Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M. & Maitra, A. Pancreatic cancer: advances and challenges. Cell 186, 1729–1754 (2023).
Hidalgo, M. et al. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology 15, 8–18 (2015).
Park, W., Chawla, A. & O’Reilly, E. M. Pancreatic cancer: a review. JAMA 326, 851–862 (2021).
Groot, V. P. et al. Implications of the pattern of disease recurrence on survival following pancreatectomy for pancreatic ductal adenocarcinoma. Ann. Surg. Oncol. 25, 2475–2483 (2018).
Liu, K. H. et al. Lung metastases in patients with stage IV pancreatic cancer: prevalence, risk factors, and survival impact. J. Clin. Med. 8, 1402 (2019).
Sahin, I. H., Elias, H., Chou, J. F., Capanu, M. & O’Reilly, E. M. Pancreatic adenocarcinoma: insights into patterns of recurrence and disease behavior. BMC Cancer 18, 769 (2018).
Yachida, S. et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467, 1114–1117 (2010).
Yachida, S. et al. Clinical significance of the genetic landscape of pancreatic cancer and implications for identification of potential long-term survivors. Clin. Cancer Res. 18, 6339–6347 (2012).
Makohon-Moore, A. P. et al. Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer. Nat. Genet. 49, 358–366 (2017).
Reiter, J. G. et al. Minimal functional driver gene heterogeneity among untreated metastases. Science 361, 1033–1037 (2018).
Notta, F. et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 538, 378–382 (2016).
McDonald, O. G. et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat. Genet. 49, 367–376 (2017).
Kim, M. S. et al. Heterogeneity of pancreatic cancer metastases in a single patient revealed by quantitative proteomics. Mol. Cell. Proteomics 13, 2803–2811 (2014).
Erickson, A. et al. Spatially resolved clonal copy number alterations in benign and malignant tissue. Nature 608, 360–367 (2022).
O’Kane, G. M. et al. GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer. Clin. Cancer Res. 26, 4901–4910 (2020).
Raghavan, S. et al. Microenvironment drives cell state, plasticity, and drug response in pancreatic cancer. Cell 184, 6119–6137 (2021).
Wormann, S. M. et al. APOBEC3A drives deaminase domain-independent chromosomal instability to promote pancreatic cancer metastasis. Nat. Cancer 2, 1338–1356 (2021).
Collisson, E. A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17, 500–503 (2011).
Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).
Gavish, A. et al. Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours. Nature 618, 598–606 (2023).
Gabitova-Cornell, L. et al. Cholesterol pathway inhibition induces TGF-β signaling to promote basal differentiation in pancreatic cancer. Cancer Cell 38, 567–583 (2020).
Zhang, D. et al. Inferring super-resolution tissue architecture by integrating spatial transcriptomics with histology. Nat. Biotechnol. 42, 1372–1377 (2024).
Elyada, E. et al. Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discov. 9, 1102–1123 (2019).
Sahai, E. et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20, 174–186 (2020).
Dilly, J. et al. Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer. Cancer Discov. 14, 2135–2161 (2024).
Zhang, Y. et al. Macropinocytosis in cancer-associated fibroblasts is dependent on CaMKK2/ARHGEF2 signaling and functions to support tumor and stromal cell fitness. Cancer Discov. 11, 1808–1825 (2021).
Ma, R. Y., Black, A. & Qian, B. Z. Macrophage diversity in cancer revisited in the era of single-cell omics. Trends Immunol. 43, 546–563 (2022).
Blando, J. et al. Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc. Natl Acad. Sci. USA 116, 1692–1697 (2019).
Carstens, J. L. et al. Spatial computation of intratumoral T cells correlates with survival of patients with pancreatic cancer. Nat. Commun. 8, 15095 (2017).
Falcomata, C. et al. Context-specific determinants of the immunosuppressive tumor microenvironment in pancreatic cancer. Cancer Discov. 13, 278–297 (2023).
Biffi, G. et al. IL1-induced JAK/STAT signaling is antagonized by TGFβ to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. Cancer Discov. 9, 282–301 (2019).
Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).
Jiang, H. et al. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nat. Med. 22, 851–860 (2016).
He, S. et al. High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging. Nat. Biotechnol. 40, 1794–1806 (2022).
Connor, A. A. et al. Integration of genomic and transcriptional features in pancreatic cancer reveals increased cell cycle progression in metastases. Cancer Cell 35, 267–282 (2019).
Chan-Seng-Yue, M. et al. Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution. Nat. Genet. 52, 231–240 (2020).
Moffitt, R. A. et al. Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–1178 (2015).
