FABP4 as a key determinant of metastatic potential of ovarian cancer.

The standard treatment for high-grade serous ovarian cancer is primary debulking surgery followed by chemotherapy. The extent of metastasis and invasive potential of lesions can influence the outcome of these primary surgeries. Here, we explored the underlying mechanisms that could increase metastatic potential in ovarian cancer. We discovered that FABP4 (fatty acid binding protein) can substantially increase the metastatic potential of cancer cells. We also found that miR-409-3p regulates FABP4 in ovarian cancer cells and that hypoxia decreases miR-409-3p levels. Treatment with DOPC nanoliposomes containing either miR-409-3p mimic or FABP4 siRNA inhibited tumor progression in mouse models. With RPPA and metabolite arrays, we found that FABP4 regulates pathways associated with metastasis and affects metabolic pathways in ovarian cancer cells. Collectively, these findings demonstrate that FABP4 is functionally responsible for aggressive patterns of disease that likely contribute to poor prognosis in ovarian cancer.

Stress hormones promote EGFR inhibitor resistance in NSCLC: Implications for combinations with ß-blockers.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance mediated by T790M-independent mechanisms remains a major challenge in the treatment of non-small cell lung cancer (NSCLC). We identified a targetable mechanism of EGFR inhibitor resistance whereby stress hormones activate ß2-adrenergic receptors (ß2-ARs) on NSCLC cells, which cooperatively signal with mutant EGFR, resulting in the inactivation of the tumor suppressor, liver kinase B1 (LKB1), and subsequently induce interleukin-6 (IL-6) expression. We show that stress and ß2-AR activation promote tumor growth and EGFR inhibitor resistance, which can be abrogated with ß-blockers or IL-6 inhibition. IL-6 was associated with a worse outcome in EGFR TKI-treated NSCLC patients, and ß-blocker use was associated with lower IL-6 concentrations and improved benefit from EGFR inhibitors. These findings provide evidence that chronic stress hormones promote EGFR TKI resistance via ß2-AR signaling by an LKB1/CREB (cyclic adenosine 3',5'-monophosphate response element-binding protein)/IL-6-dependent mechanism and suggest that combinations of ß-blockers with EGFR TKIs merit further investigation as a strategy to abrogate resistance.

The ZNF304-integrin axis protects against anoikis in cancer.

Ovarian cancer (OC) is a highly metastatic disease, but no effective strategies to target this process are currently available. Here, an integrative computational analysis of the Cancer Genome Atlas OC data set and experimental validation identifies a zinc finger transcription factor ZNF304 associated with OC metastasis. High tumoral ZNF304 expression is associated with poor overall survival in OC patients. Through reverse phase protein array analysis, we demonstrate that ZNF304 promotes multiple proto-oncogenic pathways important for cell survival, migration and invasion. ZNF304 transcriptionally regulates ß1 integrin, which subsequently regulates Src/focal adhesion kinase and paxillin and prevents anoikis. In vivo delivery of ZNF304 siRNA by a dual assembly nanoparticle leads to sustained gene silencing for 14 days, increased anoikis and reduced tumour growth in orthotopic mouse models of OC. Taken together, ZNF304 is a transcriptional regulator of ß1 integrin, promotes cancer cell survival and protects against anoikis in OC.