The proto-oncogene c-Myc is frequently deregulated in human tumors and its overexpression associates with poor prognosis in patients. Particularly, 90% of Burkitt's lymphoma cases exhibit constitutive expression of c- Myc as a result of translocations. Considering the paradoxical role of c-Myc as an inducer of both proliferation and apoptosis, it is essential to understand how c-Myc dependent tumors disable the apoptosis arm of c-Myc while maintaining its pro-tumorigenic properties. Our group has shown that activation of the PERK-eiF2a-ATF4 arm of the Unfolded Protein Response (UPR), a protein homeostasis mechanism is required for survival of c- Myc-induced apoptosis both in vitro and in vivo, suggesting this pathway is utilized by c-Myc overexpressing cells to overcome oncogenic stress. Moreover, evidence for activation of the PERK arm of the UPR in lymphoma patient samples compared to normal B cells bolsters the clinical relevance of this pathway during c- Myc induced lymphomagenesis. However, how PERK mediates its pro-survival roles, including activation of cytoprotective autophagy, remains unexplored. Employing ATF4-/- MEFs, I have demonstrated that one of the downstream effector of PERK, ATF4, promotes survival and mediates activation of autophagy during c-Myc induction. ATF4-dependent autophagy in the context of hypoxia eliminates Reactive Oxygen Species (ROS) and accumulated proteins, recycling nutrients to fuel growth. Although ATF4 has been shown to promote survival in extrinsic stresses, it is not clear how it promotes survival during oncogene-induced, intrinsic stress. Furthermore, the augmentation of protein synthesis and unique metabolism of c-Myc driven cancer cells, makes them prone to both ER and oxidative stress. Therefore, activation of stress coping mechanisms, such as those that promote degradation of excess proteins as well as damaged organelles and promote redox homeostasis become vital to overcome oncogene induced stress. Thus, I hypothesize that ATF4 promotes survival of c-Myc overexpressing cells by inducing autophagy and suppressing oxidative stress. To test my hypothesis, I will employ both cell culture and a relevant transgenic mouse model system. The transgenic mouse model will be the first to test the role of ATF4 during tumor initiation and progression in vivo. Using this syste I can deplete ATF4 in the cell of origin of lymphomas, B-cells, in an established model of lymphoma, E?-Myc. Additionally, I will perform microarray analysis to identify ATF4-dependent pathways during c-Myc activation. Despite the observation that ATF4 is upregulated in lymphomas, its requirement in c- Myc induced tumorigenesis in vivo has not been well studied. My study will provide insights in to mechanisms that c-Myc overexpressing cells rely on for survival and may extend to other c-Myc dependent tumors.

Public Health Relevance

Deregulation of the pro-oncogenic protein c-Myc is present and drives progression of many human tumors including lymphomas. Cellular pro-survival mechanisms that confer advantage to c-Myc driven tumors are not fully elucidated. My proposed study will investigate how a particular stress response pathway cooperates with c-Myc during tumorigenesis and could thereby facilitate development of novel targets for therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA183569-04
Application #
9186519
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mcneil Ford, Nicole
Project Start
2013-12-13
Project End
2017-12-12
Budget Start
2016-12-13
Budget End
2017-12-12
Support Year
4
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Nguyen, Hao G; Conn, Crystal S; Kye, Yae et al. (2018) Development of a stress response therapy targeting aggressive prostate cancer. Sci Transl Med 10:
Tameire, Feven; Verginadis, Ioannis I; Koumenis, Constantinos (2015) Cell intrinsic and extrinsic activators of the unfolded protein response in cancer: Mechanisms and targets for therapy. Semin Cancer Biol 33:3-15