Liver cancers adopt a fetal-like environment to escape immune surveillance and
grow more aggressively
From left: Dr Florent Ginhoux, Prof Jerry Chan, Prof Pierce Chow, Dr Ramanuj DasGupta, and Dr Ankur Sharma (Copyright: A*STAR’s Genome Institute of Singapore)
SINGAPORE – A team of researchers and clinician-scientists from A*STAR’s Genome Institute of Singapore (GIS), Singapore Immunology Network (SIgN), National Cancer Centre Singapore (NCCS), and KK Women’s and Children’s Hospital (KKH), have identified a pivotal “fetal-like” reprogramming of the tumour ecosystem in human hepatocellular carcinoma (HCC). This study leveraged the platform established by the National Medical Research Council (NMRC) Translational and Clinical Research (TCR) Flagship Programme in Liver Cancer1 and was recently published in Cell on 24 September 2020.
HCC, or primary liver cancer, is the sixth most common cancer in the world, and the second most common cause of cancer deaths globally2. It is estimated that approximately 80% of all HCC are found in Asia. Tumours represent a complex ecosystem of diverse cell types that exhibit molecular and functional heterogeneity and plasticity. Previous studies have noted the similarities between embryonic development and tumours, specifically in the expression of fetal-like antigens in cancers. Most notably, alpha-fetoprotein (AFP) is one of the key onco-fetal proteins found to be elevated in more than 80% of HCC, especially in those with poorly differentiated cell types which are clinically more aggressive. The fetal immune system and placental-fetal system are known to be largely immunologically tolerant, allowing their co-existence within the mother until birth. It has long been suggested that cancers may have similar mechanisms to avoid rejection by the body. While it is known that HCC can undergo onco-fetal reprogramming, the relationship between HCC and its micro-environment has not been examined in detail.
In this comparative study, the researchers mapped approximately 200,000 single cells in the
human liver across the timeline from fetal development to terminal liver cancer. It led to the
discovery of two new fetal-associated cell types in the tumour ecosystem in HCC.
Specifically, the team identified the reappearance of fetal-like endothelial cells that are
responsible for blood supply, and fetal-like macrophages, an immune cell type that serves
as the body’s first line of defence against pathogens, but are also associated with tissue
The researchers discovered that during development of the fetal liver (a process that shares
many characteristics typically associated with cancer growth), these cell types (fetal
endothelial and macrophages) help in organ growth and protect the tissue against the body’s
own immune system. The team identified the sequential activation of VEGF and Notch
signalling pathways that led to fetal-like reprogramming of endothelial cells and
macrophages. Importantly, the authors showed that these signalling pathways are activated
during fetal-liver growth, and switched off thereafter, but are re-activated during the
development of liver cancer.
A dividing cancer cell first activates VEGF pathway in endothelial cells, which in turn
communicate with macrophages in tumours via Notch-Delta interactions. The fetal-like programme in tumours allows uncontrolled growth and protection from the immune system.
This study provides unprecedented and fundamental insights into the processes that drive
cancer development, and may provide new therapeutic strategies to re-activate the immune
system in the fight against cancer.
Dr Ramanuj DasGupta, cancer biologist and Senior Group Leader at GIS, and the lead
corresponding author of the study, said, “Our research underscores a fundamental
understanding of how early developmental processes can be hijacked by cancers in order
to facilitate their own growth, and escape immune surveillance. This study also opens up
exciting possibilities for the discovery of biomarkers and novel therapeutic targets
associated with non-malignant cells, especially in the context of combinatorial
immunotherapy with anti-angiogenic drugs. Most importantly, it highlights the power of likeminded scientists and clinicians coming together to solve big problems. I am absolutely
thrilled to be working with this dream-team of exceptional scientists and clinicians.”