Puleo, F. et al. Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features. Gastroenterology 155, 1999–2013 (2018).
Lee, J. J. et al. Elucidation of tumor-stromal heterogeneity and the ligand-receptor interactome by single-cell transcriptomics in real-world pancreatic cancer biopsies. Clin. Cancer Res. 27, 5912–5921 (2021).
Topham, J. T. et al. Subtype-discordant pancreatic ductal adenocarcinoma tumors show intermediate clinical and molecular characteristics. Clin. Cancer Res. 27, 150–157 (2021).
Williams, H. L. et al. Spatially resolved single-cell assessment of pancreatic cancer expression subtypes reveals co-expressor phenotypes and extensive intratumoral heterogeneity. Cancer Res. 83, 441–455 (2023).
Wang, Z. et al. Carcinomas assemble a filamentous CXCL12-keratin-19 coating that suppresses T cell-mediated immune attack. Proc. Natl Acad. Sci. USA 119, e2119463119 (2022).
Yan, R., Moresco, P., Gegenhuber, B. & Fearon, D. T. T cell-mediated development of stromal fibroblasts with an immune-enhancing chemokine profile. Cancer Immunol. Res. 11, 1044–1054 (2023).
Meylan, M. et al. Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer. Immunity 55, 527–541 (2022).
Law, H. C. et al. The proteomic landscape of pancreatic ductal adenocarcinoma liver metastases identifies molecular subtypes and associations with clinical response. Clin. Cancer Res. 26, 1065–1076 (2020).
Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902 (2019).
McInnes, L., Healy, J., Saul, N. & Grossberger, L. UMAP: uniform manifold approximation and projection. J. Open Source Softw. 3, 861 (2018).
Chu, Y. et al. Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Nat. Med. 29, 1550–1562 (2023).
Wang, R. et al. Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression. Cancer Cell 41, 1407–1426 (2023).
Wang, R. et al. Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma. Nat. Med. 27, 141–151 (2021).
Sans, M. et al. Spatial transcriptomics of intraductal papillary mucinous neoplasms of the pancreas identifies NKX6-2 as a driver of gastric differentiation and indolent biological potential. Cancer Discov. 13, 1844–1861 (2023).
Yu, G., Smith, D. K., Zhu, H., Guan, Y. & Lam, T. T. Y. ggtree: an R package for visualization and annotation of phylogenetic trees with their covariates and other associated data. Methods Ecol. Evol. 8, 28–36 (2017).
Gao, R. et al. Delineating copy number and clonal substructure in human tumors from single-cell transcriptomes. Nat. Biotechnol. 39, 599–608 (2021).
De Falco, A., Caruso, F., Su, X.-D., Iavarone, A. & Ceccarelli, M. A variational algorithm to detect the clonal copy number substructure of tumors from scRNA-seq data. Nat. Commun. 14, 1074 (2023).
Schliep, K. phangorn: phylogenetic analysis in R. Bioinformatics 27, 592–593 (2011).
Liberzon, A. et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417–425 (2015).
Hao, D. et al. The single-cell immunogenomic landscape of B and plasma cells in early-stage lung adenocarcinoma. Cancer Discov. 12, 2626–2645 (2022).
Liao, Y., Wang, J., Jaehnig, E. J., Shi, Z. & Zhang, B. WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs. Nucleic Acids Res. 47, W199–W205 (2019).
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995).
Ohlund, D. et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J. Exp. Med. 214, 579–596 (2017).
Cable, D. M. et al. Robust decomposition of cell type mixtures in spatial transcriptomics. Nat. Biotechnol. 40, 517–526 (2022).
Wei, R. et al. Spatial charting of single-cell transcriptomes in tissues. Nat. Biotechnol. 40, 1190–1199 (2022).
Vahid, M. R. et al. High-resolution alignment of single-cell and spatial transcriptomes with CytoSPACE. Nat. Biotechnol. 41, 1543–1548 (2023).
Pei, G. et al. deCS: a tool for systematic cell type annotations of single-cell RNA sequencing data among human tissues. Genomics Proteomics Bioinformatics 21, 370–384 (2023).
Belle, J. I. & DeNardo, D. G. A single-cell window into pancreas cancer fibroblast heterogeneity. Cancer Discov. 9, 1001–1002 (2019).
Boyd, L. N. C., Andini, K. D., Peters, G. J., Kazemier, G. & Giovannetti, E. Heterogeneity and plasticity of cancer-associated fibroblasts in the pancreatic tumor microenvironment. Semin. Cancer Biol. 82, 184–196 (2022).
Hanzelmann, S., Castelo, R. & Guinney, J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 14, 7 (2013).
