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Date: 11 March 2025 (Tue)
Time: 11am - 12:00pm (SGT) Format: Virtual (Zoom Meeting) Host: Adrian TEO, Institute of Molecular and Cell Biology, Singapore Co-host: Dongho Choi, Hanyang University, Korea |
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Speaker's information
Bon-Kyoung KOO Institute for Basic Science, Korea "Epithelial WNT secretion drives niche escape of developing gastric cancer" Pubmed |
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ABSTRACT
WNT signaling plays a crucial role in cancer development, with APC as the primary tumor suppressor in colon cancer. In gastric cancer, WNT signaling is essential for maintaining the gastric epithelium and driving tumor progression, but mechanisms of WNT self-sufficiency remain unclear, as APC and CTNNB1 mutations are relatively rare. Using human and mouse gastric organoids and in vivo mouse models, we found that mesenchymal WNTs maintain normal gastric epithelium, while KRAS activation induces epithelial WNT secretion, enabling WNT self-sufficiency. Single-cell multi-omics revealed that KRAS-driven MAPK signaling activates SMAD2/3, unlocking the WNT7B locus and generating WNT7B+ niche cells within the epithelium. In human gastric cancer, HER2-KRAS-MAPK activation or WNT2 amplification drives epithelial WNT production. Our findings identify epithelial WNT secretion as a key mechanism of WNT self-sufficiency in gastric tumorigenesis. Unlike APC or CTNNB1 mutations in colon cancer, this process is targetable, offering potential therapeutic opportunities.
BIO
Dr. Bon-Kyoung Koo is an experienced mouse geneticist actively employing the emerging organoid culture technology to study stem cell maintenance and activation in the mouse and human intestine and colon. Following his PhD in the laboratory of Prof. Young-Yun Kong at POSTECH, Dr. Koo joined the group of Prof. Hans Clevers at the Hubrecht Institute, Netherlands in 2009. Here he witnessed the first establishment of the Lgr5+ cell-derived intestinal organoid culture system. In the following years Dr. Koo has utilised this novel culture system to perform sophisticated gene correction with CRISPR/Cas9, to unravel the molecular regulation of adult stem cells and to prove the stem cell properties of a Troy+, quiescent reserve stem cell population in the stomach. After group leader positionsat the Cambridge Stem Cell Institute (2013-17) and the Institute of Molecular Biotechnology (IMBA, 2017-2022), he moved his group to the Center for Genome Engineering at the IBS, Korea, where he is serving as the director. Currently, his group focuses on clonal dynamics of adult epithelial stem cells both in homeostasis and during injury-mediated repair.
WNT signaling plays a crucial role in cancer development, with APC as the primary tumor suppressor in colon cancer. In gastric cancer, WNT signaling is essential for maintaining the gastric epithelium and driving tumor progression, but mechanisms of WNT self-sufficiency remain unclear, as APC and CTNNB1 mutations are relatively rare. Using human and mouse gastric organoids and in vivo mouse models, we found that mesenchymal WNTs maintain normal gastric epithelium, while KRAS activation induces epithelial WNT secretion, enabling WNT self-sufficiency. Single-cell multi-omics revealed that KRAS-driven MAPK signaling activates SMAD2/3, unlocking the WNT7B locus and generating WNT7B+ niche cells within the epithelium. In human gastric cancer, HER2-KRAS-MAPK activation or WNT2 amplification drives epithelial WNT production. Our findings identify epithelial WNT secretion as a key mechanism of WNT self-sufficiency in gastric tumorigenesis. Unlike APC or CTNNB1 mutations in colon cancer, this process is targetable, offering potential therapeutic opportunities.
