IAS / School of Science Joint Lecture

Epithelial Tumor Suppression by Cell Competition

Abstract

Normal epithelial cells often exert anti-tumor effects against nearby oncogenic cells. In Drosophila imaginal epithelium, clones of oncogenic cells mutant for apico-basal polarity genes scribble (scrib) or discs large (dlg) are actively eliminated by “cell competition” when surrounded by wild-type cells. Although scientists have previously shown that Jun amino-terminal kinases (JNK) signaling plays a crucial role in this cell elimination, the initial event occurring at the interface between normal cells and polarity-deficient cells remained unknown. To address this, the speaker conducted a genetic screen in Drosophila and identified the ligand Sas and the receptor-type tyrosine phosphatase PTP10D as the cell-surface ligand-receptor system that drives tumor-suppressive cell competition. At the interface between wild-type “winner” and polarity-deficient “loser” clones, winner cells relocalize Sas to the lateral cell surface while loser cells relocalize PTP10D to the lateral cell surface. This leads to trans-activation of Sas-PTP10D signaling in loser cells that restrains epidermal growth factor receptor (EGFR) signaling, thereby enabling elevated JNK signaling in loser cells to trigger cell elimination. In the absence of Sas-PTP10D, elevated EGFR signaling in loser cells switches JNK’s role from pro-apoptotic to pro-growth by inactivating the Hippo pathway, thereby driving overgrowth of polarity-deficient cells. These findings uncovered the mechanism by which normal epithelial cells recognize oncogenic polarity-deficient neighbors to drive cell elimination. The speaker will also discuss other factors isolated from the screen, as well as the physiological roles of tumor-suppressive cell competition.

 

About the speaker

Prof. Tatsushi Igaki received his BS and MS in Pharmaceutical Sciences from Okayama University in 1993 and 1995. He researched at the Kyorin Pharmaceutical Company before earning his PhD from Osaka University Graduate School of Medicine in 2003. He then furthered his research career at Yale University School of Medicine. In 2007, he joined Kobe University Graduate School of Medicine as an Assistant Professor and was promoted to Associate Professor in 2009. Later in 2013, he joined Kyoto University where he is currently the Professor of Kyoto University Graduate School of Biostudies.

In the field of cell competition, Prof. Igaki is a leading expert, who has uncovered the molecular mechanisms of how unfit cells are recognized and selectively eliminated in the body. He serves on editorial boards for a number of peer-reviewed journals such as Disease Models & Mechanisms and Cell Structure and Function.

Along his career, Prof. Igaki has been granted a number of fellowship in support of his research. He has been a Long-term Fellow of Human Frontier Science Program (HFSP) (2004-2007) and a Fellow of Japan Society for the Promotion of Science (JSPS) (2000-2003). Besides, he was the award recipient of Japanese National Institute of Science and Technology Policy Award (2014), 11th Japan Society for the Promotion of Science Prize (2014), Human Frontier Science Program Career Development Award (2009) and Astellas Award for the Best Biomedical Research (2008).


  

 

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