Publications
Aberrant activation of mRNA translation is emerging as a common theme in many malignancies. Molecular pathways that affect global translation have been implicated in cancer. Our research focused on the mechanisms of translation programs in cancer. Using genome-wide ribosome footprinting we have succeeded in identifying the molecular mechanisms that enforce key oncogenic translation programs. Our work uncovers regulatory RNA motifs, mechanisms, and new protein forms that create a therapeutic vulnerability in cancer.
Rapamycin-Induced Feedback Activation of eIF4E-EIF4A Dependent mRNA Translation in Pancreatic Cancer
Pancreatic cancer cells adapt molecular mechanisms to activate the protein synthesis to support tumor growth. This study reports the mTOR inhibitor rapamycin's specific and genome-wide effect on mRNA translation.
In short, we establish the specific effect of mTOR-S6 on translation in cells lacking 4EBP1 and show that mTOR inhibition leads to feedback activation of translation via AKT-RSK1-eIF4E signals. Therefore, targeting translation downstream of mTOR presents a more efficient therapeutic strategy in pancreatic cancer.
Frequent 4EBP1 Amplification Induces Synthetic Dependence on FGFR Signaling in Cancer
The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown.We show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K-mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites. This implies that not 4EBP1 but instead FGFR1 is the genetic target of Chr. 8p11 gains in breast and lung cancer. Accordingly, these tumors show increased sensitivity to FGFR1 and PI3K inhibition, and this is a therapeutic vulnerability through restoring the tumor-suppressive function of 4EBP1. Ribosome profiling reveals genes involved in insulin signaling, glucose metabolism, and the inositol pathway to be the relevant translational targets of 4EBP1.In summary, we identified the translational targets of 4EBP1-EIF4E that facilitate the tumor suppressor function of 4EBP1 in cancer.
RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer
We have established a mechanism of inhibiting translation that depends on RNA helicase eIF4A activity, RNA G-quadruplex structures, and is selective in deterring the production of critical oncogenic proteins, including MYC, NOTCH1, BCL2, and inducing strong anti-cancer effects.
c-MYC regulates mRNA translation efficiency and start site selection in lymphoma
MYC activation in lymphoma impacts the translation program by regulating translation efficiency and translation start site selection. We identify an SRSF1 dependent RNA motif that regulates the translation efficiency of the mitochondrial respiration complex. Mapping the translation start site suggests that MYC activation favors translation from upstream start sites resulting in the generation of short peptides. In contrast, MYC inactivation facilitates translation from downstream start sites leading to N-terminally truncated protein of key translation activating proteins and immune receptors. This has profound effects on functional proteome in cancer. For example, immune receptor CD19 gets truncated due to an alternate translation start site leading to loss of its extracellular domain. This impairs the response to CD19 directed CART therapy in lymphoma. Altogether MYC induced translation reprogramming contributes to c-MYC’s biological function including cellular metabolism and immunotherapy response
Targeting eIF4A-Dependent Translation of KRAS Signaling Molecules
We discovered that the translation of KRAS and key downstream effectors of KRAS depends on the RNA helicase eIF4A. This is mediated through the RNA G-quadruplex structure present in the 5'UTR of KRAS and other KRAS effector proteins. Specific inhibitors of eIF4A, Silvestrol, and its chemical analog CR-1-31B, selectively target the translation of mRNAs containing RNA G-quadruplex in their 5'UTR and therefore, show efficacy in pancreatic cancer models.