P92. Redefining the etiology of dysplastic progression in IPMN: Hydrostatic pressure, and not size, is associated with neoplastic change

Saturday, March 7, 2026

8:53 AM - 9:00 AM MST

Location: 105A-C

Primary Presenter(s)

TP

Tommaso Pollini, MD

Postdoctoral Research Fellow
University Of California San Francisco
Rochester, Minnesota, United States

Co-Author(s)

KJ

Kashish Jain, PhD

University of California San Francisco
San Francisco, California, United States
JL

Johnathon Lakins, PhD

University of California San Francisco
San Francisco, California, United States
Konstantinos Stasinos, MD, PhD (he/him/his)

Postdoctoral Scholar
University of California San Francisco
San Francisco, California, United States
PW

Paul Wong, MD

Resident
Brigham and Women's Hospital/Mass General Brigham
Boston, Massachusetts, United States
VW

Valerie M. Weaver, PhD

Professor
University of California San Francisco
San Francisco, California, United States
GK

Grace E. Kim, MD

Professor
University of California San Francisco, Department of Pathology
San Francisco, California, United States
Ajay V. Maker, MD, FACS

Professor of Surgery and Chief, Division of Surgical Oncology
University of California San Francisco
San Francisco, California, United States

Introduction: The biological mechanisms driving dysplastic progression in intraductal papillary mucinous neoplasms (IPMNs) remain poorly understood. Current guidelines prioritize cyst size as a predictor of dysplasia, however, most cysts resected under these criteria ultimately harbor only low-grade dysplasia. We hypothesize that intracystic pressure, rather than cyst size, drives profibrotic signaling and microenvironment remodeling that promote dysplastic progression.

Methods: We quantified stromal content on H&E whole-slide images using a Random Forest pixel classifier across normal pancreas, pancreatitis, IPMN, and PDAC (n = 56). Observing a progressive increase in cellular and noncellular stroma, we tested whether hydrostatic pressure could induce this fibrotic phenotype. Human pancreatic ductal epithelial (HPDE) and stellate (HPSC) cells were exposed to 1 psi for 1 hour in a bioreactor, followed by bulk RNA-seq to derive a composite pressure-response signature. This signature was evaluated using single-nucleus RNA-seq (snRNA-seq) from 12 resected IPMN samples spanning dysplasia grades. Trends were analyzed by Spearman correlation.

Results: Whole-slide analysis showed stepwise stromal expansion: LGD < HGD (Δ = 25%, p = 0.001) and LGD < Invasive (Δ = 29%, p ≤ 0.001) (Fig1.A). In vitro, pressure upregulated extracellular matrix genes (e.g. Fibronectin, Collagen 6, Metalloproteinases; p ≤ 1×10⁻¹⁴) from which we created a unique expression signature. Gene ontology terms were enriched for response to mechanical stimulus and extracellular-matrix organization (FDR ≤ 0.005). Scoring of the pressure signature in snRNA-seq (99,463 cells) showed progressive increase with dysplasia (p < 1×10⁻¹⁰), strongest in acinar (p < 1×10⁻¹¹⁶) and ductal (p < 1×10⁻⁴⁷) cells, followed by endothelial, B-, and T-cell populations (p ≤ 10⁻⁴). At the patient level, pressure signature correlated with dysplasia (p = 0.034) more strongly than cyst size (p = 0.130) (Fig1.B).

Conclusions: In pancreatic ductal and stellate cells, hydrostatic pressure activates a mechano-responsive program, and the resulting pressure-derived gene signature increases progressively across IPMN dysplasia. These findings implicate ductal pressure as a driver of fibrosis and dysplastic progression in IPMN. Collectively, this work reframes our understanding of IPMN evolution, highlighting cyst pressure over cyst size as a determinant of malignant progression and a novel avenue for candidate biomarkers and therapeutic intervention.

Learning Objectives:

Critique current size-based resection criteria for IPMN and explain why hydrostatic pressure may be a superior predictor of advanced disease compared to the size thresholds used in existing guidelines.
Recognize the clinical limitations of relying solely on cyst size for operative decision-making, given that pressure-derived signatures correlate more strongly with dysplastic progression than size in predicting malignant risk.
Anticipate future diagnostic and therapeutic strategies that may emerge from pressure-based biomarkers, including how intracystic pressure measurement or pressure-response gene signatures could potentially improve patient selection for resection versus surveillance.