Dr Ankur Sharma, Research Scientist at GIS, the first and co-corresponding author of the
study, said, “Our research provides insights into the mirror worlds of fetal and tumour
ecosystem, where certain cell types first appear during organ development and later
reappear in cancer. The ‘reappearance’ of fetal-like cells provides the perfect environment
for tumour growth by supressing the immune system. Our work demonstrates the
importance of embryonic macrophages in tumour growth and immune suppression. This
study opens new avenues to understand the embryonic origin of cancers and its implication
in discovering new therapeutic approaches, especially in the realm of immunotherapy.”
Dr Florent Ginhoux, scientist and Senior Principal Investigator at SIgN, and cocorresponding author of the study said, “The macrophages are one of the first immune cells
to arise during development as their raison d’être is to provide adequate organ building and
tissue maintenance. These embryonic macrophages are endowed with immunesuppressive
properties as inflammation too early would be detrimental to the correct
development of fetal tissues. Our work uncovers that tumour cells exploit embryonic
macrophage’s raison d’être for their own growth, by recreating an artificial fetal-like
environment and taking macrophages ‘back in time’ mimicking early developmental settings.
This study will help to understand the importance of macrophage ontogeny in cancer
development and open new strategies to eradicate cancer.”
Prof Pierce Chow, Clinician-Scientist and Liver Surgeon at NCCS, Principal Investigator of
the NMRC TCR Flagship Programme in Liver Cancer, and co-corresponding author of the
study, said, “This study provides mechanistic confirmation of what many liver cancer
specialists have suspected – regression to a fetal state allows HCC to grow aggressively.
The findings potentially opens up new approaches in the prevention and treatment of HCC.
It is also a showcase of what multi-disciplinary collaborative research between clinicianscientists
from different specialities and scientists with different expertise can achieve.”
Prof Chow who is also a Programme Director with Duke-NUS Medical School added that he
may include the investigation for proteins uncovered by this study in a prospective cohort
study of patients at high risk of developing liver cancer, which has been planned to start at
the end of 2020.
Prof Jerry Chan, Clinician-Scientist and Senior Consultant at KKH’s Department of
Reproductive Medicine and co-author of the study, said, “Globally, cancer cases have risen
rapidly over the years. Understanding the behaviour of how cancer cells reprogramme their
environment to simulate a fetal environment, and thereby promoting their growth and
avoiding immune destruction, may be key to developing a cure. KKH is proud to contribute
to this novel discovery through underlying expertise in the developing fetal immune system3,
in collaboration with A*STAR and others."
Prof William Hwang, Medical Director at NCCS, said, “Indeed, the multi-institutional
collaboration has allowed the team to leverage on each other’s expertise, leading to the
discovery of onco-fetal reprogramming in liver cancer. I’m glad we are one step closer to
understanding and treating liver cancer.”
Prof Patrick Tan, Executive Director of GIS, said, “The discovery of onco-fetal
reprogramming in liver tumours opens up new avenues of investigating this process in other
cancers and inflammatory diseases. This work also demonstrates the power of single-cell
and spatial genomics in uncovering fundamental biological insights. It is a true example of
‘SG United’ where scientists across the different Singapore institutions formed a team to
discover new biological processes with translational implications in the clinic.”
1 The National Medical Research Council (NMRC) Translational and Clinical Research (TCR) Flagship
Programme in Liver Cancer is a prospective clinical and multi-omics cohort study that leverages on multi-region
sampling of surgically resected HCC. The genomics, immunomics, and metabolomics profiles of these samples are
correlated to the clinical trajectories of the patients, especially to cancer recurrence and survival.
2 Venook et al The oncologist. 2010; 15 Suppl (4): 5-13. doi: 10.1634/theoncologist.2010-S4-05
About A*STAR’s Genome Institute of Singapore (GIS)
The Genome Institute of Singapore (GIS) is an institute of the Agency for Science, Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to achieve extraordinary improvements in human health and public prosperity. Established in 2000 as a centre for genomic discovery, the GIS pursues the integration of technology, genetics and biology towards academic, economic and societal impact, with a mission to "read, reveal and write DNA for a better Singapore and world".
