Oral Presentation 33rd Lorne Cancer Conference 2021

Oncofetal Ecosystem: Embryonic Tale of Tumorigenesis (#31)

Ankur Sharma 1
  1. Harry Perkins Institute of Medical Research, Murdoch, WA, Australia

Tumor cells are known to exhibit phenotypic plasticity which facilitates cellular diversity and tumor evolution. Documented similarities between embryonic development and tumorigenesis have given credence to the notion that tumor cells can reprogram and/or transdifferentiate into cancer stem-like cells (CSC). Additionally, some malignant cells are known to express antigens specific to fetal development, a classic example being the expression of alpha-fetoprotein (AFP) in hepatocellular carcinoma (HCC). Taken together, these observations link phenotypic characteristics of malignant cells with early developmental programs. However, the ability of the tumor ecosystem (immune and stromal elements) to recapitulate early developmental hallmarks has not been investigated. In a recent study, we set out to generate a comprehensive atlas of human liver encompassing fetal development, adult homeostasis, and carcinoma. We elucidated a remarkable fetal-like reprogramming of the tumor microenvironment (TME). Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including the re-emergence of fetal-associated endothelial cells (PLVAP+/VEGFR2+), and fetal-like (FOLR2+) tumor-associated macrophages (TAMs). Furthermore, gene regulatory analysis, spatial transcriptomics, and in vitro functional assays implicates VEGF and NOTCH signaling in maintaining this oncofetal ecosystem. Our discovery of a shared immunosuppressive oncofetal ecosystem between HCC and human fetal liver is of particular interest in the light of the recent IMBrave150 HCC clinical trial.