Biology subjects

Chan-Seng-Yue, M.

Publications and source records attributed to Chan-Seng-Yue, M..

10 recordsLinked to original sources

bioRxiv2026

Extra-lineage tissue programs define the transcription states of human pancreatic cancer

Cancers acquire alternate transcriptional states as they evolve, but the origins, timing and determinants of this plasticity are poorly understood in many tumours. We investigated the transcriptional states of pancreatic cancer by integrating [~]1000 tumour-enriched genomes and transcriptomes from 464 patients combined with scRNA-seq, multiome profiling, and spatial proteomics. Four epithelial states covering the spectrum of lineage plasticity were identified (Classical-1, Classical-2, Basal-1, Basal-2). Comparing these states to normal and pan-cancer human single cell atlases showed each state reflects distinct tissue programs found in other malignancies. Single cell analysis uncovered that the main transcription state of this disease (Classical-1) emerges before KRAS mutations. Spatial proteomics from patients and cancer-free donors showed that the Classical-1 program emerges during acinar-to-ductal metaplasia, and also unexpectedly, in normal ducts without disrupting their morphology. Overall, these findings link the extensive lineage plasticity potential of this organ to the origins of the transcriptional states.

cancer biology↗

bioRxiv2026

Transcriptomic, Genomic, and Clinical Characterization of Morphological Classes in Localized and Metastatic Pancreatic Cancer

BackgroundHistomorphology is a strong prognostic biomarker correlated with basal-like and classical programs in surgically resected pancreatic ductal adenocarcinoma (PDAC). However, the spectrum of morphology and its biological associations remain poorly defined in advanced disease. ObjectivesWe explored the transcriptomic and genomic underpinnings and clinical relevance of morphological classes across localized and metastatic PDAC. DesignWe unified morphological classifications into four classes: glandular, cribriform, solid, and squamous. We integrated transcriptome and whole-genome sequencing following laser-capture microdissection with morphological classifications in 348 PDAC patients, where half of the cohort included locally advance and metastatic stages to uncover molecular associations. ResultsNon-glandular morphologies comprised three distinct classes that were enriched in metastatic disease. Transcriptomic profiling exhibited that glandular tumours predominantly expressed classical epithelial programs, although a subset displayed partial or full epithelial- mesenchymal transition signatures. In contrast, non-glandular morphologies showed basal-like transcriptional programs with subtype-specific pathways, including ciliogenesis in cribriform tumours, extracellular matrix remodelling and immune evasion in solid tumours, and keratinisation programs in squamous tumours. The solid class was significantly enriched in liver metastatic lesions and was associated with increased intra-tumoural morphological heterogeneity, whole-genome doubling, KRAS major allelic imbalance, and elevated KRAS-ERK signalling. ConclusionNon-glandular morphologies identify biologically distinct PDAC tumour states that are enriched in liver metastases and associated with subtype-specific transcriptional programs and KRAS-driven genomic alterations.

cancer biology↗

bioRxiv2025

The subclonal footprint of pervasive early dissemination in pancreatic cancer

Early is too late describes a central problem in pancreatic cancer referring to its relentless drive to disseminate and highlights the need to understand how this disease spreads so rapidly. In this study, we profiled 1,013 samples from 277 donors, including tissue whole genome and RNA sequencing combined with plasma whole genome sequencing at [~]25x. Strikingly, local primary tumours, including some reaching 7cm, were found to shed little to no circulating tumour DNA (ctDNA). Instead, metastatic burden in the liver but not extrahepatic sites, was a main physiologic determinant of ctDNA levels. Whole-genome duplication (WGD), high cell cycle activity, and non-glandular differentiation emerged as tumour-intrinsic features related to increased ctDNA shedding. By contrast, decreased shedding was related to extrinsic features including a reactive microenvironment and unexpectedly, humoral immunity. Analysis of tumour clonal architecture showed that in patients with low ctDNA levels, the signal disproportionately originated from subclones and this signal persisted even when the primary tumour was removed. Disseminated subclones were a significant source of ctDNA in early-stage patients. Longitudinal analysis of patients revealed that subclones seeded metastases and shed ctDNA in the blood years before detection. This first report of paired tissue and plasma whole genomes in pancreatic cancer is a unique resource and has broad implications for disease surveillance, treatment monitoring, and early detection in this disease.

