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C03: HCC and the hepatic vascular niche: Analysis of angiocrine and adhesive vascular targets

The angiogenic activity of hepatocellular carcinoma (HCC) has been correlated with high risk of microvascular invasion, metastasis and poor prognosis. Correspondingly, HCC is among the few tumor types in which anti-angiogenesis has some efficacy as monotherapy. Yet, the overall clinical efficacy is limited and the molecular mechanisms of HCC angiogenesis remain poorly understood. Moreover, no treatment is capable to reduce the high frequency of post-resection HCC recurrence that remains a major clinical concern for the prognosis of HCC. The intrahepatic sinusoidal vasculature has unique organ-specific characteristics with a dual arterial/venous blood supply. It is therefore conceivable that tumor angiogenic processes in HCC are mechanistically different from angiogenesis in other solid tumors including hitherto poorly understood processes of vascular reprogramming termed “capillarization”. To systematically study the mechanisms and therapeutic potential of HCC angiogenesis, the two partnering laboratories have joined forces to exploit their labs’ specific expertise in liver sinusoidal endothelial cell (LSEC) biology (Goerdt laboratory) and tumor angiogenesis (Augustin laboratory) towards a concerted effort to study tumor-vessel interactions during HCC progression and postsurgical recurrence. On the basis of this collaboration, we have thoroughly studied (i) the molecular repertoire of LSEC including angiocrine regulation of liver homeostasis and hepatocyte proliferation as well as (ii) hepatic microvascular reprogramming during hepatocarcinogenesis in a novel preclinical HCC model suitable for proof-of-concept therapy experiments (iAST model). These findings straightforwardly guide the experimental program of project C3: First, we propose to mechanistically study the functional crosstalk between LSEC and HCC cells concentrating on LSEC-specific angiokines (Wnt, Bmp2 and HGF) as well as on candidate molecules for liver-specific HCC-EC adhesion and transmigration (stabilin 2, LYVE-1, and CD44).
Second, we propose to identify and validate known and novel angiocrine and angiogenic factors as vascular targets in HCC and to exploit the therapy-validated iAST model for the systematic and rational preclinical development of novel angio-directed combination therapies. The iAST model will towards this end be advanced to a locally induced tumor model that upon primary tumor removal allows the study of metastasis and recurrence providing the first mouse model recapitulating post-surgical recurrence of human HCC. This advanced tumor model coupled to above mentioned pre-clinical studies (combination therapies) will enable the assessment of the functional role of different candidate molecules in promoting HCC recurrence. Together, the experimental program aims to unravel the complexity of tumor-vessel crosstalk during HCC angiogenesis and microvascular invasion for the preclinical validation and proof-of-principle exploitation of novel therapeutic targets.

