Stress Activated Protein Kinase Pathways And Metastasis PDF Download

"Cancer metastasis is a multi-step process. This thesis focuses on two critical steps of the metastatic process in breast cancer: (1) the transition from non-invasive to invasive disease, and (2) immune evasion that supports metastasis. MAP kinase-interacting serine/threonine-protein kinases 1 and 2 (MNK1/2) are ubiquitously expressed serine/threonine kinases downstream of the ERK1/2 and p38 pathways. Hyper-activation of MNK1/2 due to external stimuli such as growth factors or stress signaling can enhance tumor cell invasion and metastasis in multiple solid malignancies including breast cancer, but the molecular mechanisms underpinning these effects of MNK1/2 remain largely unknown. Using in vitro and in vivo models, we demonstrated a novel function of MNK1, where the kinase drives the transition of breast ductal carcinoma in situ (DCIS), a non-invasive “stage 0” disease, into invasive ductal carcinoma (IDC). At the mechanistic level, MNK1 upregulates the expression of NODAL, a pro-tumorigenic morphogen, to support a partial epithelial-mesenchymal transition (EMT), and to maintain cancer stemness properties that increase the risk of tumor relapse and metastasis. The best characterized function of MNK1/2 is to phosphorylate the eukaryotic translation initiation factor 4E (eIF4E) at Ser209. Multiple pro-oncogenic pathways converge on the MNK1/2-eIF4E axis, which serves as a critical regulator of the translation of mRNAs that encode for proteins that promote cell invasion. The MNK1/2-eIF4E axis has been recently reported to reinforce the survival of pro-metastatic neutrophils in breast cancer. However, our knowledge of how aberrant mRNA translation regulates breast tumor immunity remains limited. We chose to study post-partum breast cancer (PPBC), an aggressive subtype of breast cancer, as it has been characterized by robust immune cell suppression, to examine how the MNK1/2-eIF4E axis shapes pro-tumorigenic immunity during metastasis. We demonstrate that eIF4E phosphorylation is important to support tumor immune evasion for PPBC metastasis. Using a mouse model that is devoid of eIF4E phosphorylation, and inhibitors of MNK1/2, we show that type 2 innate lymphoid cell (ILC2) function, myeloid-derived suppressor cells (MDSCs) accumulation, and cytotoxic T cell exclusion, are dependent on the MNK1/2-eIF4E axis. Immune targeted therapies have not shown great promise in breast cancer. We showed that the inhibition of MNK1/2 using the inhibitor SEL201, can work in concert with anti-PD1 immune targeted therapy to inhibit PPBC metastasis. Thus, we show the possibility of enhancing the efficacy of immunotherapy by using a small molecule inhibitor that blocks mRNA translation"--