Group Breuhahn/Weiler

Hepatocellular Carcinoma (HCC): A Global Challenge

With over 700,000 new cases annually, hepatocellular carcinoma (HCC) ranks among the leading causes of cancer-related mortality worldwide. While its risk factors—such as chronic viral hepatitis, alcoholic and non-alcoholic steatohepatitis—are well-defined and detectable in up to 90% of cases, the genetic heterogeneity of HCC severely complicates the development of effective therapies. We believe that the current lack of efficient systemic treatments underscores the urgent need for innovative therapeutic strategies.

Liver cancer development is a multi-step process

Chronic hepatitis triggers repeated cycles of hepatocyte death and tissue regeneration. Activation of hepatic stellate cells and extracellular matrix production are hallmarks of advanced liver disease, including fibrosis and cirrhosis. Mitotically active hepatocytes acquire somatic mutations and copy-number alterations, promoting early HCC formation. Additional epigenetic changes and deregulation of molecular signaling pathways drive HCC progression.

Transcriptional Regulators (TRs) - Cellular Bottlenecks in Signal Transduction Transcriptional Regulators (TRs) - Cellular Bottlenecks in Signal Transduction

TRs—such as transcription factors and co-activators—act as cellular bottlenecks in signal transduction. In carcinogenesis, numerous TRs and their upstream regulators are deregulated, leading to tumor cell proliferation and resistance to apoptosis. Our group focuses on the regulation and function of TRs involved in regenerative processes, HCC development, and progression. We aim to elucidate how TRs support tumorigenesis and whether they can serve as biomarkers for patient stratification.

The Hippo Signaling Pathway: YAP/TAZ as Central Oncogenes

The Hippo signaling pathway detects cell density and inhibits its transcriptional coactivators, yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). In hepatocarcinogenesis, YAP acts as an oncogene because inactivating Hippo pathway components (such as Mst1/2) or overexpressing YAP quickly triggers liver tumor development in mice. We found that YAP is overexpressed in a subset of human HCCs and promotes tumor cell growth and invasion.

1. Septins in Cell Physiology and Carcinogenesis (SME Weiler) Septins, alongside actin, microtubules, and intermediate filaments, form the fourth component of the cytoskeleton. Our work shows that the YAP/TAZ target gene SEPTIN10 is upregulated in liver cancer and correlates with poor patient prognosis. SEPTIN10 acts as a mechanotransducer, regulating actin and microtubule structures. We aim to investigate the roles of septins in YAP/TAZ regulation and their contribution to hepatocarcinogenesis.

2. Long Non-Coding RNAs (lncRNAs) as Cancer Biomarkers (K Breuhahn) lncRNAs influence liver tumorigenesis through diverse mechanisms and can serve as biomarkers for tumor-supporting signaling pathways. This project aims to define lncRNA signatures that provide insights into cellular processes in tissue or serum from cancer patients, enabling early detection of dysregulated oncogenes or pathways—even before imaging detects solid tumors.

Patent: Diagnostic Methods and Assays for lncRNA Detection (European patent application: 22210144.6; filed: Nov 29, 2022; published: Jun 5, 2024).

Principal Investigators
• Prof. Dr. Kai Breuhahn (kai.breuhahn(at)med.uni-heidelberg.de)
• Dr. Sofia ME Weiler (sofia.weiler(at)med.uni-heidelberg.de)

Team 
• Fabiola Pedrini (fabiola.pedrini(at)med.uni-heidelberg.de)
• Karl Gustav Mau (karlgustav.mau(at)med.uni-heidelberg.de)
• Michaela Bissinger (michaela.bissinger(at)med.uni-heidelberg.de)
• Jennifer Schmitt (jennifer.schmitt(at)med.uni-heidelberg.de)
• Nicolas Johannes Müller (nicolas.mueller(at)stud.uni-heidelberg.de)
• Bianca Metze (Lab Support; bianca.metze(at)med.uni-heidelberg.de)
 

• Prof. Arndt Vogel (MHH, Hannover)
• PD Dr. Anna Saborowski (MHH, Hannover)
• Prof. Heike Bantel (MHH, Hannover)
• Prof. Jan Hengstler (IfADo, Dortmund)
• Prof. Ahmed Abdelaziz Fahmy (NewGiza University, Cairo)
• Prof. Mathias Heikenwälder (M3 Research Center, Tübingen)

• Wilhelm Sander Foundation (WSS)
• German Research Foundation (DFG)
• German Cancer Aid (Deutsche Krebshilfe)
 

• Medical students for experimental projects (2 semesters full-time)
• Master’s students for thesis projects (supervised by experienced scientists/PhD students)
• Researchers with external funding
 

Tóth M, ... Weiler SME, Breuhahn K. The Cell Polarity Protein MPP5/PALS1 Controls the Subcellular Localization of the Oncogenes YAP and TAZ in Liver Cancer. Int J Mol Sci. 2025; 14;26(2):660. (not available, yet)

Wesener MC, Weiler SME, ... Breuhahn K. CRKL Enhances YAP Signaling through Binding and JNK/JUN Pathway Activation in Liver Cancer. Int J Mol Sci 2024; Aug 5;25(15):8549. (IF: 4.9)

Liu K, ... Weiler SME, ... Breuhahn K. Dynamic YAP expression in the non-parenchymal liver cell compartment controls heterologous cell communication. Cell Mol Life Sci 2024; 81: 115. (IF: 6.2)