Publications

Wohlfeil SA, Häfele V, Dietsch B, Schledzewski K, Winkler M, Zierow J, Leibing T, Malek Mohammadi M, Heineke J, Sticht C, Olsavszky V, Koch PS, Géraud C, Goerdt S (2018) Hepatic endothelial Notch activation protects against liver metastasis by regulating endothelial-tumor cell adhesion independent of angiocrine signaling. Cancer Res, pii: canres.1752.2018.
Singhal M, Liu X, Inverso D, Jiang K, Dai J, He H, Bartels S, Li W, Abdul Pari AA, Gengenbacher N, Besemfelder E, Hui L, Augustin HG*, Hu J* (2018) Endothelial cell fitness dictates the source of regenerating liver vasculature. J Exp Med, 215:2497-508 (*equal contribution).
Schmid CD, Schledzewski K, Mogler C, Waldburger N, Kalna V, Marx A, Randi AM, Géraud C, Goerdt S, Koch PS (2018) GPR182 is a novel marker for sinusoidal endothelial differentiation with distinct GPCR signaling activity in vitro. Biochem Biophys Res Commun, 497: 32-8.
Leibing T*, Géraud C*, Augustin I, Boutros M, Augustin HG, Okun JG, Langhans CD, Zierow J, Wohlfeil SA, Olsavszky V, Schledzewski K, Goerdt S, Koch PS (2018) Angiocrine Wnt signaling controls liver growth and metabolic maturation in mice. Hepatology, 68: 707-22 (*equal contribution).
Olsavszky V, Ulbrich F, Singh S, Diett M, Sticht C, Schmid CD, Zierow J, Wohlfeil SA, Schledzewski K, Dooley S, Gaitantzi H, Breitkopf-Heinlein K, Géraud C, Goerdt S, Koch PS (2017) GATA4 and LMO3 balance angiocrine signaling and autocrine inflammatory activation by BMP2 in liver sinusoidal endothelial cells. Gene, 627: 491-9.
Augustin HG, Koh GY (2017) Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology. Science, 357, pii: eaal2379.
Géraud C, Koch PS, Zierow J, Klapproth K, Busch K, Olsavszky V, Leibing T, Demory A, Ulbrich F, Diett M, Singh S, Sticht C, Breitkopf-Heinlein K, Richter K, Karppinen SM, Pihlajaniemi T, Arnold B, Rodewald HR, Augustin HG, Schledzewski K, Goerdt S (2017) GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis. J Clin Invest, 127: 1099-114.
Koch PS#, Olsavszky V#, Ulbrich F, Sticht C, Demory A, Leibing T, Henzler T, Meyer M, Zierow J, Schneider S, Breitkopf-Heinlein K, Gaitantzi H, Spencer-Dene B, Arnold B, Klapproth K, Schledzewski K, Goerdt S*, Géraud C* (2017) Angiocrine Bmp2 signaling in murine liver controls normal iron homeostasis. Blood, 129: 415-9 (#,*equal contribution).
Mogler C, König C, Wieland M, Runge A, Besemfelder E, Komljenovic D, Longerich T, Schirmacher P, Augustin HG (2017) Hepatic stellate cells limit hepatocellular carcinoma progression through the orphan receptor endosialin. EMBO Mol Med, 9:741-9.
Viski C#, König C#, Kijewska M, Mogler C, Isacke CM*, Augustin HG* (2016) Endosialin-expressing pericytes promote metastatic dissemination. Cancer Res, 76: 5313-25,c 2016 (#,*equal contribution).
Mogler C, Wieland M, K.nig C, Hu J, Runge A, Korn C, Besemfelder E, Breitkopf-Heinlein K, Komljenovic D, Dooley S, Schirmacher P , Longerich T, Augustin HG (2015) Hepatic stellate cellexpressed Endosialin balances fibrogenesis and hepatocyte proliferation during liver damage. EMBO Mol Med, 7:332-338.
Runge A, Hu J, Wieland M, Bergeest JP, Mogler C, Neumann A, Géraud C, Arnold B, Rohr K, Komljenovic D, Schirmacher P, Goerdt S, Augustin HG (2014) An inducible hepatocellular carcinoma model for preclinical evaluation of antiangiogenic therapy in adult mice. Cancer Res, 74:4157-69.
Hu J, Srivastava K, Wieland M, Runge A, Mogler C, Besemfelder E, Terhardt D, Vogel MJ, Cao L, Korn C, Bartels S, Thomas M, Augustin HG (2014). Endothelial cell-derived angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science, 343:416-9.
Géraud C, Mogler C, Runge A, Evdokimov K, Lu S, Schledzewski K, Arnold B, Hämmerling G, Koch P, Breuhahn K, Longerich T, Marx A, Weiss C, Schmieder A, Schirmacher P, Augustin HG, Goerdt S (2013) Endothelial transdifferentiation in hepatocellular carcinoma: loss of stabilin-2 expression in peritumorous liver tissue correlates with increased survival. Liver Int, 33:1428-40.
Géraud C*, Evdokimov K*, Straub BK, Peitsch WK, Demory A, Dorflinger Y, Schledzewski K, Schmieder A, Schemmer P, Augustin HG, Schirmacher P, Goerdt S (2012) Unique cell type-specific junctional complexes in vascular endothelium of human and rat liver sinusoids. PloS One, 7:e34206.
Felcht M, Luck R, Schering A, Seidel P, Srivastava K, Hu J, Bartol A, Kienast Y, Vettel C, Loos EK, Kutschera S, Bartels S, Appak S, Besemfelder E, Terhardt D, Chavakis E, Wieland T, Klein C, Thomas M, Uemura A, Goerdt S, Augustin HG (2012) Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling. J Clin Invest, 122:1991-2005.
Schledzewski K*, Géraud C*, Arnold B, Wang S, Gr.ne HJ, Kempf T, Wollert KC, Straub BK, Schirmacher P, Demory A, Schönhaber H, Gratchev A, Dietz L, Thierse HJ, Kzhyshkowska J, Goerdt S (2011) Deficiency of liver sinusoidal scavenger receptors stabilin-1 and -2 in mice causes glomerulofibrotic nephropathy via impaired hepatic clearance of noxious blood factors. J Clin Invest, 121:703-14.
Géraud C*, Schledzewski K*, Demory A, Klein D, Kaus M, Peyre F, Sticht C, Evdokimov K, Lu S, Schmieder A, Goerdt S (2010) Liver sinusoidal endothelium: a microenvironment-dependent differentiation program in rat including the novel junctional protein liver endothelial differentiation-associated protein-1. Hepatology, 52:313-326.