BIO
Dr. Bon-Kyoung Koo is an experienced mouse geneticist actively employing the emerging organoid culture technology to study stem cell maintenance and activation in the mouse and human intestine and colon. Following his PhD in the laboratory of Prof. Young-Yun Kong at POSTECH, Dr. Koo joined the group of Prof. Hans Clevers at the Hubrecht Institute, Netherlands in 2009. Here he witnessed the first establishment of the Lgr5+ cell-derived intestinal organoid culture system. In the following years Dr. Koo has utilised this novel culture system to perform sophisticated gene correction with CRISPR/Cas9, to unravel the molecular regulation of adult stem cells and to prove the stem cell properties of a Troy+, quiescent reserve stem cell population in the stomach. After group leader positionsat the Cambridge Stem Cell Institute (2013-17) and the Institute of Molecular Biotechnology (IMBA, 2017-2022), he moved his group to the Center for Genome Engineering at the IBS, Korea, where he is serving as the director. Currently, his group focuses on clonal dynamics of adult epithelial stem cells both in homeostasis and during injury-mediated repair.
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Grace YEO Hui Ting
Genome Institute of Singapore, Singapore "Spatial omics reveals regional neighborhoods associated with intra-tumoral epithelial heterogeneity in colorectal cancer" |
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ABSTRACT
Colorectal cancer (CRC) is a clinically and molecularly heterogeneous disease. Single-cell RNA-sequencing (scRNA-seq) has enabled us to describe the diverse cell types within the CRC tumor microenvironment. However, the complex interplay between heterogeneous epithelial cell states and their spatial niches remains poorly understood. To address this, we employ state-of-the-art spatial omics technologies to generate high-resolution maps of primary CRC tumors, comprising over 9 million cells from 63 samples and 34 patients. Our results reveal how the organized architecture of the normal colon becomes disrupted in cancer. We identify molecular markers related to biological signatures such as stem-like properties and response to hypoxia that exhibit spatial patterning within tumor glands. We also identify tumor-enriched spatial neighborhoods, including a tumor budding neighborhood enriched at the tumor-normal interface of invasive samples. Our study provides a valuable resource for investigating the spatial organization of tumor epithelial states in CRC.
BIO
Dr. Grace Yeo is a GIS/BII Fellow in the Single Cell and Spatial Omics Domain at GIS. She received her PhD from MIT in the Computational and Systems Biology program under the supervision of Dr. David Gifford. During her PhD, she developed computational analysis pipelines for novel scRNA-based perturbation assays, as well as deep learning methods for modeling biological processes such as cellular differentiation. As part of the Shyam Prabhakar Lab at GIS, she develops imaging and downstream analysis pipelines for spatial assays applied to colorectal cancer. Her research interests revolve around the integration of modern machine learning methods with state-of-the-art –omic technologies for studying complex biological systems.
Colorectal cancer (CRC) is a clinically and molecularly heterogeneous disease. Single-cell RNA-sequencing (scRNA-seq) has enabled us to describe the diverse cell types within the CRC tumor microenvironment. However, the complex interplay between heterogeneous epithelial cell states and their spatial niches remains poorly understood. To address this, we employ state-of-the-art spatial omics technologies to generate high-resolution maps of primary CRC tumors, comprising over 9 million cells from 63 samples and 34 patients. Our results reveal how the organized architecture of the normal colon becomes disrupted in cancer. We identify molecular markers related to biological signatures such as stem-like properties and response to hypoxia that exhibit spatial patterning within tumor glands. We also identify tumor-enriched spatial neighborhoods, including a tumor budding neighborhood enriched at the tumor-normal interface of invasive samples. Our study provides a valuable resource for investigating the spatial organization of tumor epithelial states in CRC.
BIO
Dr. Grace Yeo is a GIS/BII Fellow in the Single Cell and Spatial Omics Domain at GIS. She received her PhD from MIT in the Computational and Systems Biology program under the supervision of Dr. David Gifford. During her PhD, she developed computational analysis pipelines for novel scRNA-based perturbation assays, as well as deep learning methods for modeling biological processes such as cellular differentiation. As part of the Shyam Prabhakar Lab at GIS, she develops imaging and downstream analysis pipelines for spatial assays applied to colorectal cancer. Her research interests revolve around the integration of modern machine learning methods with state-of-the-art –omic technologies for studying complex biological systems.