Weiler SME, ... Breuhahn K. SEPTIN10-mediated crosstalk between cytoskeletal networks controls mechanotransduction and oncogenic YAP/TAZ signaling. Cancer Lett; 2024 Mar 1:584:216637. (IF: 9.1)

Tang Y, ... Weiler SME, ... Breuhahn K. α-catenin interaction with YAP/FoxM1/TEAD-induced CEP55 supports liver cancer cell migration. Cell Commun Signal 2023 Jun 28;21(1):162. (IF: 8.4)

Wehling L, ... Breuhahn K. Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury. eLife. 2022 Oct 8;11:e78540. (IF: 7.7)

Tóth M, ... Weiler SME, ... Breuhahn K, Co-expression of YAP and TAZ associates with chromosomal instability in human cholangiocarcinoma. BMC Cancer. 2021 Oct 6;21(1):1079. (IF: 4.64)

Thomann S, Weiler SME, ... Breuhahn K. YAP-induced Ccl2 expression is associated with a switch in hepatic macrophage identity and vascular remodelling in liver cancer. Liver Int. 2021 Dec;41(12):3011-3023. (IF: 8.75)

Marquard S, ... Weiler SME, ... Breuhahn K. Yes-associated protein (YAP) induces a secretome phenotype and transcriptionally regulates plasminogen activator Inhibitor-1 (PAI-1) expression in hepatocarcinogenesis. Cell Commun Signal. 2020 Oct 23;18(1):166. (IF: 5.71)

Thomann S, Weiler SME, ... Breuhahn K. YAP Orchestrates Heterotypic Endothelial Cell Communication via HGF/c-MET Signaling in Liver Tumorigenesis. Cancer Res. 2020 Dec 15;80(24):5502-5514.  (IF: 12.70)

Weiler SME, ... Breuhahn K. TAZ target gene ITGAV regulates invasion and feeds back positively on YAP and TAZ in liver cancer cells. Cancer Lett. 2020 Mar 31;473:164-175. (IF: 8.68)

Wei T, Weiler SME, ... Breuhahn K. YAP-dependent induction of UHMK1 supports nuclear enrichment of the oncogene MYBL2 and proliferation in liver cancer cells. Oncogene. 2019 Jul;38(27):5541-5550. (IF: 6.6)

Wan S, ... Weiler SME, ... Breuhahn K. Cytoplasmic localization of the cell polarity factor scribble supports liver tumor formation and tumor cell invasiveness. Hepatology. 2018 May;67(5):1842-1856. (IF: 15.0)

Weiler SME, ... Breuhahn K. Induction of Chromosome Instability by Activation of Yes-Associated Protein and Forkhead Box M1 in Liver Cancer. Gastroenterology. 2017Jun;152(8):2037-2051. (IF: 20.8)

Tschaharganeh DF, ... Breuhahn K. Yes-Associated Protein Up-regulates Jagged-1 and Activates the NOTCH Pathway in Human Hepatocellular Carcinoma. Gastroenterology. 2013 Jun;144(7):1530-1542. (IF: 13.9)

Straßburger K, ... Breuhahn K, Teleman AA. Insulin/IGF signaling drives cell proliferation in part via Yorkie/YAP. Dev Biol. 2012 Jul 15;367(2):187-96. (IF: 3.2)

Breuhahn K, Schirmacher P. A cellular view of Nf2 in liver homeostasis and tumorigenesis. Dev Cell. 2010 Sep 14;19(3):363-4. (IF: 9.3)

Elias Klossok (medical student)
Solomiia Savchenko (medical student)
Dr. Amruta Damle-Vartak (scientist)
Dr. Marcell Tóth (medical student)
Stefania Bonusi (Master student)
Patrizia Birner (technician)
Tobias Klessinger (medical student)
Camilla Maggi (Master student)
Dr. Lena Thiess (PhD student)
Dr. Yingyue Tang (medical student)
Dr. Klára Schulc (guest scientist) Dr. Fabian Rose (PhD student)
Dr. Lilija Wehling (PhD student, scientist)
Fabian von Bubnoff (medical student)
Dr. Marie Wesener (medical student)
Dr. Paula Fernández-Palanca (guest scientist)
Dr. Kaijing Liu (medical student)
Dr. Nada El-Ekiaby (guest scientist)
Dr. Dr. Stefan Thomann (PhD student, scientist)
Dr. Teng Wei (Dr. sc. hum. student)
Dr. Simone Marquard (medical student)
Dr. Margarita González-Vallinas Garrachón (scientist)
Dr. Federico Pinna (scientist)
Dr. Jana Samarin (diploma student, scientist)
Dr. Mona Malz (PhD student, scientist)
Dr. Sabrina Schmitt (scientist)
Dr. Maria Knaub (PhD student)
Dr. Shan Wan (PhD student)
Dr. Benedikt Müller (PhD student)
Dr. Antje Brauckhoff (PhD student)
Dr. Tanja Nussbaum (PhD student)
Dr. Stephanie Schnickman (PhD student)
Dr. Sebastian Vreden (PhD student)
Dr. Charlotte Jankovitz (medical student)
Dr. Teresa Lutz (medical student)
Dr. Philipp Latzko (medical student)
Dr. Michael Bovet (medical student)
Dr. Pia Moinzadeh (medical student)
Anne-Sophie Meyer (physician)
Dr. Christian Rupp (physician)
Prof. Darjus Tschaharganeh (physician)
Prof. Stephan Singer (physician)
Vera Riehmer (diploma student)
Yelena Burda (diploma student)
Ute Müller (technician)
Petra Hubbe (technician)
Martina Keith (technician)