Page 44 - Rappaport Institute Magazine 2024

CELL BIOLOGY AND CANCER SCIENCE
Amir Orian MD, PhD Professor of Medicine
MD, 1999 – Technion, Israel PhD, 2000 – Technion, Israel
Cell identity and “degradation resistant” cancers
My laboratory studies the biology of ubiquitin pathway in cancer, combining Drosophila genetics, cancer biology, and patients’ materials and data. We focus on:
1. “Cell identity”; Maintaining cell identity requires active supervision, and failure to maintain the differentiated state is a hallmark of aging and results in cancer. We are interested in studying genes and molecular mechanisms involved in supervising cell identity. We also discover and study Identity Breakers, genes that unlock cell identity and drive tumorigenesis.
2. “Degradation resistant tumors” We discovered a Ubiquitin-dependent protein stabilization pathway that stabilizes and hyper-activates oncoproteins. This pathway is essential for survival of aggressive cancers and confers resistance to molecular therapy. However, this pathway is less critical for naïve, non-transformed cells, suggesting that enzymes in this pathway may be of clinical importance. Therefore, we developed diagnostic tools for the identification of cancers where the stabilization pathway is abnormally hyper-activated, predicting resistance to therapy. We are currently developing novel inhibitors to key enzymes in this pathway. More about the lab can be found at: https://orian.net.technion.ac.il
Selected Publications
ˆ Novak R, Abu Ahmed1Y, Timaner M, Bitman-Lotan L, Oknin-Vaisman A, Nikomarov D, Diefenbacher M, Shaked Y, Orian A. (2022) RNF4-RGMb axis is required for osteogenic differentiation and cancer cell survival. Cell Death & Disease 13:820.
ˆ Avitan-Hersh E., Feng Y., Oknin-Vaisman A., Abu-Ahmed Y., Zhang T., Zohar Y., Lazar I., Khalil S., Feiler Y., Lee S J., Kluger H., Kahana H., Brown K., Ruppin E., Ronai Z., Orian A. (2020) Regulation of eIF2a by RNF4 underlies melanoma development and therapy resistance. J. Investigative Dermatology 29: 31404-3114.
ˆ Thomas JJ, Abed M, Heuberger J, Novak R, Zohar Y, Beltran Lopez AP, Trausch-Azar JS, Ilgan M, Benhamou D, Dittmar G, Kopan R Birchmeier W, Schwartz AL, and Orian A. (2016) RNF4-dependent oncogene activation by protein stabilization Cell Reports 16, 3388-3400.
ˆ Erez, N., Israitel L., Bitman-Lotan E., Wong, W. H., Raz G., Danial S., Flint Brodsly N., Belova, E., Maksimenko, O., Georgiev P., Druley, T., Mohan R., Orian A. (2021) A Non- stop identity complex (NIC) supervises enterocyte identity and protects from pre-mature aging. e-Life 10:e62312.
ˆ åFlint-Brodsly, N. Bitman-Lotan E, Boico O, Shafat A, Monastirioti M, Gessler M, Delidakis C, Rincon-Arano H, Orian A. (2019) The transcription factor Hey and nuclear lamins specify and maintain cell identity, e-Life pii: e44745.
mdoryan@technion.ac.il
Amir Orian Lab
Microscopy image of Drosophila gut
tissue that lost its identity exhibiting hyperproliferation of progenitor cells (green).