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2. Divergent lineage trajectories and genetic landscapes in human gastric intestinal metaplasia organoids associated with early neoplastic progression

Author

Yue, Sarah SK, primary, Tong, Yin, additional, Siu, Hoi Cheong, additional, Ho, Siu Lun, additional, Law, Simon YK, additional, Tsui, Wai Yin, additional, Chan, Dessy, additional, Huang, Yuanhua, additional, Chan, Annie SY, additional, Yun, Shui Wa, additional, Hui, Ho Sang, additional, Chan, April S, additional, Yuen, Siu Tsan, additional, Clevers, Hans, additional, Leung, Suet Yi, additional, and Yan, Helen HN, additional

Published
2024
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3. A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening

Author

Yan, Helen H.N., Siu, Hoi Cheong, Law, Simon, Ho, Siu Lun, Yue, Sarah S.K., Tsui, Wai Yin, Chan, Dessy, Chan, April S., Ma, Stephanie, Lam, Ka On, Bartfeld, Sina, Man, Alice H.Y., Lee, Bernard C.H., Chan, Annie S.Y., Wong, Jason W.H., Cheng, Priscilla S.W., Chan, Anthony K.W., Zhang, Jiangwen, Shi, Jue, Fan, Xiaodan, Kwong, Dora L.W., Mak, Tak W., Yuen, Siu Tsan, Clevers, Hans, and Leung, Suet Yi

Published
2018
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5. Escape from cell-cell and cell-matrix adhesion dependence underscores disease progression in gastric cancer organoid models

Author

Tong, Yin, primary, Cheng, Priscilla S W, additional, Or, Chung Sze, additional, Yue, Sarah S K, additional, Siu, Hoi Cheong, additional, Ho, Siu Lun, additional, Law, Simon Y K, additional, Tsui, Wai Yin, additional, Chan, Dessy, additional, Ma, Stephanie, additional, Lee, Siu Po, additional, Chan, Annie S Y, additional, Chan, April S, additional, Yun, Shui Wa, additional, Hui, Ho Sang, additional, Yuen, Siu Tsan, additional, Leung, Suet Yi, additional, and Yan, Helen H N, additional

Published
2022
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6. A Bayesian model for identifying cancer subtypes from paired methylation profiles.

Author

Fan, Yetian, Chan, April S, Zhu, Jun, Leung, Suet Yi, and Fan, Xiaodan

Subjects
*DNA methylation, *TUMOR classification, *METHYLATION, *CARCINOGENESIS, *ETIOLOGY of cancer
Abstract

Aberrant DNA methylation is the most common molecular lesion that is crucial for the occurrence and development of cancer, but has thus far been underappreciated as a clinical tool for cancer classification, diagnosis or as a guide for therapeutic decisions. Partly, this has been due to a lack of proven algorithms that can use methylation data to stratify patients into clinically relevant risk groups and subtypes that are of prognostic importance. Here, we proposed a novel Bayesian model to capture the methylation signatures of different subtypes from paired normal and tumor methylation array data. Application of our model to synthetic and empirical data showed high clustering accuracy, and was able to identify the possible epigenetic cause of a cancer subtype. [ABSTRACT FROM AUTHOR]

Published
2023
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8. Escape from cell-cell and cell-matrix adhesion dependence underscores disease progression in gastric cancer organoid models

Author

Tong, Yin, Cheng, Priscilla S W, Or, Chung Sze, Yue, Sarah S K, Siu, Hoi Cheong, Ho, Siu Lun, Law, Simon Y K, Tsui, Wai Yin, Chan, Dessy, Ma, Stephanie, Lee, Siu Po, Chan, Annie S Y, Chan, April S, Yun, Shui Wa, Hui, Ho Sang, Yuen, Siu Tsan, Leung, Suet Yi, and Yan, Helen H N

