BIO SEMINAR: Identification of novel players in breast cancer...

Guest: Yunus Akkoç

Title: Identification of novel players in breast cancer classification, treatment and cancer-stroma crosstalk

Date/Time: April 29, 2024 13:40

Location: FENS G035

Abstract: MicroRNAs (miRNAs) are endogenous non-coding small RNAs that negatively regulate gene expression at a post-transcriptional level to control fundamental biological processes. Accumulating data in the literature indicate that dysregulation of miRNA expression contributes to the mechanisms of cancer formation, invasion, metastasis, and affects response to therapeutics. There is a growing list of miRNA levels of which deregulated under cancer-related conditions. Breast cancer is one of the most common cancers and the second leading cause of cancer-related deaths among women worldwide. Routine clinical evaluation, diagnosis and treatment modalities of breast cancer are categorized into three major distinct molecular subtypes based on their hormone receptor status, proliferation capacity and stage of the disease. However, a large group of patients still cannot benefit from available treatment strategies. Further breast cancer subtyping is clinically useful thereby, our discovery of elevated expression of MIR376B especially in T2 tumors is quite important under these circumstances and it may lead the discovery of better treatment modalities. Here we proposed a novel role of MIR376B through its autophagy inhibitory action and our findings might be critical for the sub-classification of breast cancer and development of therapeutics by altering autophagy and determining cell size in cancer. In addition, we contributed to the development of innovative theranostic autophagy-modulating nanoparticles that serve as miRNA carriers. In nude mice xenograft models of human breast cancer, we proved that miRNA-carrying nanoparticles potentiated chemotherapy-induced tumor elimination, which could be used as an adjuvant cancer drug.

Tumors do not only consist of cancerous cells, but they also harbor several normal-like cell types and non-cellular components. In addition to cancerous cells, normal cells surrounding or penetrating tumors are also considered important components of the malignant disease. Communication between cancer cells and these normal cells leads to their transdifferention to cancer-associated “stroma” components. Cancer-associated fibroblasts (CAFs) are one of these cellular components that are found predominantly in the tumor stroma. These stroma cells, including CAFs, are key determinants supporting cancer growth, drug resistance and metastasis, etc. Yet, only a few cytokine/lymphokine factors (e.g. TFG-beta and IL-6) were described as cancer-derived signals resulting in fibroblast activation and CAF formation. We discovered for the first time that a cytokine previously involved in normal tissue homeostasis, Cardiotrophin-1 (CT-1), is a mediator of tumor-stroma interaction, and a rate-limiting factor for CAF formation. Using cellular systems, patient-derived cells and tumor tissues, we proved that CT-1 was indispensable for CAF-assisted cancer cell migration and invasion, and high CT-1 secretion from tumors was associated with lymph node metastasis in patients.

Therefore, our holistic approach both focusing on cancer and stroma led to the discovery of several strong connections and innovative diagnosis and treatment approaches based on original discoveries.

Bio: Dr. Akkoc received his Ph.D. degree in Molecular Biology, Genetics and Bioengineering from Sabancı University, under the supervision of Dr. Devrim Gozuacik. His doctoral studies were focused on deciphering abnormalities of the autophagic machinery in cancers by investigating autophagy-regulating miRNAs. During his post-doctoral studies, he mainly focused on the identification of possible molecules that are leading to the crosstalk of tumor stroma. As a Koç University Research Center for Translational Medicine (KUTTAM) Researcher, he is leading two TÜBİTAK 1001 projects as a PI and is participating in one TÜBİTAK supported 1001 project as a consultant and one TÜBİTAK 1004 and one TÜSEB B-group project as a researcher. He holds an outstanding research record with the co-authoring of >27 high-impact, highly-cited scientific papers and book chapters, and as an inventor of several patents. He has received several prestigious research and teaching awards including the Turkish Biochemical Society Prof. Dr. Nazmi Özer Science Award. He serves on the editorial board of the Turkish Journal of Biology and he is also serving as a reviewer of a list of high-impact journals (e.g., Molecular Cancer, Autophagy, ACS Nano etc.). He is an active member of several professional organizations and he has given several talks at major international and national conferences (e.g., Gordon Research Conferences (GRC), European Association of Cancer Research (EACR), Federation of European Biochemical Societies (FEBS)) and contributed to the organization of international meetings. He also delivers several courses at Koç University Graduate School of Health Sciences including Mechanisms of Cell Death, Tumor Microenvironment and Mechanism of Metastasis.