Stressed cancer cells resist treatment

A combination of high-throughput analyses uncovers mechanism of stress-induced chemoresistance

Resistance of cancer cells against therapeutic agents is a major cause of treatment failure, especially in recurrent diseases. An international team of researchers in the e:Med junior research alliance SUPR-G has identified a novel mechanism of chemoresistance which has now been published in ‘Nature Communications’. It is driven by the Unfolded Protein Response (UPR), a cellular stress response pathway that alters gene expression and cellular metabolism to promote cell survival under stress.

The molecular mechanisms driving chemoresistance in cancer cells are diverse and often only poorly understood. In many cases cellular stress has been identified as a major contributor that causes resistance to treatment through the activation of cellular stress response pathways. These genetic programs allow the cells to adapt to harsh environmental conditions and challenges, promoting survival and, as a consequence, chemoresistance. A better understanding of stress response pathways is therefore urgently required to develop novel therapeutic concepts aimed at overcoming resistance to therapeutic agents. The combined effort of the e:Med SUPR-G junior alliance has now identified a molecular pathway underlying stress-mediated chemoresistance.

A closer look into cellular stress response
“We are particularly interested in the Unfolded Protein Response (UPR), an adaptive pathway triggered by the accumulation of unfolded proteins. It does not only contribute to cancer development, progression and chemoresistance, but also it plays an important role in numerous other diseases, among them diabetes and neurodegenerative disorders such as Alzheimer’s disease”, says Dr. Jan Medenbach, speaker of the SUPR-G research consortium. “A detailed biochemical understanding of the UPR is critically required to better define its role in disease. This would allow us to develop novel therapeutic strategies.” To produce a comprehensive description of the UPR, the researchers employed several state-of-the-art analytical tools in a ‘multi-omics’ approach, combining large datasets from genetics and proteomics. The result is a quantitative list of genes (the UPR regulon) that are activated to promote cell survival under stress. “Besides the previously known factors, we identified to our surprise numerous genes that have not previously been implicated in stress response pathways”, explains Dr. Jan Medenbach, “and many of them have key functions in cancer development and cellular metabolism”.

Stress in tumor cell leads to resistance
Changes in cellular metabolism are a hallmark of cancer cells and allow to sustain rapid tumor growth. Chemotherapy often aims at interfering with these metabolic pathways. In their study, the researchers discovered stress-mediated genetic regulation of enzymes involved in amino acid biosynthesis and one-carbon (1C) metabolism that relies on the vitamin folate as a cofactor. Moreover, upon stress, cancer cells became fully resistant to chemotherapeutic agents which target this specific metabolic pathway. This includes Methotrexate, a drug commonly employed in the treatment of cancer and rheumatic disease. Detailed biochemical and genetic investigations revealed that resistance is driven by a previously unrecognized mechanism. According to the study authors, its precise molecular characterization might lead to novel therapeutic concepts aimed at overcoming chemoresistance n cancer therapy.

Collaborations paved the way to scientific success
"Fundamental to the scientific success of this amibitious project were the close and multiprofessional collaborations in the junior research alliance SUPR-G. This includes scientific teams at the Leibniz Institute for Analytical Sciences (ISAS, Dortmund), the University of Regensburg, the German Cancer Research Centre (DKFZ, Heidelberg), the European Molecular Biology Laboratory (EMBL, Heidelberg) and the University of Düsseldorf. The research activities were made possible by the financial support of the BMBF in the framework of the systems medicine network e:Med" explains PD Jan Medenbach the joint success.

Original Publication:
Reich S, Nguyen CDL, Has C, Steltgens S, Soni H, Coman C, Freyberg M, Bichler A, Seifert N, Conrad D, Knobbe-Thomsen CB, Tews B, Toedt G, Ahrends R, und Medenbach J, “A multi-omics analysis reveals the unfolded protein response regulon and stress-induced resistance to folate-based antimetabolites”, Nature Communications (2020). DOI: 10.1038/s41467-020-16747-y

Scientific contact:
PD Dr. Jan Medenbach, SUPR-G
Institute of Biochemistry, University of Regensburg
medenbachlab.de;  Tel.: +49-941-943 1721; Email: Jan.Medenbach@ur.de
Ass.-Prof. Dr. Robert Ahrends, SUPR-G TP2
Institute for Analytical Chemistry, University of Vienna
lipidomics.at; Tel.: +43-1-4277-52304;  Email: robert.ahrends@univie.ac.at