Roles For The Cancer Stem Cell Marker Aldh1a1 In Merlin Null Nervous System Tumors

Our lab is interested in the development and growth of schwannoma and meningioma tumors of the nervous system. Approximately 70% of these tumors arise due to loss of the tumor suppressor Merlin. In a mouse model of schwannoma (P0-CRE NF2fl/fl), we observed increased mRNA levels of the cancer stem cell marker Aldehyde dehydrogenase 1A1 (Aldh1A1) in Merlin-null Schwann cells. Immunostaining showed elevated levels of Aldh1A1 protein in this mouse model and in another mouse model (Postn-CRE NF2fl/fl), in which schwannoma tumors arise spontaneously within the vestibulocochlear nerve and dorsal root ganglia of the nervous system. Similarly, staining of human schwannoma samples also showed a strong elevation of Aldh1A1 protein in all tumor cells. Parallel analysis of meningioma tumor samples, in which Merlin loss also occurs, also showed a strong increase of Aldh1A1 protein levels. Western blotting enabled identification of the mechanism by which Merlin loss regulates Aldh1A1. Merlin/TAZ double knockout, but not Merlin/YAP double knockout, sciatic nerves show reduced Aldh1A1 expression. This implicates Hippo signalling through the TAZ effector as the mechanism of Aldh1A1 upregulation both in vitro and in vivo in both tumor types. Chemical inhibition with Aldh1a1-specific inhibitor (NCT-505) or shRNA knockdown of Aldh1A1 in Merlin-null schwannoma and meningioma cells in culture attenuated tumor cell growth, proving Aldh1A1 has a role in tumor cell proliferation; studies using Aldh1A1 null mice to test this in vivo are ongoing. A major target of Aldh1A1 signalling is the regulation of retinoic acid (RA) signalling. We are examining expression and activation of components of RA signalling in both schwannoma and meningioma tumor cells to identify whether this may be of therapeutic use in the future for these two tumor types. In conclusion, the TAZ-dependent upregulation of Aldh1A1 in Merlin-null schwannoma and meningioma tumor cells has a functional role in driving cell proliferation in these two clinically important tumor types. Further work will seek to identify the mechanism by which Aldh1A1 activity contributes to tumor growth. Citation Format: Lily Hillson, Liyam Laraba, Aditya G. Shivane, Philip Edwards, Ganesha Bantukallu, Anton Simeonov, Natalia J. Martinez, Shyh-Ming Yang, David B. Parkinson. Roles for the cancer stem cell marker Aldh1A1 in Merlin null nervous system tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5957.