Dataset Information

Metaplastic tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer.

ABSTRACT:

Background

Pancreatic cancer is partly derived from the transdifferentiation of acinar cells into metaplastic ducts that act as precursors of neoplasia and cancer. Tuft cells are solitary chemosensory cells not found in the normal pancreas but arise in metaplasia and neoplasia, gradually disappearing as neoplastic lesions progress to carcinoma. Metaplastic tuft cells (mTCs) functionally suppress tumor progression through communication with the tumor microenvironment, but their fate during progression is unknown.

Methods

To determine the fate of mTCs during PDA progression, we have created a lineage tracing model that uses a tamoxifen-inducible tuft-cell specific Pou2f3^CreERT/+ driver to induce transgene expression, including the lineage tracer tdTomato or cMyc. FlpO-driven, mTC lineage trace models of pancreatic neoplasia (Ptf1a^FlpO/+; FSF-KRAS^G12D/+; Pou2f3^CreERT/+; ROSA26LSL-TdTomato/+, "KF-P2f3T") and carcinoma (Ptf1aFlpO/+; FSF-KRASG12D/+; Trp53Frt-Exons 2 ^{to 5-Frt/+}; Pou2f3^CreERT/+; ROSA26^{LSL-TdTomato/+}, "KPF-P2f3T") were used to follow mTC fate. Co-immunofluorescence was used to determine the identity of lineage-traced cells throughout the progression of neoplasia and carcinoma.

Results

We found that mTCs, specifically in the KPF-P2f3T carcinoma model, transdifferentiate spontaneously into neural-like progenitor cells (NRPs), a cell type associated with poor survival in pancreatic cancer patients. This Tuft-to-Neuroendocrine Transition (TNT) does not occur in KF-P2f3T neoplasia until cMyc expression is targeted directly in mTCs.

SUBMITTER: Salas-Escabillas DJ

PROVIDER: S-EPMC10888969 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Publications

Tuft cells transdifferentiate to neural-like progenitor cells in the progression of pancreatic cancer.

Salas-Escabillas Daniel J DJ Hoffman Megan T MT Moore Jacee S JS Brender Sydney M SM Wen Hui-Ju HJ Benitz Simone S Davis Erick T ET Long Dan D Wombwell Allison M AM Steele Nina G NG Sears Rosalie C RC Matsumoto Ichiro I DelGiorno Kathleen E KE Crawford Howard C HC

bioRxiv : the preprint server for biology 20240423

Pancreatic ductal adenocarcinoma (PDA) is partly initiated through the transdifferentiation of acinar cells to metaplastic ducts that act as precursors of neoplasia and cancer. Tuft cells are solitary chemosensory cells not found in the normal pancreas but arise in metaplasia and neoplasia, diminishing as neoplastic lesions progress to carcinoma. Metaplastic tuft cells (mTCs) function to suppress tumor progression through communication with the tumor microenvironment, but their fate during progr ...[more]

PMID: 38405804

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