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Title: | R-spondin 2 drives liver tumor development in a yes-associated protein-dependent manner | Authors: | Conboy, CB Velez-Reyes, GL Tschida, BR Hu, H Kaufmann, G Koes, N Keller, B Alsinet, C Cornella, H Pinyol, R Abrahante, JE Temiz, NA Linden, MA Amin, K Kuka, TP Keng, VW Llovet, JM Starr, TK Largaespada, DA |
Issue Date: | Nov-2019 | Source: | Hepatology communications, Nov. 2019, , v. 3, no. 11, p. 1496-1509 | Abstract: | Each year, more than 25,000 people succumb to liver cancer in the United States, and this neoplasm represents the second cause of cancer-related death globally. R-spondins (RSPOs) are secreted regulators of Wnt signaling that function in development and promote tissue stem cell renewal. In cancer, RSPOs 2 and 3 are oncogenes first identified by insertional mutagenesis screens in tumors induced by mouse mammary tumor virus and by transposon mutagenesis in the colonic epithelium of rodents. RSPO2 has been reported to be activated by chromosomal rearrangements in colorectal cancer and overexpressed in a subset of hepatocellular carcinoma. Using human liver tumor gene expression data, we first discovered that a subset of liver cancers were characterized by high levels of RSPO2 in contrast to low levels in adjacent nontumor tissue. To determine if RSPOs are capable of inducing liver tumors, we used an in vivo model from which we found that overexpression of RSPO2 in the liver promoted Wnt signaling, hepatomegaly, and enhanced liver tumor formation when combined with loss of transformation-related protein 53 (Trp53). Moreover, the Hippo/yes-associated protein (Yap) pathway has been implicated in many human cancers, influencing cell survival. Histologic and gene expression studies showed activation of Wnt/beta-catenin and Hippo/Yap pathways following RSPO2 overexpression. We demonstrate that knockdown of Yap1 leads to reduced tumor penetrance following RSPO2 overexpression in the context of loss of Trp53. Conclusion: RSPO2 overexpression leads to tumor formation in the mouse liver in a Hippo/Yap-dependent manner. Overall, our results suggest a role for Yap in the initiation and progression of liver tumors and uncover a novel pathway activated in RSPO2-induced malignancies. We show that RSPO2 promotes liver tumor formation in vivo and in vitro and that RSPO2's oncogenic activity requires Hippo/Yap activation in hepatocytes. Both RSPO2 and YAP1 are suggested to represent novel druggable targets in Wnt-driven tumors of the liver. | Publisher: | John Wiley & Sons | Journal: | Hepatology communications | EISSN: | 2471-254X | DOI: | 10.1002/hep4.1422 | Rights: | © 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. The following publication Conboy, C.B., Vélez‐Reyes, G.L., Tschida, B.R., Hu, H., Kaufmann, G., Koes, N., Keller, B., Alsinet, C., Cornellà, H., Pinyol, R., Abrahante, J.E., Temiz, N.A., Linden, M.A., Amin, K., Kuka, T.P., Keng, V.W., Llovet, J.M., Starr, T.K. and Largaespada, D.A. (2019), R‐spondin 2 Drives Liver Tumor Development in a Yes‐Associated Protein‐Dependent Manner. Hepatol Commun, 3: 1496-1509 is available at https://dx.doi.org/10.1002/hep4.1422 |
Appears in Collections: | Journal/Magazine Article |
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