Regina Men Men Wong

Bio: Regina Men Men Wong is an academic researcher from Genome Institute of Singapore. The author has contributed to research in topics: Notch signaling pathway & Tumor microenvironment. The author has an hindex of 4, co-authored 5 publications receiving 95 citations.

Onco-fetal Reprogramming of Endothelial Cells Drives Immunosuppressive Macrophages in Hepatocellular Carcinoma

Abstract: We employed scRNA sequencing to extensively characterize the cellular landscape of human liver from development to disease. Analysis of ∼212,000 cells representing human fetal, hepatocellular carcinoma (HCC), and mouse liver revealed remarkable fetal-like reprogramming of the tumor microenvironment. Specifically, the HCC ecosystem displayed features reminiscent of fetal development, including re-emergence of fetal-associated endothelial cells (PLVAP/VEGFR2) and fetal-like (FOLR2) tumor-associated macrophages. In a cross-species comparative analysis, we discovered remarkable similarity between mouse embryonic, fetal-liver, and tumor macrophages. Spatial transcriptomics further revealed a shared onco-fetal ecosystem between fetal liver and HCC. Furthermore, gene regulatory analysis, spatial transcriptomics, and in vitro functional assays implicated VEGF and NOTCH signaling in maintaining onco-fetal ecosystem. Taken together, we report a shared immunosuppressive onco-fetal ecosystem in fetal liver and HCC. Our results unravel a previously unexplored onco-fetal reprogramming of the tumor ecosystem, provide novel targets for therapeutic interventions in HCC, and open avenues for identifying similar paradigms in other cancers and disease.

Single-Cell RNA Sequencing for Precision Oncology: Current State-of-Art.

Abstract: Tumors exhibit genetic and phenotypic diversity leading to intra-tumor heterogeneity (ITH). Further complex ecosystem (stromal and immune cells) of tumors contributes into the ITH. This ITH allows tumors to overcome various selection pressures such as anti-cancer therapies and metastasis at distant organs. Single-cell RNA-seq (scRNA-seq) has provided unprecedented insights into ITH and its implications in drug resistance and metastasis. As scRNA-seq technology grows and provides many new findings, new tools on different programming platforms are frequently generated. Here, we aim to provide a framework and guidelines for new entrants into the field of scRNA-seq. In this review, we discuss the current state-of-art of scRNA-seq analysis step-by-step including filtering, normalization and analysis. First, we discuss the brief history of experimental methods, followed by data processing and implications in precision oncology.

Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches

Abstract: INTRODUCTION Resident tissue macrophages (RTMs) are a heterogeneous population of immune cells occupying multiple tissue niches and exhibiting microenvironment-specific phenotypes and functions. In certain tissues such as the brain, lung, and liver, embryonically derived RTMs maintain themselves by self-renewal, whereas others, including those in the gut, dermis, and pancreas, are replaced by monocytes, at levels that are tissue specific. Once they arrive in their tissue of residence, monocytes undergo extensive differentiation according to molecular cues provided by their distinct tissue-specific niches, enabling their development into specialized RTMs that support local tissue function. RATIONALE As a result of this ontogenetic and tissue niche heterogeneity, each tissue contains multiple populations of macrophages. For example, in the murine lung, alveolar macrophages are the major embryonically derived population in the alveolar spaces, whereas a minor population named interstitial macrophages (IMs) resides within the lung parenchyma. Previous results reported several phenotypically distinct IM subpopulations, whose relationship remained unknown. Do they represent independent populations or, rather, different points on the spectrum of maturation and activation states? How do these differences relate to their localization in tissue or roles in tissue function in health and disease? Does such macrophage heterogeneity also exist in other tissues? RESULTS Here, using single-cell mRNA sequencing, we unbiasedly identified two independent populations exhibiting distinct gene expression profiles and phenotypes: Lyve1loMHCIIhiCX3CR1hi (Lyve1loMHCIIhi) and Lyve1hiMHCIIloCX3CR1lo (Lyve1hiMHCIIlo) RTMs. We uncovered evidence of parallel populations in multiple others tissues, including the heart, fat, and dermis, as well as in human lung and omental and subcutaneous fat tissues, suggesting that a similar dichotomy is observed in human tissues. We further demonstrated that both populations are slowly replaced by Ly6Chi monocytes. Importantly, using complementary fate-mapping models, we showed that monocyte-derived RTMs (MRTMs) are two separate lineages, rather than representing points along a developmental or maturation continuum. Notably, these distinct MRTM populations preferentially reside within different, but conserved, subtissular niches, located either adjacent to nerve bundles and fibers (Lyve1loMHCIIhi) or blood vessels (Lyve1hiMHCIIlo) across tissues. Finally, by acutely depleting Lyve1hiMHCIIlo MRTMs using a mouse model of inducible macrophage depletion during the induction of fibrosis, we found that the absence of Lyve1hiMHCIIlo IMs exacerbated experimental lung and heart fibrosis, demonstrating their critical role in tissue inflammation. CONCLUSION Two independent MRTMs populations exist across tissues with specific niche-dependent phenotype and functional programming. Their different roles in homeostasis, immune regulation, and fibrosis renders them attractive and separate cellular targets for the therapeutic exploitation of RTM subsets.