Highlights
- •ADAMTSL5 overexpression in HCC is associated with gene body CGI hypermethylation.
- •ADAMTSL5 is strongly expressed in a large fraction of human HCC.
- •Targeting ADAMTSL5 diminishes RTK inputs and interferes with tumorigenicity.
- •ADAMTSL5 confers tumorigenicity to sensitized, non-transformed liver cells.
- •Targeting ADAMTSL5 sensitizes HCC cells to drugs currently used in the clinic.
Background & Aims
The tumour microenvironment shapes tumour growth through cellular communications that
include both direct interactions and secreted factors. The aim of this study was to
characterize the impact of the secreted glycoprotein ADAMTSL5, whose role in cancer
has not been previously investigated, on hepatocellular carcinoma (HCC).
Methods
ADAMTSL5 methylation status was evaluated through bisulfite sequencing, and publicly available
data analysis. ADAMTSL5 RNA and protein expression were assessed in mouse models and
HCC patient samples and compared to data from published datasets. Functional studies,
including association of ADAMTSL5 depletion with responsiveness to clinically relevant
drugs, were performed in cellular and in vivo models. Molecular alterations associated with ADAMTSL5 targeting were determined
using proteomics, biochemistry, and reverse-transcription quantitative PCR.
Results
Methylome analysis revealed hypermethylated gene body CpG islands at the ADAMTSL5 locus in both mouse and human HCC, correlating with higher ADAMTSL5 expression. ADAMTSL5 targeting interfered with tumorigenic properties of HCC cells
in vitro and in vivo, whereas ADAMTSL5 overexpression conferred tumorigenicity to pre-tumoural hepatocytes
sensitized to transformation by a modest level of MET receptor expression. Mechanistically,
ADAMTSL5 abrogation led to a reduction of several oncogenic inputs relevant to HCC,
including reduced expression and/or phosphorylation levels of receptor tyrosine kinases
MET, EGFR, PDGFRβ, IGF1Rβ, or FGFR4. This phenotype was associated with significantly
increased sensitivity of HCC cells to clinically relevant drugs, namely sorafenib,
lenvatinib, and regorafenib. Moreover, ADAMTSL5 depletion drastically increased expression
of AXL, accompanied by a sensitization to bemcentinib.
Conclusions
Our results point to a role for ADAMTSL5 in maintaining the function of key oncogenic
signalling pathways, suggesting that it may act as a master regulator of tumorigenicity
and drug resistance in HCC.
Lay summary
The environment of cancer cells has profound effects on establishment, progression,
and response of a tumour to treatment. Herein, we show that ADAMTSL5, a protein secreted
by liver cancer cells and overlooked in cancer so far, is increased in this tumour
type, is necessary for tumour formation and supports drug resistance. Adamtsl5 removal conferred sensitivity of liver cancer cells to drugs used in current treatment.
This suggests ADAMTSL5 as a potential marker in liver cancer as well as a possible
drug target.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: November 13, 2020
Accepted:
November 2,
2020
Received in revised form:
October 29,
2020
Received:
April 10,
2020
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
