BEYOND INFECTION: INNATE IMMUNE RECEPTORS AS AN EMERGING BRAKE ON METASTASIS ABSTRACT Innate immune signaling is a key mammalian defense against pathogens. Importantly, these signaling networks are critically linked to human disease even outside the realm of infections. This facet of innate immunity remains largely elusive and forms the subject of my research. My thesis focuses on the pseudokinase RNase L, which is most strongly activated during infection. RNase L is triggered by 2'-5'-linked iso-RNAs, produced by oligoadenylate synthetases (OASs) upon sensing double-stranded RNA (dsRNA) commonly thought to come from RNA viruses. RNase L is essential for coping with bacterial and viral infections. RNase L is also a major regulator of cell cycle progression, differentiation, and apoptosis, processes often misregulated in cancers. Notably, many RNase L mutations predispose men to an elevated risk of inherited prostate cancer. Moreover, my preliminary results uncover that dampened RNase L expression strongly correlates with increased breast cancer aggressiveness. The effect of RNase L on tumor suppression is striking but its molecular mechanism is unclear. My work identifies the first cellular targets of human RNase L outside infection, tackling a challenge faced since the discovery of RNase L in 1980. Serendipitously, RNase L targets perfectly overlap with those of a well-established tumor-suppressor, miR-200, and one of their common targets is the master regulator of metastasis, ZEB1. These results suggest a direct molecular mechanism for the role of RNase L in controlling metastasis, which I seek to examine during my F99 phase. In addition, I will isolate endogenous dsRNAs, predicted to be elevated in cancers, which can feed into the OAS/RNase L axis. Thus, I will test if OASs are a dsRNA surveillance mechanism against not only viruses but also cancer. This work will uncover the molecular mechanism for a major non-immune function of the OAS/RNase L axis, informing novel diagnostic and therapeutic strategies against metastasis. My thesis initiates me into the emerging field of innate immunity in cancer and seeds my postdoctoral research directions. With rigorous training and an exciting potential to serve human health, I am on a perfect trajectory to launch an independent career at the forefront of cancer immunology.
The innate immune receptor RNase L is a promising diagnostic and therapeutic target because it is not only critical for combating viral and bacterial infections, but is also a major regulator of growth, cell proliferation and differentiation, which are strong determinants of cancer risk. My thesis work begins to elucidate the molecular mechanism for the role of RNase L-induced RNA decay in breast cancer metastasis for the first time. This work provides a fundamentally novel framework to treat human cancers by targeting innate immune receptors which inspires my postdoctoral and independent research directions.