cancer biology↗

bioRxiv2025

Integrated spatial proteomics of human PDAC uncovers an expanded tumour-immune-stroma spectrum with genomic associations

Distinctively, pancreatic ductal adenocarcinoma (PDAC) consists of sparse tumour lesions intertwined with extensive desmoplastic stroma. The complexity of tumour-microenvironment interactions within this desmoplasia poses a challenge for accurate tumour profiling and patient stratification, and characterizes a profoundly chemoresistant tumour. Here we mapped the spatial relationships between tumour, stroma, and immune cell compartments delineating tumour and microenvironment types that expand the classical to basal spectrum of human PDAC. We used imaging mass cytometry to profile the in situ multi-cellular organization of 81 cell types in resected cases with paired whole genome sequencing. Cell types, functions, and pathway activation were distributed as highly reproducible environments in discrete locations throughout these tumours, which we deep-profiled using laser-capture mass spectrometry. We show that the connections between tumour phenotypes, vascularization, immune response, and stromal biophysical state are reinforced by genomic aberrations, altered by treatment, and associated with patient outcome. Predictive machine-learning models showed that spatial single cell data outperformed genomic or clinical features but integrated multi-omics models provide the best prediction of patient survival with compressed models requiring only 10 non-redundant robust molecular measures associated with the phenotypic spectrum of PDAC. Together, these findings define a phenotypic and molecular framework of PDAC that captures tumour-microenvironment co-dependencies and offers a refined basis for patient stratification and therapeutic targeting.

cancer biology↗

bioRxiv2024

Hematopoietic Tet2 inactivation enhances the response to checkpoint blockade immunotherapy

Somatic mutations inactivating TET2 are among the most common drivers of clonal hematopoiesis (CH). While TET2 inactivation is associated with monocyte-derived inflammation and improved chimeric antigen-receptor-T cell function, its impact on immunotherapy response is unknown. In our mouse model, hematopoietic Tet2 mutation enhanced immune checkpoint blockade (ICB) response. Enhanced ICB response with Tet2 mutation required phagocytes, CD4 and CD8 T cells. Mechanistically, in Tet2-mutant tumor-infiltrating leukocytes (TILs), ICB preferentially induced anti-tumor states and restricted cell states linked to tumor progression. Tet2-mutant monocytes activated costimulatory programs, while Tet2-mutant T cells showed enhanced T cell memory signatures, lesser exhaustion and decreased regulatory phenotype. Our murine data was clinically relevant, since we found that melanomas from patients with TET2 driver mutation-CH (TET2-CH) showed enhanced immune infiltration, T cell activation, and T cell memory programs. In melanoma patients treated with ICB, TET2-CH was associated with 6-fold greater odds of clinical benefit. Collectively, our data establishes that hematopoietic Tet2 inactivation primes leukocytes for anti-tumor states associated with immunotherapy response and provides a potential biomarker for personalized therapy.

cancer biology↗

bioRxiv2023

Single cell dissection of developmental origins and transcriptional heterogeneity in B-cell acute lymphoblastic leukemia

Sequencing of bulk tumor populations has improved genetic classification and risk assessment of B-ALL, but does not directly examine intratumor heterogeneity or infer leukemia cellular origins. We profiled 89 B-ALL samples by single-cell RNA-seq (scRNA-seq) and compared them to a reference map of normal human B-cell development established using both functional and molecular assays. Intra-sample heterogeneity was driven by cell cycle, metabolism, differentiation, and inflammation transcriptional programs. By inference of B lineage developmental state composition, nearly all samples possessed a high abundance of pro-B cells, with variation between samples mainly driven by sub-populations. However, ZNF384-r and DUX4- r B-ALL showed composition enrichment of hematopoietic stem cells, BCR::ABL1 and KMT2A-r ALL of Early Lymphoid progenitors, MEF2D-r and TCF3::PBX1 of Pre-B cells. Enrichment of Early Lymphoid progenitors correlated with high-risk clinical features. Understanding variation in transcriptional programs and developmental states of B-ALL by scRNA-seq refines existing clinical and genomic classifications and improves prediction of treatment outcome.

cancer biology↗

bioRxiv2022

A primary patient-derived model for investigating functional heterogeneity within the human Leukemic Stem Cell Compartment

The ability of leukemic stem cells (LSC) to evade therapy and fuel leukemic progression causing relapse impedes therapeutic success in acute myeloid leukemia (AML). The LSC pool within a patient sample is not homogenous but comprises distinct LSC subsets that vary in self-renewal and propagation properties. The stemness programs that underlie LSC types are poorly understood since human LSC studies require primary patient samples where LSC numbers are low and isolation methods impure. To overcome these challenges, we developed a patient-derived AML model system (OCI-AML22) displaying a functionally, transcriptionally and epigenetically defined cellular hierarchy driven by functional LSCs that can be immunophenotypically identified and isolated. Through single cell and functional approaches, the OCI-AML22 LSC fraction was found to contain distinct LSCs that vary in proliferative and differentiation properties. OCI-AML22 represents a valuable resource to decipher mechanisms driving stemness and the multiple layers of heterogeneity within LSCs.

cancer biology↗

bioRxiv2022

A cellular hierarchy framework for understanding heterogeneity and predicting drug response in AML

The treatment landscape of AML is evolving with promising therapies entering clinical translation, yet patient responses remain heterogeneous and biomarkers for tailoring treatment are lacking. To understand how disease heterogeneity links with therapy response, we determined the leukemia cell hierarchy make-up from bulk transcriptomes of over 1000 patients through deconvolution using single-cell reference profiles of leukemia stem, progenitor, and mature cell types. Leukemia hierarchy composition was associated with functional, genomic, and clinical properties and converged into four overall classes, spanning Primitive, Mature, GMP, and Intermediate. Critically, variation in hierarchy composition along the Primitive vs GMP or Primitive vs Mature axes were associated with response to chemotherapy or drug sensitivity profiles of targeted therapies, respectively. A 7-gene biomarker derived from the Primitive vs Mature axis was predictive of patient response to 105 investigational drugs. Thus, hierarchy composition constitutes a novel framework for understanding disease biology and advancing precision medicine in AML.

cancer biology↗

bioRxiv2021

Dichotomous regulation of lysosomes by MYC and TFEB controls hematopoietic stem cell fate

It is critical to understand how quiescent long-term hematopoietic stem cells (LT-HSC) sense demand from daily and stress-mediated cues and transition into bioenergetically active progeny to differentiate and meet these cellular needs. Here, we show that lysosomes, which are sophisticated nutrient sensing and signaling centers, are dichotomously regulated by the Transcription Factor EB (TFEB) and MYC to balance catabolic and anabolic processes required for activating LT-HSC and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway causes membrane receptor degradation, limiting LT-HSC metabolic and mitogenic activation, which promotes quiescence, self-renewal and governs erythroid-myeloid commitment. By contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism to drive LT-HSC activation. Collectively, our study identifies lysosomes as a central regulatory hub for proper and coordinated stem cell fate determination.

cell biology↗

bioRxiv2020

Mapping the Cellular Origin and Early Evolution of Leukemia in Down Syndrome

Children with Down syndrome have a 150-fold increased risk of developing myeloid leukemia, but the mechanism of predisposition is unclear. As Down syndrome leukemogenesis initiates during fetal development, we characterized the cellular context of preleukemic initiation and leukemic progression using gene editing in human disomic and trisomic fetal liver hematopoietic cells and xenotransplantation. GATA1 mutations caused transient preleukemia only when introduced into trisomy 21 long-term hematopoietic stem cells, where a subset of chromosome 21 miRNAs triggers predisposition to preleukemia. By contrast, progression to leukemia was independent of trisomy 21 and originated in various stem and progenitor cells through additional mutations in cohesin genes. CD117+/KIT cells mediated the propagation of preleukemia and leukemia, and functional KIT inhibition targeted preleukemic stem cells, blocking progression to leukemia.

cancer biology↗