#IDIBELLseminars: Tumor cell-intrinsic and -extrinsic roles of the integrated stress response in malignant progression and metastasis

Constantinos Koumenis
Perelman School of Medicine, University of Pennsylvania, PA, USA

Tumor progression and metastasis is associated with the development of a range of microenvironmental stresses including hypoxia, nutrient limitation, and inflammation as well as intrinsic stresses, such as those imposed by oncogenic activation. When confronted with such stress, cells elicit adaptive pro-survival responses, including the integrated stress response (ISR). The ISR refers to a conserved and coordinated pathway comprised of four kinases that converge on phosphorylation of the eukaryotic translation initiation factor eIF2α. ISR activation via eIF2α phosphorylation conserves resources by downregulating global, cap-dependent translation while promoting translational upregulation of specific mRNAs via features in the 5’-untranslated region. The best-studied of these codes for the ATF4 transcription factor, which regulates expression of mRNAs involved in amino acid transport and biosynthesis, redox balance, angiogenesis and autophagy. Activation of the ISR has been reported in many human tumors including breast and prostate cancer, lymphomas, sarcomas, melanomas, etc.
In the first part of my talk, I will present some of our published work supporting a critical role of ATF4 in promoting tumor cell survival in the context of dysregulation of the proto-oncogene c-Myc. I will also outline an emerging role of ATF4 as a “rheostat” of Myc’s potent upregulation od translational activity and metabolic reprogramming, thereby enabling Myc-dependent tumorigenesis. Although the pro-tumorigenic role of the ISR in a tumor cell-intrinsic manner has been established, its role in cell-extrinsic processes remains unexplored. In the second part of my talk, I will present unpublished data from my lab, where using novel conditional knockout ATF4 mouse models, we show that global, or fibroblast (FB)-specific loss of host ATF4 results in abnormal tumor vascularization and a pronounced tumor growth delay in syngeneic melanoma and pancreatic tumor models. We find that loss of host ATF4 results in attenuation of cancer associated fibroblast (CAF) activation and that ATF4 directly regulates expression of the collagen genes as well as biosynthesis of glycine and proline, the major amino acids comprising collagen fibers.
Together, the tumor-intrinsic and -extrinsic roles of the ISR in cancer progression and metastasis make a strong case for targeting components of these pathways as effective anti-tumor strategies.

Hosted by Cristina Muñoz-Pinedo

Dr. Koumenis was born in Nicosia, Cyprus. He received his B.S degree in Pharmacy (with honors) from the Aristotle University of Thessaloniki, Greece in 1989 and his Ph.D. degree in Biochemistry from the University of Houston, TX, USA, in 1994. He then trained as a podstdoctoral fellow in Radiation and Tumor Biology at Stanford University. His first faculty appointment was at Wake Forest University School of Medicine where he was Assistant Professor from 1999 to 2006. He then moved to the University of Pennsylvania (UPenn) in Philadelphia, PA, USA, as Associate Professor. He is currently the Richard Chamberlain Endowed Professor and Vice-Chair for Research, in the Department of Radiation Oncology at UPenn’s Perelman School of Medicine. His scientific research interests include the study of the role of the tumor microenvironment on tumor progression, metastasis and resistance to therapy. He and his team are also engaged in the development of novel radiation toxicity mouse models and the testing of new radiation technologies and modalities such as FLASH radiotherapy. He is currently the Principal Investigator or co-PI on multiple research and training grants from the National Institutes of Health (NIH) and he has published over 120 manuscripts in high-impact journals. He currently serves as a standing member on NIH grant review committees and is a member of the Radiation and Medicine Working Group steering committee of the American Association for Cancer Research. Since 2018, Dr. Koumenis also serves as the Associate Director for Translational Research of the Abramson Comprehensive Cancer Center at the University of Pennsylvania. Over his career Dr. Koumenis has been the advisor of 10 PhD Doctoral students and 7 MS graduate students, some of which currently hold faculty positions in major research institutions or are principal scientists in industry.