A team of clinicians, scientists, and researchers from the National Cancer Centre Singapore (NCCS), the Agency for Science, Technology and Research (A*STAR), the Harry Perkins Institute of Medical Research, and global research partners has identified a causal relationship between the presence of oncofetal ecosystems (reappearance of fetal programs/characteristics controlled by the tumor) in primary liver cancer – Hepatocellular Carcinoma (HCC), the recurrence of cancer, and response to immunotherapy. These groundbreaking findings, paving the way for the use of oncofetal ecosystems as biomarkers for the treatment of HCC, were recently published in Nature Cancer on January 2, 2024.
Liver cancer is the sixth most common cancer worldwide and the fourth most common cause of cancer death globally. In Singapore, it is the third leading cause of cancer death in men and the fifth in women. HCC is usually diagnosed at a late stage when the prognosis is poor, highlighting the pressing clinical need to improve understanding of HCC for better disease management.
An earlier groundbreaking study by the same research team found that HCC cells adopt a fetal environment to escape immune surveillance and grow more aggressively, shedding light on the processes driving HCC development.
In their latest work published in Nature Cancer this year, the team built on their previous discovery and focused on understanding how changes in oncofetal ecosystems, known as oncofetal reprogramming, affect HCC. Oncofetal reprogramming leads to the cancer cell environment in the liver mimicking certain aspects of cells in fetal development, suppressing the body’s immune system. The team created a single-cell atlas of 251,761 cells from over 80 liver cancer donors and utilized advanced techniques such as single-cell RNA sequencing and single-cell spatial transcriptomics to analyze them, identifying a cell named POSTN+ cancer-associated fibroblast that plays a central role in this process.
Further analysis revealed that oncofetal reprogramming is involved in the EMT (epithelial-mesenchymal transition, a process that makes cancer more aggressive) and tumor cell proliferation, ultimately playing a role in early recurrence and response to immunotherapy.
Oncofetal cells are highly adaptable and behave like embryonic cells. They arise in the tissue surrounding tumors and provide a „fertile ground“ for „malignant seeds.“ This is the reason why these cells persist even after the surgical removal of a tumor and can lead to cancer recurrence. By analyzing the microenvironment surrounding and nourishing the tumor, we found that some patients have a high proportion of fetal-like cells. Their presence predicts the likelihood of recurrence.
– Ankur Sharma, Co-Senior-Author of the study, Professor, Laboratory Head of the Onco-Fetal Ecosystem Laboratory at the Harry Perkins Institute of Medical Research in Perth, Western Australia
„This translational discovery, based on basic research mapping the tumor microenvironment, not only provides us with a novel biomarker but, more importantly, offers a tangible solution for the better management of HCC – a ray of hope for patients and a new direction for oncology,“ said Co-Senior Associate Professor Florent Ginhoux, Senior Principal Investigator, A*STAR’s Singapore Immunology Network (SIgN).
„We can now link the discovery of fetal reprogramming of the tumor ecosystem with a clinical outcome in HCC patients. This is very significant as it opens promising avenues for grouping early-stage HCC patients where the likelihood of early recurrence and improvement is higher for their care management. It also provides the possibility to target therapeutically the cell-based signature in the tumor microenvironment with combined immunotherapy,“ said the study’s Co-Senior Author, Professor Pierce Chow, Senior Consultant Surgeon, Singapore General Hospital and NCCS and Professor, Duke-NUS Medical School.
Furthermore, the team plans to investigate if fetal POSTN+ cancer-associated fibroblasts also occur in other cancer types. Another clinical application of this study would be the development of a biomarker indicating a response to combined immunotherapy.
This research is supported by the National Medical Research Council of the Ministry of Health of Singapore under its Open Fund-Large Collaborative Grant (MOH-001067), Translational Research Investigator Award (TCR/015-NCC/2016), and by the Biomedical Research Council (BMRC) Award for Use-Inspired Basic Research (UIBR) and the National Research Foundation Singapore under its Singapore National Research Foundation Senior Investigatorship (NRF2016NRF-NRFI001-02). It is also supported by the Ideas Grant from the National Health and Medical Research Council (NHMRC) [2021/GNT2010795] and the Medical Research Future Fund (MRFF) Early to Mid-Career Researcher (EMCR) grant [2022/MRF2016215].
Li, Z., et al. (2024). The presence of oncofetal neighborhoods in hepatocellular carcinoma is associated with relapse and response to immunotherapy. Nature Cancer. doi.org/10.1038/s43018-023-00672-2.