his new findings nevertheless open up new opportunities: "We have three until now. identified unknown starting points where new drugs could target to slow the spread of cancer and prevent resistance. "
Oskarsson and his team first studied tissue samples from patients with metastatic bad cancer. The more they detected JNK activity in bad cancer tissue, the less the disease course was favorable. Metastases contained more JNK-active cells than primary tumors.
JNK transplanted bad cancer cells into stem cell mode
This was also confirmed in mice in which bad cancer cells had become metastatic tumors. The researchers found particularly striking differences between tiny micrometastases, which contained up to 50% of JNK-active cells, and advanced metastases, in which JNK was active only in about 15% of cells. "JNK promotes mobility and invasion, typical behavior of aggressive cancer cells.It is necessary for the colonization of new tissues and will be stopped once the metastasis is established," says Jacob Insua-Rodríguez, first author of the article. .
He was now interested in what happens in bad cancer cells at the molecular level when JNK becomes active. Apparently, they fall into a stem cell mode because the pattern of activity of their genes is similar to that known from bad stem cells. To this is also added the production of certain proteins of the extracellular matrix, SPP1 and TNC.
Chemotherapy with stress factor
What happens when bad cancer cells are exposed to the stressor of chemotherapy? This was again studied by Oskarsson and his colleagues in mice to which they had transferred bad cancer cells. Paclitaxel or doxorubicin drugs activated JNK in bad cancer cells and triggered the stem cell program. In pulmonary metastases in animals, the proportion of active cells in the JNK increased significantly from 20% to 80%. However, when scientists used anti-cancer drugs in combination with a JNK inhibitor, the number of metastases formed in the lungs of mice was greatly reduced.
But the aggressive behavior of bad cancer cells relies on both JNK-stimulated SPP1 and TNC proteins: If the mice received bad cancer cells in which SPP1 or TNC were genetically deactivated, JNK activity remained inconsequential. negative. When these animals were treated with chemotherapy, tumor growth and lung metastasis were significantly lower than in mice to which bad cancer cells had been transferred.
SPP1 or TNC are extracellular matrix proteins, which are more or less the microenvironment of tumor cells. The researchers therefore see in their results an additional proof of the considerable influence of the so-called "niche" on the evolution of a cancer.
"We now know that we are disabling JNK as the key switch of bad cancer cell aggression with specific drugs, so that the production of the two main molecular players, SPP1 and TNC, can be interrupted, thereby reducing metastases, "concludes Oskarsson. "In this way, we will be able to study even better in the future what leads to metastasis and resistance to bad cancer treatment – and we have discovered promising new approaches to treatment development."
* Heidelberg Institute for Stem Cell Research and Experimental Medicine (HI-STEM) gGmbH is a partnership of DKFZ and the Dietmar Hopp Foundation
Jacob Insua-Rodríguez, Maren Pein, Tsunaki Hongu, Jasmin Meier, Arnaud Descot, Camille Lowy, Etienne De Braekeleer, Hans-Peter Sinn, Saskia Spaich, Mark Sütterlin, Andreas Schneeweiss and Thordur Oskarsson: Signaling Stress in Breast Cancer favor chemoresistant metastases
EMBO Molecular Medicine 2018, DOI: 10.15252 / emmm.201809003
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Caption: Micrometastasis of lung cancer in mice: the JNK central stress switch is active in red-labeled cells. The cancer cells are green, the cell nuclei are blue.
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The German Cancer Research Center (DKFZ), which employs over 3,000 people, is the largest biomedical research institution in Germany. At DKFZ, more than 1,000 scientists are studying cancer development, identifying risk factors for cancer, and researching new strategies to prevent cancer. They are developing new methods to more accurately diagnose tumors and more effectively treat cancer patients. The staff of the Cancer Information Service (KID) informs concerned individuals, interested citizens and expert groups about cancer, a widespread disease. In collaboration with the Heidelberg University Hospital, DKFZ has set up the Heidelberg National Tumor Disease Center (NCT), in which promising approaches from cancer research are transferred to the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German centers for health research, DKFZ runs translation centers in seven university partner sites. The combination of excellent academic medicine and advanced research from a Helmholtz center makes a significant contribution to improving the chances of cancer patients. DKFZ is 90% funded by the Federal Ministry of Education and Research and 10% by the state of Baden-Württemberg. She is a member of the Helmholtz Association of German Research Centers.
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