STOmics technology:BGI Stereomics Stereo-Seq

Data type:Raw sequence reads, Transcriptome or Gene expression, Spatial transcriptomics

Sample scope:Multiisolate

Summary:Pancreatic ductal adenocarcinoma (PDAC) is the deadliest common malignancy1. Benign lesions named pancreatic intraepithelial neoplasia (PanIN) are important precursors to PDAC, but these are extremely common in the general population2. The mechanisms underlying the lethal conversion of benign PanINs to invasive PDAC is poorly understood. Here we harness Stereo-seq, a high resolution spatial transcriptomic profiling platform3, to identify a core transcriptional program associated with invasive growth in human PDAC. This program, highly conserved in mice, is predominantly comprised of genes activated to drive reepithelialization during wound healing. Genes of this wound-like program are required for conversion of PanINs into invasive PDAC in mice. Benign PanINs continually produce a small reservoir of wound-like epithelial cells that activate key tumor suppressor genes (TSGs), keeping the incipient malignant cells in check. TSG KO in PanINs leads to rapid outgrowth of the wound-like population, unleashing invasive growth. Wound-induced AP-1 transcription factors (TFs) FOSL1 and JUNB are specifically activated in invasive PDAC cells and enforced expression of FOSL1 in PanIN drives wound-like gene expression and benign-to-malignant plasticity. Malignant PDAC cells are surrounded by a conserved population of CTHRC1-expressing cancer-associated fibroblasts (CAFs) that possess a transcriptional program strikingly similar to one activated in a population of wound-emergent fibroblasts in skin. Bidirectional interactions between malignant cancer cells and the wound-like CAFs result in a feedback loop that enforces the malignant state.

Contributor(s):HAOHAO DENG.

Submitter:杨晨露,BGI

Release date:2025-12-01

Updated:2025-12-01