Rahib, L. et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 74, 2913–2921 (2014).
Google Scholar
Bazeed, A. Y., Day, C. M. & Garg, S. Pancreatic cancer: challenges and opportunities in locoregional therapies. Cancers 14, 4257 (2022).
Google Scholar
Kirkegård, J., Bojesen, A. B., Nielsen, M. F. & Mortensen, F. V. Trends in pancreatic cancer incidence, characteristics, and outcomes in Denmark 1980–2019: a nationwide cohort study. Cancer Epidemiol. 80, 102230 (2022).
Google Scholar
Wang, S. et al. The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives. Signal Transduct. Target. Ther. 6, 249 (2021).
Google Scholar
Ebelt, N. D., Zamloot, V. & Manuel, E. R. Targeting desmoplasia in pancreatic cancer as an essential first step to effective therapy. Oncotarget 11, 3486 (2020).
Google Scholar
Olajubutu, O., Ogundipe, O. D., Adebayo, A. & Adesina, S. K. Drug delivery strategies for the treatment of pancreatic cancer. Pharmaceutics 15, 1318 (2023).
Google Scholar
Cancer of the pancreas—cancer stat facts. SEER https://seer.cancer.gov/statfacts/html/pancreas.html (2025).
Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531, 47–52 (2016).
Google Scholar
Waddell, N. et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518, 495–501 (2015).
Google Scholar
Biankin, A. V. et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491, 399–405 (2012).
Google Scholar
Maitra, A. & Hruban, R. H. Pancreatic cancer. Annu. Rev. Pathol. 3, 157–188 (2008).
Google Scholar
Raphael, B. J. et al. Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 32, 185–203 (2017).
Google Scholar
DeWilde, R. F., Hruban, R. H., Maitra, A. & Offerhaus, G. J. A. Reporting precursors to invasive pancreatic cancer: pancreatic intraepithelial neoplasia, intraductal neoplasms and mucinous cystic neoplasm. Diagn. Histopathol. 18, 17–30 (2012).
Google Scholar
Leung, L. et al. Loss of canonical Smad4 signaling promotes KRAS driven malignant transformation of human pancreatic duct epithelial cells and metastasis. PLoS ONE 8, e84366 (2013).
Google Scholar
Whittle, M. C. et al. RUNX3 controls a metastatic switch in pancreatic ductal adenocarcinoma. Cell 161, 1345–1360 (2015).
Google Scholar
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).
Google Scholar
Escobar-Hoyos, L. F. et al. Altered RNA splicing by mutant p53 activates oncogenic RAS signaling in pancreatic cancer. Cancer Cell 38, 198–211 (2020).
Google Scholar
Collisson, E. A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nat. Med. 17, 500–503 (2011).
Google Scholar
Moffitt, R. A. et al. Virtual microdissection identifies distinct tumor-and stroma-specific subtypes of pancreatic ductal adenocarcinoma. Nat. Genet. 47, 1168–1178 (2015).
Google Scholar
Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).
Google Scholar
Aguirre, A. J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003).
Google Scholar
Ijichi, H. et al. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-β signaling in cooperation with active Kras expression. Genes Dev. 20, 3147–3160 (2006).
Google Scholar
Kojima, K. et al. Inactivation of Smad4 accelerates KrasG12D-mediated pancreatic neoplasia. Cancer Res. 67, 8121–8130 (2007).
Google Scholar
Tran, P. T. et al. Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis. PLoS Genet. 8, e1002650 (2012).
Google Scholar
Collado, M. & Serrano, M. Senescence in tumours: evidence from mice and humans. Nat. Rev. Cancer 10, 51–57 (2010).
Google Scholar
Thisse, B., el Messal, M. & Perrin-Schmitt, F. The twist gene: isolation of a Drosophila zygotle gene necessary for the establishment of dorsoventral pattern. Nucleic Acids Res. 15, 3439–3453 (1987).
Google Scholar
Wolf, C. et al. The M-twist gene of Mus is expressed in subsets of mesodermal cells and is closely related to the Xenopus X-twi and the Drosophila twist genes. Dev. Biol. 143, 363–373 (1991).
Google Scholar
Wang, S. M. et al. Cloning of the human twist gene: its expression is retained in adult mesodermally-derived tissues. Gene 187, 83–92 (1997).
Google Scholar
Martin, T. A., Goyal, A., Watkins, G. & Jiang, W. G. Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann. Surg. Oncol. 12, 488–496 (2005).
