Natural Killer cell activation and pancreatic cancer
The hippo pathway is an established regulator of proliferation and cell fate during development, with loss of activity associated with nearly all solid cancers. The pathway transduces cellular signals via the RASSF1-6 and Sav1 protein scaffolds to MST and LATS kinases to modify transcription factors Runx2, p73 and YAP/TAZ. Single cell sequencing has identified enhanced expression of RASSF1A in discrete immune populations of T and NK cells, indicating a potential functional relevance in these cells. We previously found loss of RASSF1A expression in breast and lung tumours was associated with reduced IL2 and IL15 signalling (Pefani et al. 2016), which are activating cytokines of NK cells. Activation of NK cells upon viral infection also results in epigenetic marking of the RASSF1 which is proposed to predispose to tumours (Okamoto et al.). Moreover, Loss of RASSF1A by epigenetic silencing, or an inactivating polymorphism, is widely described to contribute to tumour development. However, we do not know the effect of RASSF1A loss on NK cell function or whether this contributes to control of emerging tumours in vivo. Interestingly the RASSF1A interacting kinases MST1 and MST2, also contribute to iNKT development (Raynor et al.), suggest RASSF1A/MST component of hippo signalling is preserved.
This project is a collaboration between Eric O’Neill (hippo pathway signalling pancreatic cancer) and Dimitra Peppa, Nuffield Department Medicine research building (NK cell biology) in which we will question how RASSF1A and MST kinases contribute to NK cell activation.
We have also developed a mouse model expressing the RASSF1A inactivating polymorphism (rs2073498; outlined in Yee et al.; Pefani et al.) and find this also accelerates colorectal and pancreatic dysplasia. We want to investigate whether NK cells contribute to these phenotypes or progression of cancers in the tumour prone KrasG12D mouse model. The ultimate aim is to determine whether NK cells are an important component of tumour control in pancreatic cancer.
- Pefani et al. Mol Cell 2016
- Okamoto et al. Gasteroenterology 2014
- Raynor et al. J Exp Med. 2020
- Yee et al. Cancer Res 2012;
- Pefani et al. Nat cell Biol 2014