Amphiregulin's involvement in nuclear chromatin structure and associated resistance events in therapies against melanoma

• Applicant: Professorin Dr. Silke Kuphal
• Subject Area: Dermatology ; Hematology, Oncology ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 523756532

The subject of the proposal is the multifaceted molecule amphiregulin (AREG), which has been exclusively assigned a role as a ligand for EGFR in recent years. In association with beeing a ligand for EGFR AREG was described as oncogene. Recent data consider an ambivalent (amphi-=dual) role of AREG, independent of the extracellular signaling pathway and also independent of EGFR. Indeed, data in melanoma showed that expression of AREG does not necessarily correlate with expression of EGFR. However, in melanoma signaling pathways are relevant which are dependend on AREG protein modifications, peptidase activity of involved enzymes (AREG shedding), endocytosis, and cytoplasmic or nuclear localization of AREG that may be tumor suppressive or oncogenic. We already detected different protein sizes of AREG and also different localizations of the molecule in melanoma. In particular, a ~50 kDa nuclear variant of AREG seems to affect chromatin and chromatin-associated molecules. Our preliminary data indicate that nuclear localization of AREG and chromatin alterations are found in melanoma and these are associated with a slow-cycling melanoma phenotype and resistance to vemurafenib. The goal of this proposal is to determine in detail how nuclear AREG affects chromatin structure and thus regulates resistance, and to clarify which splice variants or protein modifications of AREG are important in melanoma. We will clarify whether nuclear AREG-positive cells - in a primary tumor - are already a deleterious indicator of intrinsic resistance or merely inhibit cancer aggressiveness toward arrest of proliferation. In addition, analyses will reveal whether an increase in amphiregulin accumulation in the nucleus occurs only as a consequence of therapies and associated acquired resistance. Investigating the role of AREG in acquired resistance and the mechanism of AREG accumulation in the nucleus is of importance to define a new therapeutic target. Our goal is to find a responsible enzyme or protein modification involved in resistance development by AREG that could prevent amphiregulin accumulation in the nucleus and associated resistance.

• DFG Programme: Research Grants
• International Connection: Japan
• Cooperation Partner: Professor Dr. Shinji Fukuda