Abstract LB-321: TP63 isoforms regulate distinct and cooperative transcriptional signatures that drive cancer progression and predict clinical outcomes

TP63 is required to maintain stem cell pluripotency and suppresses the metastatic potential of cancer cells through multiple mechanisms. Even though roles for Tp63 in cancer have been described, the transcriptional roles of TP63 isoforms, namely TAp63 and ΔNp63, in tumor development and progression have been perplexing due to their variable expression in tissues, their complex interaction with each other and with TP53, and the lack of adequate antibodies to distinguish between their isoforms. Of concern is the use of total p63 as a diagnostic marker for many epithelial cancers in the clinic with disregard of the existence and functions of the various isoforms, which may lead to improper diagnosis. These notions necessitate a deeper understanding of how the distinct transcriptional programs controlled by TP63 isoforms affect cancer progression and patient outcomes. To shed light on the activities of the TP63 isoforms in cancer development and progression, we conducted a pan-cancer analysis of The Cancer Genome Atlas (TCGA) to identify the transcriptional networks regulated by TAp63 and ΔNp63 using transcriptomes derived from epidermal cells of TAp63-/- and ΔNp63-/- mice. We then derived 17 cancer developmental (tumor versus corresponding normal) and 27 cancer progression (high stage versus low stage) signatures. Our analysis revealed a consistent tumor suppressive pattern for TAp63. In contrast, we identified pleiotropic roles for ΔNp63 in tumor development and progression. Our findings revealed a cooperative role between TAp63 and ΔNp63 via their gene signatures that predict survival and correlates with progression of cancer patients in bladder cancer (BLCA), clear cell renal cell carcinoma (KIRC), papillary renal cell carcinoma (KIRP) and low grade glioma. Importantly, we found that ΔNp63 transcriptional activity integrates the remodeling of extracellular matrix remodeling to provide an ideal environment in these cancers to undergo epithelial to mesenchymal transition and gain pluripotent stem cell characteristics, thus supporting tumor progression, while TAp63 activity acts to regulate the cell cycle required in stem cell maintenance which may further allow tumors to progress. These signatures are not only predictive of survival across stages, but can even stratify patients within the same stage into different survival groups in the genitourinary tumors as well as in low grade gliomas. We then validated our findings in independent cohorts. Our data describe a global approach for understanding transcriptional activities of TP63 isoforms across a large number of cancer types, potentially enabling the identification of patient subsets most likely to benefit from therapies predicated on manipulating specific TP63 isoforms in order to inhibit the acquisition of pluripotency potential. Citation Format: Hussein Abbas, Kimal Rajapakshe, Justin Wong, Ngoc Hoang Bao Bui, Preethi Gunaratne, Kenneth Tsai, Cristian Coarfa, Elsa Flores. TP63 isoforms regulate distinct and cooperative transcriptional signatures that drive cancer progression and predict clinical outcomes. [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 LB-321.