A fundamental response to oncogenic transformation is enhanced cellular stress (e.g. oxidative, metabolic, and DNA damage), which is a hallmark of cancer cells. These common stress phenotypes must be tolerated by cancer cells through stress support pathways. Moreover, adaptation to stress is required for cancer cell survival, and consequently they may become dependent on stress response pathways that do not ordinarily perform such a vital function in normal cells. Thus, targeting these associated vulnerabilities to stress adaptation are clearly vital and offer a tremendous window of opportunity for a synthetic lethal interaction that may elicit selective death of cancer cells. Despite the tremendous importance of the stress phenotype of cancer cells, there is a large gap in our understanding of the genetic basis for how stress tolerance is maintained in transformed cells, thereby limiting our ability to design rational therapeutic agents. Our preliminary findings reveal that the major cap-binding protein eIF4E is a central integrator of the translation program for the adaption of cancer cells to oncogenic stress. By generating the first genetic loss-of-function mouse model for eIF4E, we have unexpectedly discovered that a 50% reduction in eIF4E has no effect on normal development, but strikingly is limiting for oncogenic transformation. Utilizing unbiased genome-wide translational profiling, we find that eIF4E selects for the translation of specific subsets of mRNAs involved in cellular stress response pathways, including oxidative stress. This proposal aims to undertake a multifaceted approach to delineate the contribution of eIF4E- dependent control of reactive oxygen species in tumor development and maintenance of non-small cell lung carcinoma in vivo, and explore the therapeutic potential of inhibiting eIF4E in combination with small molecules that induce oxidative stress. Furthermore, our finding that eIF4E is rate limiting for only a subset of mRNAs that regulate cellular stress response pathways is striking, and suggests that a novel regulatory program promotes selectivity for cancer cell survival.
We aim to define the underlying molecular mechanisms by which an identified novel cis-acting regulatory motif, in the 5'UTR of select mRNAs, confers eIF4E sensitivity. Collectively, our data demonstrate that eIF4E-dependent control of these stress response pathways is critical for oncogenic transformation and tumor cell survival. These findings lay the foundation for this proposal, which seeks to open a new portal into our understanding of the translation program that maintains the adaptation of cancer cells to stress and develop a novel therapeutic regimen to target this vulnerability of transformed cells.
One fundamental hallmark of cancer cells is their adaptation to cellular stress allowing for tumor survival. This proposal will utilize several state-of-the-art technologies, including mouse models that recapitulate human cancer, in order to study eIF4E-translational control of the 'cancer stress response'that is required for tumor development. Thereby, our research will unravel the genetic and molecular mechanisms that underlie and maintain the adaptation of cancer cells to stress, while contributing to the identification and clinical validation of novel therapies with the potential to target early events of tumorigenesis.
| Truitt, Morgan L; Conn, Crystal S; Shi, Zhen et al. (2015) Differential Requirements for eIF4E Dose in Normal Development and Cancer. Cell 162:59-71 |