Abstract

ObjectiveCell-cell (CC) and cell-matrix (CM) adhesions are essential for epithelial cell survival, yet dissociation-induced apoptosis is frequently circumvented in malignant cells.DesignWe explored CC and CM dependence in 58 gastric cancer (GC) organoids by withdrawing either ROCK inhibitor, matrix or both to evaluate their tumorigenic potential in terms of apoptosis resistance, correlation with oncogenic driver mutations and clinical behaviour. We performed mechanistic studies to determine the role of diffuse-type GC drivers: ARHGAPfusions, RHOAand CDH1,in modulating CC (CCi) or CM (CMi) adhesion independence.Results97% of the tumour organoids were CMi, 66% were CCi and 52% were resistant to double withdrawal (CCi/CMi), while normal organoids were neither CMi nor CCi. Clinically, the CCi/CMi phenotype was associated with an infiltrative tumour edge and advanced tumour stage. Moreover, the CCi/CMi transcriptome signature was associated with poor patient survival when applied to three public GC datasets. CCi/CMi and CCi phenotypes were enriched in diffuse-type GC organoids, especially in those with oncogenic driver perturbation of RHO signalling via RHOAmutation or ARHGAPfusions. Inducible knockout of ARHGAPfusions in CCi/CMi tumour organoids led to resensitisation to CC/CM dissociation-induced apoptosis, upregulation of focal adhesion and tight junction genes, partial reversion to a more normal cystic phenotype and inhibited xenograft formation. Normal gastric organoids engineered with CDH1or RHOAmutations became CMi or CCi, respectively.ConclusionsThe CCi/CMi phenotype has a critical role in malignant transformation and tumour progression, offering new mechanistic information on RHO-ROCK pathway inhibition that contributes to GC pathogenicity.

Published
2023
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9. Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles

Author

Yan, Helen H N, primary, Siu, Hoi Cheong, additional, Ho, Siu Lun, additional, Yue, Sarah S K, additional, Gao, Yang, additional, Tsui, Wai Yin, additional, Chan, Dessy, additional, Chan, April S, additional, Wong, Jason W H, additional, Man, Alice H Y, additional, Lee, Bernard C H, additional, Chan, Annie S Y, additional, Chan, Anthony K W, additional, Hui, Ho Sang, additional, Cheung, Arthur K L, additional, Law, Wai Lun, additional, Lo, Oswens S H, additional, Yuen, Siu Tsan, additional, Clevers, Hans, additional, and Leung, Suet Yi, additional

Published
2020
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10. Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles

Author

Yan, Helen H N, Siu, Hoi Cheong, Ho, Siu Lun, Yue, Sarah S K, Gao, Yang, Tsui, Wai Yin, Chan, Dessy, Chan, April S, Wong, Jason W H, Man, Alice H Y, Lee, Bernard C H, Chan, Annie S Y, Chan, Anthony K W, Hui, Ho Sang, Cheung, Arthur K L, Law, Wai Lun, Lo, Oswens S H, Yuen, Siu Tsan, Clevers, Hans, Leung, Suet Yi, Yan, Helen H N, Siu, Hoi Cheong, Ho, Siu Lun, Yue, Sarah S K, Gao, Yang, Tsui, Wai Yin, Chan, Dessy, Chan, April S, Wong, Jason W H, Man, Alice H Y, Lee, Bernard C H, Chan, Annie S Y, Chan, Anthony K W, Hui, Ho Sang, Cheung, Arthur K L, Law, Wai Lun, Lo, Oswens S H, Yuen, Siu Tsan, Clevers, Hans, and Leung, Suet Yi

Abstract

OBJECTIVE: Sporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs.DESIGN: We established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed.RESULTS: We observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time.CONCLUSIONS: These organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.

