Drivers of lineage reprogramming in malignant transformation of diffuse gastric cancer

The National Cancer Institute awarded Sloan-Kettering Institute for Cancer Research $736,625 under Cancer Biology Research (CFDA 93.396) on September 3, 2026, to identify early drivers of malignant transformation in diffuse gastric cancer through spatial and single-cell transcriptomic analysis of hereditary and sporadic disease models.

The project, titled "Drivers of Lineage Reprogramming in Malignant Transformation of Diffuse Gastric Cancer," will develop an integrated workflow to characterize signet-ring cell carcinoma biology and elucidate distinct cell states and their progression pathways. The research examines hereditary diffuse gastric cancer (caused by CDH1 and CTNNA1 mutations) as a model for understanding early malignant transformation, comparing convergent and divergent neoplastic pathways between hereditary and sporadic disease. Preliminary spatial transcriptomic studies have identified three distinct signet-ring cell states based on gene expression programs—enterocyte-like, goblet-like, and stem-like—with differing anatomical distribution and clonal characteristics. The award funds investigation of how cell state reprogramming drives malignant progression and discovery of biomarkers for intervention in this aggressive malignancy with high 5-year mortality.

The period of performance runs through August 31, 2031. Work is performed in New York, New York.

Abstract

Identifying early drivers of malignant transformation is essential to improving outcomes in diffuse gastric cancer (DGC), an aggressive malignancy with a high 5-year mortality due to late diagnosis and poor response to standard therapies. Hereditary DGC (HDGC), a model of DGC initiation, is a syndrome caused by mutations in CDH1 and CTNNA1 and conveys a 33-70% lifetime risk of invasive cancer. The stomachs of most patients with HDGC contain small clusters of signet-ring cell (SRC) carcinoma from an early age, which may remain dormant yet unpredictably and rapidly progress to metastatic disease. Prior analyses have failed to identify genes associated with early malignant transformation of srcs. Moreover, little is known about convergent and divergent pathways of neoplastic transformation in HDGC compared to sporadic DGC (SDGC), where individuals lack a hereditary predisposition but accumulate somatic mutations in genes like CDH1, leading to malignancy. We have successfully developed an integrated, multidisciplinary workflow to overcome longstanding challenges of studying enigmatic, rare srcs in human tissues. Our preliminary spatial and single-cell transcriptomic studies of HDGC unveil remarkable details on the biology of srcs. We have found previously uncharacterized gene expression programs that identify srcs and delineate 3 distinct, spatially segregated SRC states: enterocyte-like srcs found in superficial lesions, expressing SLC26A3; goblet-like srcs found in deeper mucosal lesions, expressing TFF3; and stem-like srcs found in submucosal advanced tumors, characterized by OLFM4. SRC lesions demonstrate early fibroblast infiltration, while advanced multi-focal lesions reveal shared clonal origin with copy number alterations. Based on these data, we hypothesize that malignant transformation in DGC proceeds through cell state reprogramming of srcs, reinforced by interactions with infiltrative fibroblasts that determine invasive potential. We will leverage our unique patient biobank along with spatially-resolved single-cell and genomic platforms to establish associations among SRC states, stromal remodeling and invasion. Because cross-sectional human data cannot directly establish temporal causality, we will use validated CDH1-knockout mouse models to determine whether inflammation drives SRC reprogramming and malignant expansion. In aim 1, we will characterize SRC transcriptional reprogramming from indolent enterocyte-like states to invasive stem-like states in CDH1- and CTNNA1-associated HDGC. In aim 2, we will elucidate how molecular interplay between srcs and fibroblasts drives SRC reprogramming and impacts malignant expansion in high-risk patient lesions and track inflammation-driven SRC transformation in the mouse model. In aim 3, we will establish the impact of somatic CDH1 inactivation of SRC transcriptional reprogramming in SDGC. Elucidating the drivers of SRC transformation in HDGC and SDGC will reshape our understanding of their common and divergent pathways, identifying markers of early neoplastic transformation and leading to clinically actionable interventions.