TY  - JOUR
AU  - Wuestefeld, Anna
AU  - Iakovleva, Viktoriia
AU  - Yap, Shirlyn Xue Ling
AU  - Ong, Agnes Bee Leng
AU  - Huang, Daniel Q
AU  - Shuen, Timothy Wai Ho
AU  - Toh, Han Chong
AU  - Dan, Yock Young
AU  - Zender, Lars
AU  - Wuestefeld, Torsten
TI  - A Pro-Regenerative Environment Triggers Premalignant to Malignant Transformation of Senescent Hepatocytes.
JO  - Cancer research
VL  - 83
IS  - 3
SN  - 0099-7013
CY  - Philadelphia, Pa.
PB  - AACR
M1  - DKFZ-2023-00298
SP  - 428 - 440
PY  - 2023
AB  - Unfortunately, available liver cancer treatments are associated with modest survival advantage. The biggest factor improving survival is early detection, but the current understanding of early transformation events is limited. Therefore, we set up a model to study these early events and investigated the relationship of premalignant, senescent hepatocytes, a regenerative environment, and the influence of secreted factors on liver tumorigenesis. Oncogene-induced senescence (OIS) was triggered in a subset of mouse hepatocytes, which under normal conditions, are eliminated by immunosurveillance. Inducing liver damage and regeneration was sufficient to trigger immunosurveillance escape of OIS hepatocytes, resulting in premalignant to malignant transformation and hepatocellular tumor development. Trefoil factor 3 (TFF3) was found to be overexpressed in OIS hepatocytes and in hepatocellular carcinoma. TFF3 deficiency strongly attenuated malignant transformation by increasing insulin-like growth factor binding protein 5 (IGFBP5) expression, which consequently dampened IGF receptor signaling. Furthermore, analysis of precancerous liver tissue validated TFF3 as an early liver cancer biomarker. Altogether, these findings provide mechanistic insights into early transformation and immunosurveillance escape in liver cancer, revealing TFF3 and IGFBP5 to be important players with opposite roles in tumorigenesis.Liver damage induces a compensatory regenerative response that can drive premalignant to malignant transformation of senescent hepatocytes.
KW  - Mice
KW  - Animals
KW  - Hepatocytes: metabolism
KW  - Carcinoma, Hepatocellular: pathology
KW  - Liver Neoplasms: pathology
KW  - Precancerous Conditions: pathology
KW  - Cell Transformation, Neoplastic: metabolism
LB  - PUB:(DE-HGF)16
C6  - pmid:36449018
DO  - DOI:10.1158/0008-5472.CAN-22-1477
UR  - https://inrepo02.dkfz.de/record/265703
ER  -