Key research areas at the GIS include Precision Medicine & Population Genomics, Genome
Informatics, Spatial & Single Cell Systems, Epigenetic & Epitranscriptomic Regulation,
Genome Architecture & Design, and Sequencing Platforms. The genomics infrastructure at
the GIS is also utilised to train new scientific talent, to function as a bridge for academic and
industrial research, and to explore scientific questions of high impact.
For more information about GIS, please visit www.a-star.edu.sg/gis.
About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public
sector R&D agency, spearheading economic-oriented research to advance scientific
discovery and develop innovative technology. Through open innovation, we collaborate with
our partners in both the public and private sectors to benefit society.
As a Science and Technology Organisation, A*STAR bridges the gap between academia
and industry. Our research creates economic growth and jobs for Singapore, and enhances
lives by contributing to societal benefits such as improving outcomes in healthcare, urban
living, and sustainability.
We play a key role in nurturing and developing a diversity of talent and leaders in our Agency
and research entities, the wider research community and industry. A*STAR’s R&D activities
span biomedical sciences and physical sciences and engineering, with research entities
primarily located in Biopolis and Fusionopolis.
ANNEX A – NOTES TO EDITOR
The research findings described in this media release can be found in the scientific journal
Cell, under the title, “Onco-fetal reprogramming of endothelial cells drivesimmunosuppressive macrophages in Hepatocellular Carcinoma” by Ankur Sharma1,2*,
Justine Jia Wen Seow1,15, Charles-Antoine Dutertre3,4,15, Rhea Pai1, Camille Blériot3, Archita
Mishra3, Regina Men Men Wong1, Gurmit Singh Naranjan Singh3, Samydurai Sudhagar1,
Shabnam Khalilnezhad3, Sergio Erdal3, Hui Min Teo1, Ahad Khalilnezhad3, Svetoslav Chakarov3, Tony Kiat Hon Lim5, Alexander Chung Yaw Fui6, Alfred Kow Wei Chieh7, Cheow
Peng Chung6, Glenn Kunnath Bonney7, Brian Goh Kim Poh6, Jerry KY Chan8,9,10, Pierce
Chow Kah Hoe11,12*, Florent Ginhoux3,13,14*, Ramanuj DasGupta1,16,*.
- Genome Institute of Singapore, A*STAR, 60 Biopolis Street, Genome, #02-01,
Singapore 138672, Singapore
- School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Institute,
Curtin University, Perth, WA 6102, Australia
- Singapore Immunology Network (SIgN), A*STAR, 8A Biomedical Grove, Immunos
Building, Level 3 and 4, Singapore 138648, Singapore
- Program in Emerging Infectious Disease, Duke-NUS Medical School, 8 College
Road, Singapore 169857, Singapore
- Department of Pathology, Singapore General Hospital, Singapore 169608,
- Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General
Hospital, Singapore 169608, Singapore
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, National
University of Hospital, Singapore 119074, Singapore
- Department of Reproductive Medicine, KK Women’s and Children’s Hospital,
Singapore 229899, Singapore
- Experimental Fetal Medicine Group, Department of Obstetrics and Gynaecology,
Yong Loo Lin School of Medicine, NUS, Singapore 117597, Singapore
- Academic Clinical Program in Obstetrics and Gynaecology, Duke-NUS Medical
School, Singapore 169857, Singapore
- Division of Surgery and Surgical Oncology, National Cancer Centre, Singapore
- Academic Clinical Programme for Surgery, Duke-NUS Medical School, Singapore
- Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine,
Shanghai 200025, China
- Translational Immunology Institute, SingHealth Duke-NUS Academic Medical
Centre, 169856, Singapore
These authors contributed equally
Lead Contact: Ramanuj DasGupta (email@example.com)
*Correspondence: Ankur Sharma (firstname.lastname@example.org), Pierce Chow Kah Hoe
(email@example.com), Florent Ginhoux (firstname.lastname@example.org.
edu.sg), Ramanuj DasGupta (email@example.com).