MNK1/NODAL Signaling Promotes Invasive Progression of Breast Ductal Carcinoma In Situ

Abstract

The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are not well understood. However, this process is critical to the acquisition of metastatic potential. MAPK-interacting serine/threonine-protein kinase 1 (MNK1) signaling can promote cell invasion. NODAL, a morphogen essential for embryogenic patterning, is often reexpressed in breast cancer. Here we describe a MNK1/NODAL signaling axis that promotes DCIS progression to IDC. We generated MNK1 knockout (KO) or constitutively active MNK1 (caMNK1)-expressing human MCF-10A-derived DCIS cell lines, which were orthotopically injected into the mammary glands of mice. Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis. Conversely, caMNK1 induced NODAL expression and promoted IDC. The MNK1/NODAL axis promoted cancer stem cell properties and invasion in vitro. The MNK½ inhibitor SEL201 blocked DCIS progression to invasive disease in vivo. In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low-grade (invasion-free) DCIS. Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease. Significance: These findings provide new mechanistic insight into progression of ductal carcinoma and support clinical application of MNK1 inhibitors to delay progression of indolent ductal carcinoma in situ to invasive ductal carcinoma.

The MNK1/2-eIF4E axis drives melanoma plasticity, progression, and resistance to immunotherapy

“…) and on-target engagement, as shown by the repression of phospho-eIF4E expression in the melanomas (Figure S7D). These data recapitulate our observations in the phospho-eIF4E deficient BRaf CA/+ /Pten lox/lox (eIF4E KI ) mice, and further supports that systemic inhibition of phospho-eIF4E by blocking MNK1/2, has efficacy in modulating both the tumor and TME in pre-clinical cancer models48,[82][83][84][85] . Strikingly, the combination therapy of SEL201 and anti-PD-1 monoclonal antibody significantly reduced primary melanoma growth, local and distant lymph node metastasis, and increased the overall survival of tumor-bearingBRaf CA/+ /Pten lox/lox mice compared to either of the therapies alone, without causing any overt toxicity (Figure 7C-7F and S7C-S7E).Analysis of plasma cytokine and chemokine levels revealed that the robust anti-tumor effect of SEL201 combined with anti-PD-1 therapy was associated with enhanced peripheral anti-tumor immunity, characterized by a decrease in the immunosuppressive cytokine/chemokine signature, including IL-6, CCL2 and CCL5 (Figure 7H).…”

“…We EMT plays an important role in tumor immune escape [95][96][97] . In this context, translational control, including the MNK1/2-eIF4E axis, has been implicated in promoting an EMT across different tumor types 10,85,98,99 . Our study links the MNK1/2-eIF4E axis with immune escape of melanoma though an EMT-like phenotype switch.…”

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

“…The data showed a positive correlation between MNK1 activity and the expression of NODAL and vimentin, regulators of invasion and metastasis. MNK1 inhibition with SEL201 could block NODAL signaling to suppress disease [103]. However, all the possible downstream factors and MNK-interactions are yet to be discovered.…”

Embryonic Protein NODAL Regulates the Breast Tumour Microenvironment by Reprogramming Cancer-Derived Secretomes

“…Because fibroblast activation (demarcated by α-SMA expression) and NODAL expression occur early during breast cancer progression 46 , we investigated whether these events could be correlated. We evaluated the expression and localization of NODAL and α-SMA in 41 primary tumour tissue samples from a cohort of 20 TNBC cases ( Table I).…”

“…In breast cancer, NODAL clinically correlates with stage and vascularization 44,45 . Moreover, NODAL expression emerges in breast cancers as they transition from DCIS into IDC 46 , wherein interactions between cancer and stromal cells are critical. NODAL inhibition reduces breast cancer-induced neovascularization and mitigates BCSC frequencies, tumour growth, and invasion [47][48][49] .…”