Published
2020

11. Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles

Author

CMM Sectie Molecular Cancer Research, Child Health, Regenerative Medicine and Stem Cells, Cancer, Hubrecht Institute with UMC, Yan, Helen H N, Siu, Hoi Cheong, Ho, Siu Lun, Yue, Sarah S K, Gao, Yang, Tsui, Wai Yin, Chan, Dessy, Chan, April S, Wong, Jason W H, Man, Alice H Y, Lee, Bernard C H, Chan, Annie S Y, Chan, Anthony K W, Hui, Ho Sang, Cheung, Arthur K L, Law, Wai Lun, Lo, Oswens S H, Yuen, Siu Tsan, Clevers, Hans, Leung, Suet Yi, CMM Sectie Molecular Cancer Research, Child Health, Regenerative Medicine and Stem Cells, Cancer, Hubrecht Institute with UMC, Yan, Helen H N, Siu, Hoi Cheong, Ho, Siu Lun, Yue, Sarah S K, Gao, Yang, Tsui, Wai Yin, Chan, Dessy, Chan, April S, Wong, Jason W H, Man, Alice H Y, Lee, Bernard C H, Chan, Annie S Y, Chan, Anthony K W, Hui, Ho Sang, Cheung, Arthur K L, Law, Wai Lun, Lo, Oswens S H, Yuen, Siu Tsan, Clevers, Hans, and Leung, Suet Yi

Published
2020

12. A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening

Author

Yan, Helen H N, Siu, Hoi Cheong, Law, Simon, Ho, Siu Lun, Yue, Sarah S K, Tsui, Wai Yin, Chan, Dessy, Chan, April S, Ma, Stephanie, Lam, Ka On, Bartfeld, Sina, Man, Alice H Y, Lee, Bernard C H, Chan, Annie S Y, Wong, Jason W H, Cheng, Priscilla S W, Chan, Anthony K W, Zhang, Jiangwen, Shi, Jue, Fan, Xiaodan, Kwong, Dora L W, Mak, Tak W, Yuen, Siu Tsan, Clevers, Hans, Leung, Suet Yi, Yan, Helen H N, Siu, Hoi Cheong, Law, Simon, Ho, Siu Lun, Yue, Sarah S K, Tsui, Wai Yin, Chan, Dessy, Chan, April S, Ma, Stephanie, Lam, Ka On, Bartfeld, Sina, Man, Alice H Y, Lee, Bernard C H, Chan, Annie S Y, Wong, Jason W H, Cheng, Priscilla S W, Chan, Anthony K W, Zhang, Jiangwen, Shi, Jue, Fan, Xiaodan, Kwong, Dora L W, Mak, Tak W, Yuen, Siu Tsan, Clevers, Hans, and Leung, Suet Yi

Abstract

Gastric cancer displays marked molecular heterogeneity with aggressive behavior and treatment resistance. Therefore, good in vitro models that encompass unique subtypes are urgently needed for precision medicine development. Here, we have established a primary gastric cancer organoid (GCO) biobank that comprises normal, dysplastic, cancer, and lymph node metastases (n = 63) from 34 patients, including detailed whole-exome and transcriptome analysis. The cohort encompasses most known molecular subtypes (including EBV, MSI, intestinal/CIN, and diffuse/GS, with CLDN18-ARHGAP6 or CTNND1-ARHGAP26 fusions or RHOA mutations), capturing regional heterogeneity and subclonal architecture, while their morphology, transcriptome, and genomic profiles remain closely similar to in vivo tumors, even after long-term culture. Large-scale drug screening revealed sensitivity to unexpected drugs that were recently approved or in clinical trials, including Napabucasin, Abemaciclib, and the ATR inhibitor VE-822. Overall, this new GCO biobank, with linked genomic data, provides a useful resource for studying both cancer cell biology and precision cancer therapy.

Published
2018

13. A Comprehensive Human Gastric Cancer Organoid Biobank Captures Tumor Subtype Heterogeneity and Enables Therapeutic Screening

