Abstract 5777: Translation of HPV mediated immortalization to cancer precision medicine

Abstract

Abstract The E6/E7 oncogenes of the high-risk HPVs are both necessary and sufficient to immortalize HFKs and their presence and expression is required for the continued proliferation of HPV-positive cervical cancer cells. We and others have shown previously that hTERT induced by E6 and cytoskeleton alteration by E7 are critical. Both E6 and feeder cells activate telomerase, while both E7 and Rock inhibitor (Y-27632) disrupt the actin cytoskeleton and inactivate Rho. Feeders and Y-27632 to induce unlimited cell proliferation of human keratinocytes. Unexpectedly, we observed that feeders and Y-27632 could be used to establish both normal and tumor cell cultures from non-keratinocyte tissues. This culture has been termed as “conditional reprogramming”, since CR cultures stop proliferating or terminally differentiate after its removal, depending on culture conditions. The Combination of CR and Organoids ( (Matrigel, air-liquid interface (ALI)) cultures represents next generation human cancer models and functional diagnostics for cancer precision medicine as described in August 2015 in the NCI precision medicine initiative and three nature review articles (Nat Rev Cancer. 2015 Dec; Nat Rev Genet. 2015 Jul; Nat Rev Clin Oncol. 2014 Nov.). The technique is relatively simple and has been reproduced in more than 50 laboratories (including an original and independent article in Science from Massachusetts General Hospital) (Science. 2014, 346(6216):1480-6.). Importantly, the CR technology can generate 2x10<6cells in a week from small biopsies, and can generate cultures from cryopreserved tissue and small biopsies. We therefore initiated studies to examine whether CR cultures reflected the biology and genotype of the original tumor and whether cultures might be used to predict clinical responses. Moreover, the epithelial cells can be propagated indefinitely in vitro, yet retain the capacity to become fully differentiated when placed into conditions that mimic their natural environment. Thus, the CR method significantly advances applications for regenerative medicine. Citation Format: Aleksandra Dakic, Nancy Palechor-Ceron, Ewa Krawczyk, Hang Yuan, Frank Suprynowicz, Seema Agarwal, Richard Schlegel, Vera Simic, Praathibha Sripadhan, Chen Chen, Jie Lu, Tung-Wei Hou, Sujata Choudhury, Xuefeng Liu. Translation of HPV mediated immortalization to cancer precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5777. doi:10.1158/1538-7445.AM2017-5777