Program Project Grant (P01): UPR/ ISR in Cancer

NIH Grant # P01-CA165997

Principal Investigator:

Project Overview:

The overall goal of this Program is to investigate the role of the Unfolded Protein Response (UPR) signaling pathway in tumor homeostasis and tumor progression. Rapidly proliferating cancer cells must thrive in amicroenvironment wherein metabolic nutrients such as glucose, oxygen and growth factors become limitingas tumor volume expands beyond the established vascularity of the tissue. The UPR functions as a sensorof the availability of key cellular nutrients, such as glucose and oxygen, that are critically important for tumorgrowth and progression. The UPR and specifically the PERK kinase, has recently been shown to facilitateoncogene-mediated tumor progression, suggesting that the UPR may also respond to bioenergeticchallenges triggered by aberrant oncogene-dependent signaling. The overall hypothesis being interrogatedby this Program Project is that the UPR and more specifically, the PERK kinase, functions as a sensor oftumor cell autonomous and non-autonomous bioenergetic stress; the ensuing activation of PERK catalyticfunction promotes tumor cell adaptation to this stress and thereby facilitates tumor progression. To test thishypothesis, three synergistic projects have been developed. Project 1 will evaluate mechanisms whereby amicro-RNA balances PERK-dependent pro-survival and pro-apoptotic functions. Key preliminary datasuggest that miR-211 is a novel regulator of the pro-apoptotic factor, CHOP, and functions to temporallyregulate CHOP expression. Project 2 will interrogate the function of PERK as a first response regulator of c-Myc-dependent bioenergetic and proteotoxic stress. Through its capacity to temper protein translation,PERK moderates cellular response to c-Myc thereby ensuring that bioenergetic capacity matches oncogenicdemand resulting in tumor growth rather than apoptosis. Project 3 will test the hypothesis that tumor cellsactivate the UPR, and, perhaps, more broadly the Integrated Stress Response (ISR) due to oncogeneactivation or oxygen and/or nutritional deficit, and thereby acquire the ability to escape the anti-proliferativeand pro-apoptotic effects of Type 1 interferons, IFNa/p. Through the synergistic functions of this Program,we will ascertain how PERK balances growth with apoptosis (Projects 1 and 2), how PERK responds toenvironmental challenge (Projects 1 and 3) and how tumor cells utilize PERK and the UPR to adapt tooncogene-triggered bioenergetic stress (Projects 1-2-3). All three projects will make extensive use ofscientific Core B (Metabolomics/ Genomics) and have already established a working, highly collaborativerelationship. It is our supposition that findings stemming from work proposed herein will provide a foundationfor the design of novel anti-cancer treatment strategies targeting this pathway.

Project 1: Micro-RNA-dependent signaling by the UPR

Project 2: The UPR effector ATF4 in metabolic reprogramming and survival during Myc-induced tumorigenesis

Project 3: Integrated Stress and Interferon Responses

Core A: Administrative Core

Core B: Metabolomics/Genomics 

External Advisory Board: