bioRxiv [Preprint]. 2026 Mar 11:2026.03.09.710586. doi: 10.64898/2026.03.09.710586.

ABSTRACT

The lack of accurate, human-based models recapitulating early-stage pancreatic ductal adenocarcinoma (PDAC) has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectory of tumor initiation and progression in vitro , validated against clinical datasets and histopathology. We demonstrate that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, while SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of pancreatic lineage program during PDAC initiation, alongside oncogenic AP-1-driven chromatin remodeling. Notably, we identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and the hypermethylation and silencing of essential pancreatic transcription factors. This model captures the genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a promising early intervention strategy for high-risk individuals.

PMID:41959451 | PMC:PMC13060829 | DOI:10.64898/2026.03.09.710586

JHEP Rep. 2026 Feb 18;8(5):101790. doi: 10.1016/j.jhepr.2026.101790. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence.

METHODS: Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry.

RESULTS: Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6⁺ ECs, enriched and spatially colocalised with tumour cells in primary tumours from patients with recurrence (p = 0.021, n = 49). A significant ANGPTL4-SDC1 ligand-receptor interaction was identified between INTS6⁺ ECs and tumour cells. Notably, INTS6⁺ ECs were enriched in microvascular invasion regions and spatially colocalised with tumour cells in patients with recurrence (p = 0.036, n = 53). These findings highlight endothelial-tumour cell interactions within the TME as potential therapeutic targets.

CONCLUSIONS: INTS6⁺ ECs are enriched in microvascular invasion regions and spatially colocalised with tumour cells in recurrent HCC, suggesting a potential role in disease recurrence and representing a promising therapeutic target within the TME.

IMPACT AND IMPLICATIONS: The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival.

PMID:41950768 | DOI:10.1016/j.jhepr.2026.101790

JHEP Rep. 2026 Feb 18;8(5):101790. doi: 10.1016/j.jhepr.2026.101790. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence.

METHODS: Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry.

RESULTS: Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6⁺ ECs, enriched and spatially colocalised with tumour cells in primary tumours from patients with recurrence (p = 0.021, n = 49). A significant ANGPTL4-SDC1 ligand-receptor interaction was identified between INTS6⁺ ECs and tumour cells. Notably, INTS6⁺ ECs were enriched in microvascular invasion regions and spatially colocalised with tumour cells in patients with recurrence (p = 0.036, n = 53). These findings highlight endothelial-tumour cell interactions within the TME as potential therapeutic targets.

CONCLUSIONS: INTS6⁺ ECs are enriched in microvascular invasion regions and spatially colocalised with tumour cells in recurrent HCC, suggesting a potential role in disease recurrence and representing a promising therapeutic target within the TME.

IMPACT AND IMPLICATIONS: The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival.

PMID:41950768 | DOI:10.1016/j.jhepr.2026.101790