American Association for Cancer Research
cd-22-1200_supplementary_figures_s1-s13_suppsf1.pdf (3.58 MB)

Supplementary Figures S1-S13 from Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential

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journal contribution
posted on 2023-07-21, 13:40 authored by Marta Sans, Yuki Makino, Jimin Min, Kimal I. Rajapakshe, Michele Yip-Schneider, C. Max Schmidt, Mark W. Hurd, Jared K. Burks, Javier A. Gomez, Fredrik I. Thege, Johannes F. Fahrmann, Robert A. Wolff, Michael P. Kim, Paola A. Guerrero, Anirban Maitra

Figure S1. Spatial maps showing number of genes detected per spot in the 13 samples used for spatial transcriptomics analyses. Figure S2. A) Uniform Manifold Approximation and Projection (UMAP) of all spots collected from the 13 samples by ST. Figure S3. A) Violin plot showing expression of CDX2 and MUC2 in the epilesional compartments of IPMN and PDAC samples. Figure S4. Cell type proportions in LG and HR IPMN compartments determined by RCTD deconvolution. Figure S5. COMET cyclic IF imaging of IPMN. Figure S6. NKX6-2 levels determined by ST and COMET analyses conducted on tissue samples from the same patient. Figure S7. NKX6-2 expression in LG IPMN samples and its associated signature. Figure S8. A) Enrichment plots for gastric REG3A positive cells, main fetal acinar cells, pancreas acinar cells, and ductal cells obtained via GSEA analyses. Figure S9. Spatial transcriptomic analyses of a murine model of IPMN. Figure S10. A) Gene set enrichment analyses (GSEA) of differentially expressed cell type signatures between Nkx6-2+ and Nkx6-2 – spots in the Gnas;Kras mice samples. Figure S11. Nkx6-2 overexpression in a Kras;Gnas cell line. Figure S12. Nkx6-2 overexpression in KPC cell lines. Figure S13. Quantification of the percentage of glandular structures in the tumors derived from Kras;GnasNkx6-2 or control cell lines in littermate (Kras;Gnas, left) mice or immunodeficient nude mice (NuJ, right).



Intraductal papillary mucinous neoplasms (IPMN) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbors a gastric foveolar-type epithelium, and these low-grade mucinous neoplasms are harbingers of IPMNs with high-grade dysplasia and cancer. The molecular underpinning of gastric differentiation in IPMNs is unknown, although identifying drivers of this indolent phenotype might enable opportunities for intercepting progression to high-grade IPMN and cancer. We conducted spatial transcriptomics on a cohort of IPMNs, followed by orthogonal and cross-species validation studies, which established the transcription factor NKX6-2 as a key determinant of gastric cell identity in low-grade IPMNs. Loss of NKX6-2 expression is a consistent feature of IPMN progression, while reexpression of Nkx6-2 in murine IPMN lines recapitulates the aforementioned gastric transcriptional program and glandular morphology. Our study identifies NKX6-2 as a previously unknown transcription factor driving indolent gastric differentiation in IPMN pathogenesis. Identification of the molecular features driving IPMN development and differentiation is critical to prevent cancer progression and enhance risk stratification. We used spatial profiling to characterize the epithelium and microenvironment of IPMN, which revealed a previously unknown link between NKX6-2 and gastric differentiation, the latter associated with indolent biological potential.

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