YAP Inhibition Restores Hepatocyte Differentiation in Advanced HCC, Leading to Tumor Regression

Cell Reports
J FitamantN Bardeesy

Abstract

Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. YAP functions as a rheostat in maintaining metabolic specialization, differentiation, and quiescence within the hepatocyte compartment. Increased or decreased YAP activity reprograms subsets of hepatocytes to different fates associated with deregulation of the HNF4A, CTNNB1, and E2F transcriptional programs that control hepatocyte quiescence and differentiation. Importantly, treatment with small interfering RNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model. Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of the positional identity of hepatocytes, supports targeting of YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype that is potentially responsive to this approach.

References

Mar 21, 2000·Genesis : the Journal of Genetics and Development·C Postic, M A Magnuson
Jun 3, 2006·Developmental Cell·Samira BenhamoucheSabine Colnot
Oct 24, 2006·The FEBS Journal·Albert BraeuningMichael Schwarz
Nov 6, 2007·Current Biology : CB·Fernando D CamargoThijn R Brummelkamp
Jul 25, 2008·The New England Journal of Medicine·Josep M LlovetUNKNOWN SHARP Investigators Study Group
Aug 15, 2008·Cancer Research·Derek Y ChiangJosep M Llovet
Nov 17, 2009·The International Journal of Biochemistry & Cell Biology·Cyril TorreSabine Colnot
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Li LuRandy L Johnson
Apr 21, 2010·Proceedings of the National Academy of Sciences of the United States of America·Kwang-Pyo LeeDae-Sik Lim
Aug 3, 2010·Genes & Development·Samira BenhamoucheAndrea I McClatchey
Aug 10, 2010·BMC Bioinformatics·Mali Salmon-DivonPaul Bertone
Oct 23, 2010·Nature Reviews. Cancer·Hugues de Thé, Zhu Chen
Mar 8, 2011·Cell·Karin SchlegelmilchFernando D Camargo
Oct 14, 2011·The New England Journal of Medicine·Hashem B El-Serag
Jul 20, 2012·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Anja LachenmayerJosep M Llovet
Feb 23, 2013·Genes & Development·Fa-Xing Yu, Kun-Liang Guan
Mar 8, 2013·Nature Reviews. Cancer·Kieran F HarveyDavid M Thomas
Mar 23, 2013·Genes & Development·Kilangsungla YangerBen Z Stanger
Nov 12, 2013·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Angélique GougeletSabine Colnot
Jun 7, 2014·Cell·Dean YimlamaiFernando D Camargo
Aug 19, 2014·Cell Stem Cell·Kilangsungla YangerBen Z Stanger

❮ Previous
Next ❯

Citations

Jun 11, 2015·Liver International : Official Journal of the International Association for the Study of the Liver·Poh Seng TanYujin Hoshida
Dec 26, 2015·Developmental Cell·Nilotpal Roy, Matthias Hebrok
Aug 15, 2015·Cellular and Molecular Gastroenterology and Hepatology·Luca MaroniGianfranco Alpini
Aug 1, 2015·Journal of Hepatology·Dean YimlamaiFernando D Camargo
Nov 15, 2015·Journal of Cellular Physiology·Justin T HuntingtonGustavo Leone
Jun 22, 2015·Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver·Quy NguyenHaibo Bai
Jun 20, 2015·Cellular and Molecular Life Sciences : CMLS·Carmen Berasain, Matías A Avila
Jun 10, 2015·Nature Reviews. Clinical Oncology·Josep M LlovetRichard S Finn
Apr 19, 2016·Nature Cell Biology·Lara Planas-PazJan S Tchorz
May 6, 2016·Nature Reviews. Gastroenterology & Hepatology·Audrey W HongKun-Liang Guan
Jun 15, 2016·Cancer Cell·Francesca ZanconatoStefano Piccolo
Jul 28, 2016·Nature Cell Biology·Dimitrios Anastasiou
Aug 23, 2016·The Journal of Clinical Investigation·Thomas BerteroStephen Y Chan
Oct 22, 2016·Current Opinion in Cell Biology·Iván M Moya, Georg Halder
Oct 22, 2016·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jing YiRandy L Johnson
Nov 4, 2016·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Wang-Yu CaiBo-An Li
Dec 23, 2016·Gastroenterology·Sachin H PatelDean Yimlamai
Jan 4, 2017·Gastroenterology·Daniela SiaJosep M Llovet
Mar 3, 2018·Genes·Saravana Kumar Kailasam Mani, Ourania Andrisani
Nov 22, 2017·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Ashley CastNikolai Timchenko
Oct 7, 2017·Cell Death and Differentiation·Noa FurthMoshe Oren
Apr 27, 2018·International Journal of Cancer. Journal International Du Cancer·Masahiro ShibataMohammad Obaidul Hoque
Oct 24, 2015·Nature Reviews. Cancer·Jens U MarquardtSnorri S Thorgeirsson
Dec 13, 2016·EMBO Molecular Medicine·Giulio LoforeseDeborah Stroka
Sep 20, 2019·The Journal of Pharmacology and Experimental Therapeutics·Taiki AbeKouichi Yoshinari
Dec 17, 2019·Therapeutic Delivery·Katherine E Redd BowmanCarol S Lim
Aug 11, 2019·Annual Review of Pathology·Sungjin KoSatdarshan P Monga
Feb 25, 2020·Molecular Systems Biology·Kirstin MeyerMarino Zerial
Nov 22, 2016·The Journal of Clinical Investigation·Wantae KimYingzi Yang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cancer Metabolism

In order for cancer cells to maintain rapid, uncontrolled cell proliferation, they must acquire a source of energy. Cancer cells acquire metabolic energy from their surrounding environment and utilize the host cell nutrients to do so. Here is the latest research on cancer metabolism.

Adrenocortical Carcinoma

Hepatocellular carcinoma is the most common type of primary liver cancer and frequently occurs in individuals with chronic liver diseases like cirrhosis. Here is the latest research.

Cancer Metabolic Reprogramming (Keystone)

Cancer metabolic reprogramming is important for the rapid growth and proliferation of cancer cells. Cancer cells have the ability to change their metabolic demands depending on their environment, regulated by the activation of oncogenes or loss of tumor suppressor genes. Here is the latest research on cancer metabolic reprogramming.

Carcinoma, Hepatocellular

Hepatocellular Carcinoma is a malignant cancer in liver epithelial cells. Discover the latest research on Hepatocellular Carcinoma here.

Cancer Metabolic Reprogramming

Cancer metabolic reprogramming is important for the rapid growth and proliferation of cancer cells. Cancer cells have the ability to change their metabolic demands depending on their environment, regulated by the activation of oncogenes or loss of tumor suppressor genes. Here is the latest research on cancer metabolic reprogramming.