WNT7B drives a program for pancreatic cancer subtype switching and progression

TL;DR

The WNT7B protein promotes aggressive pancreatic cancer by maintaining a specific cancer subtype and supporting tumor growth through cell contact.

Contribution

This study reveals how WNT7B drives pancreatic cancer progression and subtype stability through direct cell-cell interactions.

Findings

WNT7B sustains pancreatic cancer cell growth and survival by maintaining a basal-like subtype.

WNT-high and WNT-low cells coexist as stable lineages within pancreatic tumors.

WNT7B-expressing cells support neighboring cells via direct contact-dependent signaling.

Abstract

Hyperactivation of WNT signaling is a hallmark of cancer, often driven by increased expression of WNT ligands. In pancreatic ductal adenocarcinoma (PDAC), elevated WNT7B and WNT10A correlate with aggressive, basal-like disease and poor patient survival, but the mechanisms underlying this association remain unclear. Using patient-derived organoids, we show that WNT7B promotes proliferation and maintains basal-like transcriptional states by preventing differentiation toward a more classical PDAC signature. Clonal WNT7B reporter organoids reveal that WNT-high cells are heterogeneously distributed and stably coexist with WNT-low/negative lineages. Hybrid co-cultures demonstrate that WNT7B-expressing cells support the survival and growth of neighboring WNT-negative cells via short-range, contact-dependent signaling. These findings highlight the functional importance of heterogeneous WNT7B/10A expression in driving PDAC aggressiveness and suggest that targeted WNT inhibition may shift tumors toward a more differentiated, less aggressive state, offering potential therapeutic benefit.

•Epithelial WNT7B and WNT10A sustain PDAC cell growth and survival•WNThigh and WNTlow cells coexist within PDAC as stable lineages•WNT7B shifts PDAC toward a basal-like state by suppressing the classical signature•WNThigh cells support neighboring WNTlow cells via direct cell-cell contact

Epithelial WNT7B and WNT10A sustain PDAC cell growth and survival

WNThigh and WNTlow cells coexist within PDAC as stable lineages

WNT7B shifts PDAC toward a basal-like state by suppressing the classical signature

WNThigh cells support neighboring WNTlow cells via direct cell-cell contact

Cell biology; Functional aspects of cell biology; Cancer

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