Abstract 3526: Novel function of NRP2 in therapy resistant metastatic cancer

Abstract

Abstract Neuropilins (NRPs) are cell surface glycoproteins known for their role as co-receptors for plexins and VEGF family members in neuronal development and vascular and lymphatic growth. Neuropilin-2 (NRP2), a family member of NRPs has been reported to enhance the survival of cancer cells following therapeutic stress. In a recent study, our group has shown that the expression of NRP2 can be a poor prognostic factor for invasive bladder cancer patients treated with radiochemotherapy. Its expression correlated with an increased risk of an early cancer specific death and significantly decreased cancer specific survival among these patients supporting its role as a promoter of therapy resistance. This function of NRP2 is distinctly different from its known function as a co-receptor. In this study, we have provided the molecular mechanism of how NRP2 imparts therapy resistance in cancer cells. Our results indicate that depletion of NRP2 inhibits autophagy, a process which promotes survival of cancer cells during therapeutic stress. Further, we observed a role of NRP2 in the maturation of early to late endosomes. Since late endosomes are required for the fusion of autophagosomes with lysosomes, the decrease in the formation of late endosomes following NRP2 depletion can explain the defect in autophagy observed during inhibition of the NRP2 axis. We have provided a detailed molecular mechanism of how the recruitment and functions of several endocytic proteins such as EHD4, Rubicon, Mon1 and PIKFYVE are affected due to the depletion of NRP2, which resulted in the defect in endosomal trafficking. Recent evidences indicate that cancer cells maintain a high endosomal trafficking activity and the defect in trafficking promotes aberrant cellular signaling cascades either by interfering with receptor recycling to the cell surface or by inhibiting their lysosomal degradation. In this respect our data demonstrate that depletion of the NRP2 axis leads to an increased accumulation of active EGFR in early endosomes, which induces aberrant signaling cascade to promote apoptosis in cancer cells. We were also able to identify a novel downstream target of NRP2 axis known as WD Repeat and FYVE Domain Containing 1 (WDFY1). Our data indicate that depletion of NRP2 transcriptionally upregulates the expression of WDFY1. This is achieved due to an inhibition of the nuclear localization of a transcriptional inhibitor FAC1. Overall, our data suggest that NRP2 axis maintains the expression of WDFY1 in cancer cells to promote enhanced level of endocytic acitivity and autophagy. NRP2 is therefore important for the progression and survival of metastatic cancer cells and targeting this axis is crucial to enhance therapeutic efficacy of aggressive malignancies. Citation Format: Samikshan Dutta, Sohini Roy, Navatha S. Polavaram, Marissa Stanton, Surinder Batra, Michael H. Muders, Kaustubh Datta. Novel function of NRP2 in therapy resistant metastatic cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3526.