Author

Child Health, Regenerative Medicine and Stem Cells, Cancer, Hubrecht Institute with UMC, Yan, Helen H.N., Siu, Hoi Cheong, Law, Simon, Ho, Siu Lun, Yue, Sarah S.K., Tsui, Wai Yin, Chan, Dessy, Chan, April S., Ma, Stephanie, Lam, Ka On, Bartfeld, Sina, Man, Alice H.Y., Lee, Bernard C.H., Chan, Annie S.Y., Wong, Jason W.H., Cheng, Priscilla S.W., Chan, Anthony K.W., Zhang, Jiangwen, Shi, Jue, Fan, Xiaodan, Kwong, Dora L.W., Mak, Tak W., Yuen, Siu Tsan, Clevers, Hans, Leung, Suet Yi, Child Health, Regenerative Medicine and Stem Cells, Cancer, Hubrecht Institute with UMC, Yan, Helen H.N., Siu, Hoi Cheong, Law, Simon, Ho, Siu Lun, Yue, Sarah S.K., Tsui, Wai Yin, Chan, Dessy, Chan, April S., Ma, Stephanie, Lam, Ka On, Bartfeld, Sina, Man, Alice H.Y., Lee, Bernard C.H., Chan, Annie S.Y., Wong, Jason W.H., Cheng, Priscilla S.W., Chan, Anthony K.W., Zhang, Jiangwen, Shi, Jue, Fan, Xiaodan, Kwong, Dora L.W., Mak, Tak W., Yuen, Siu Tsan, Clevers, Hans, and Leung, Suet Yi

Published
2018

14. Id1 suppresses anti-tumour immune responses and promotes tumour progression by impairing myeloid cell maturation

Author

Papaspyridonos, Marianna, primary, Matei, Irina, additional, Huang, Yujie, additional, do Rosario Andre, Maria, additional, Brazier-Mitouart, Helene, additional, Waite, Janelle C., additional, Chan, April S., additional, Kalter, Julie, additional, Ramos, Ilyssa, additional, Wu, Qi, additional, Williams, Caitlin, additional, Wolchok, Jedd D., additional, Chapman, Paul B., additional, Peinado, Hector, additional, Anandasabapathy, Niroshana, additional, Ocean, Allyson J., additional, Kaplan, Rosandra N., additional, Greenfield, Jeffrey P., additional, Bromberg, Jacqueline, additional, Skokos, Dimitris, additional, and Lyden, David, additional

Published
2015
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15. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer

Author

Wang, Kai, Yuen, Siu Tsan, Xu, Jiangchun, Lee, Siu Po, Yan, Helen H N, Shi, Stephanie T, Siu, Hoi Cheong, Deng, Shibing, Chu, Kent Man, Law, Simon, Chan, Kok Hoe, Chan, Annie S Y, Tsui, Wai Yin, Ho, Siu Lun, Chan, Anthony K W, Man, Jonathan L K, Foglizzo, Valentina, Ng, Man Kin, Chan, April S, Ching, Yick Pang, Cheng, Grace H W, Xie, Tao, Fernandez, Julio, Li, Vivian S W, Clevers, Hans, Rejto, Paul A, Mao, Mao, Leung, Suet Yi, Wang, Kai, Yuen, Siu Tsan, Xu, Jiangchun, Lee, Siu Po, Yan, Helen H N, Shi, Stephanie T, Siu, Hoi Cheong, Deng, Shibing, Chu, Kent Man, Law, Simon, Chan, Kok Hoe, Chan, Annie S Y, Tsui, Wai Yin, Ho, Siu Lun, Chan, Anthony K W, Man, Jonathan L K, Foglizzo, Valentina, Ng, Man Kin, Chan, April S, Ching, Yick Pang, Cheng, Grace H W, Xie, Tao, Fernandez, Julio, Li, Vivian S W, Clevers, Hans, Rejto, Paul A, Mao, Mao, and Leung, Suet Yi

Abstract

Gastric cancer is a heterogeneous disease with diverse molecular and histological subtypes. We performed whole-genome sequencing in 100 tumor-normal pairs, along with DNA copy number, gene expression and methylation profiling, for integrative genomic analysis. We found subtype-specific genetic and epigenetic perturbations and unique mutational signatures. We identified previously known (TP53, ARID1A and CDH1) and new (MUC6, CTNNA2, GLI3, RNF43 and others) significantly mutated driver genes. Specifically, we found RHOA mutations in 14.3% of diffuse-type tumors but not in intestinal-type tumors (P < 0.001). The mutations clustered in recurrent hotspots affecting functional domains and caused defective RHOA signaling, promoting escape from anoikis in organoid cultures. The top perturbed pathways in gastric cancer included adherens junction and focal adhesion, in which RHOA and other mutated genes we identified participate as key players. These findings illustrate a multidimensional and comprehensive genomic landscape that highlights the molecular complexity of gastric cancer and provides a road map to facilitate genome-guided personalized therapy.

