A combination of high-throughput analyses uncovers novel mechanism of stress-induced chemoresistance
Resistance of cancer cells against therapeutic agents is a major cause of treatment failure, especially in recurrent diseases. In a collaborative effort with the labs of Robert Ahrends, Björn Tews, Grischa Tödt and Christiane Knobbe-Thomsen, we 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 Unfolded Protein Response (UPR), an important cellular stress response pathway, 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. A detailed biochemical understanding of the UPR is critically required to better define its role in disease and to develop novel therapeutic strategies. To produce a comprehensive description of the UPR, we employed a ‘multi-omics’ approach, combining large datasets from genetics and proteomics. This allowed us to define a list of genes (the UPR regulon) that are activated to promote cell survival under stress. Besides the previously known factors, we identified numerous genes that have not previously been implicated in stress response pathways and many of them have key functions in cancer development and cellular metabolism.
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. We demonstrated that 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 become 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. Its precise molecular characterization might lead to novel therapeutic concepts aimed at overcoming chemoresistance n cancer therapy.
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, and Medenbach J: A multi-omics analysis reveals the unfolded protein response regulon and stress-induced resistance to folate-based antimetabolites – in Nature Communications, DOI:10.1038/s41467-020-16747-y