Published
2014

16. Whole-genome sequencing and comprehensive molecular profiling identify new driver mutations in gastric cancer

Author

Wang, Kai, primary, Yuen, Siu Tsan, additional, Xu, Jiangchun, additional, Lee, Siu Po, additional, Yan, Helen H N, additional, Shi, Stephanie T, additional, Siu, Hoi Cheong, additional, Deng, Shibing, additional, Chu, Kent Man, additional, Law, Simon, additional, Chan, Kok Hoe, additional, Chan, Annie S Y, additional, Tsui, Wai Yin, additional, Ho, Siu Lun, additional, Chan, Anthony K W, additional, Man, Jonathan L K, additional, Foglizzo, Valentina, additional, Ng, Man Kin, additional, Chan, April S, additional, Ching, Yick Pang, additional, Cheng, Grace H W, additional, Xie, Tao, additional, Fernandez, Julio, additional, Li, Vivian S W, additional, Clevers, Hans, additional, Rejto, Paul A, additional, Mao, Mao, additional, and Leung, Suet Yi, additional

Published
2014
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20. Divergent lineage trajectories and genetic landscapes in human gastric intestinal metaplasia organoids associated with early neoplastic progression.

Author

Yue SSK, Tong Y, Siu HC, Ho SL, Law SYK, Tsui WY, Chan D, Huang Y, Chan ASY, Yun SW, Hui HS, Choi JE, Hsu MSS, Lai FPL, Chan AS, Yuen ST, Clevers H, Leung SY, and Yan HHN

Abstract

Background: Gastric intestinal metaplasia (IM) is a precancerous stage spanning a morphological spectrum that is poorly represented by human cell line models., Objective: We aim to establish and characterise human IM cell models to better understand IM progression along the cancer spectrum., Design: A large human gastric IM organoid (IMO) cohort (n=28), their clonal derivatives and normal gastric organoids (n=42) for comparison were established. Comprehensive multi-omics profiling and functional characterisation were performed., Results: Single-cell transcriptomes revealed IMO cells spanning a spectrum from hybrid gastric/intestinal to advanced intestinal differentiation. Their lineage trajectories connected different cycling and quiescent stem and progenitors, highlighting differences in gastric to IM transition and the potential origin of IM from STMN1 cycling isthmus stem cells. Hybrid IMOs showed impaired differentiation potential, high lineage plasticity beyond gastric or intestinal fates and reactivation of a fetal gene programme.Cell populations in gastric IM and cancer tissues were highly similar to those derived from IMOs and exhibited a fetal signature. Genomically, IMOs showed elevated mutation burden, frequent chromosome 20 gain and epigenetic deregulation of many intestinal and gastric genes. Functionally, IMOs were FGF10 independent and showed downregulated FGFR2. Several IMOs exhibited a cell-matrix adhesion independent subpopulation that displayed chromosome 20 gain but lacked key cancer driver mutations, potentially representing the earliest neoplastic precursor of IM-induced gastric cancer., Conclusions: Overall, our IMO biobank captured the heterogeneous nature of IM, revealing mechanistic insights on IM pathogenesis and progression, offering an ideal platform for studying early gastric neoplastic transformation and chemoprevention., Competing Interests: Competing interests: SYL and STY have received research sponsorships from Pfizer, Merck, Servier. HC is an inventor on multiple patents related to organoid technology and one patent on a Matrigel replacement. He is also currently head of Roche’s R&D in Basel, as a member of the executive board. His full disclosures can be found on the following website: www.uu.nl/staff/JCClevers/Additional functions. The other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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