Google Scholar
Gong, T. et al. Nuclear expression of Twist promotes lymphatic metastasis in esophageal squamous cell carcinoma. Cancer Biol. Ther. 13, 606–613 (2012).
Google Scholar
Alexander, N. R. et al. N-cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1. Cancer Res. 66, 3365–3369 (2006).
Google Scholar
Hung, J. J. et al. Prognostic significance of hypoxia-inducible factor-1α, TWIST1 and Snail expression in resectable non-small cell lung cancer. Thorax 64, 1082–1089 (2009).
Google Scholar
Qin, Q., Xu, Y., He, T., Qin, C. & Xu, J. Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms. Cell Res. 22, 90–106 (2012).
Google Scholar
Lee, K. E. & Bar-Sagi, D. Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells. Cancer Cell 18, 448–458 (2010).
Google Scholar
D’Angelo, R. C. et al. TIMP-1 via TWIST1 induces EMT phenotypes in human breast epithelial cells. Mol. Cancer Res. 12, 1324–1333 (2014).
Google Scholar
Martin, A. & Cano, A. Tumorigenesis: Twist1 links EMT to self-renewal. Nat. Cell Biol. 12, 924–925 (2010).
Google Scholar
Xu, Y. et al. Breast tumor cell-specific knockout of Twist1 inhibits cancer cell plasticity, dissemination, and lung metastasis in mice. Proc. Natl Acad. Sci. USA 114, 11494–11499 (2017).
Google Scholar
Pham, C. G. et al. Upregulation of Twist-1 by NF-κB blocks cytotoxicity induced by chemotherapeutic drugs. Mol. Cell. Biol. 27, 3920–3935 (2007).
Google Scholar
Cheng, G. Z. et al. Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion, and resistance to paclitaxel. Cancer Res. 67, 1979–1987 (2007).
Google Scholar
Thiery, J. P., Acloque, H., Huang, R. Y. J. & Nieto, M. A. Epithelial–mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).
Google Scholar
Burns, T. F. et al. Inhibition of TWIST1 leads to activation of oncogene-induced senescence in oncogene-driven non–small cell lung cancer. Mol. Cancer Res. 11, 329–338 (2013).
Google Scholar
Yochum, Z. A. et al. A first-in-class TWIST1 inhibitor with activity in oncogene-driven lung cancer. Mol. Cancer Res. 15, 1764–1776 (2017).
Google Scholar
Taparra, K. et al. O-GlcNAcylation is required for mutant KRAS-induced lung tumorigenesis. J. Clin. Invest. 128, 4924–4937 (2019).
Google Scholar
Lafargue, A. et al. Twist1-induced suppression of oncogene-induced senescence in non-small cell lung cancer requires the transactivation domain of Twist1. Neoplasia 66, 101179 (2025).
Google Scholar
Yochum, Z. A. et al. Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene 38, 656–670 (2019).
Google Scholar
Khales, S. A., Abbaszadegan, M. R., Majd, A. & Forghanifard, M. M. Linkage between EMT and stemness state through molecular association between TWIST1 and NY-ESO1 in esophageal squamous cell carcinoma. Biochimie 163, 84–93 (2019).
Google Scholar
Khales, S. A., Mozaffari-Jovin, S., Geerts, D. & Abbaszadegan, M. R. TWIST1 activates cancer stem cell marker genes to promote epithelial–mesenchymal transition and tumorigenesis in esophageal squamous cell carcinoma. BMC Cancer 22, 1272 (2022).
Google Scholar
Sasaki, K. et al. Significance of Twist expression and its association with E-cadherin in esophageal squamous cell carcinoma. J. Exp. Clin. Cancer Res. 28, 1–9 (2009).
Google Scholar
Ansieau, S., Morel, A. P., Hinkal, G., Bastid, J. & Puisieux, A. TWISTing an embryonic transcription factor into an oncoprotein. Oncogene 29, 3173–3184 (2010).
Google Scholar
Ou, D. L., Chien, H. F., Chen, C. L., Lin, T. C. & Lin, L. I. Role of Twist in head and neck carcinoma with lymph node metastasis. Anticancer Res. 28, 1355–1359 (2008).
Google Scholar
Tsai, J. H., Donaher, J. L., Murphy, D. A., Chau, S. & Yang, J. Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725–736 (2012).
Google Scholar
Hamidi, A. A. et al. Elucidated tumorigenic role of MAML1 and TWIST1 in gastric cancer is associated with Helicobacter pylori infection. Microb. Pathog. 162, 105304 (2022).
Google Scholar
Cao, L. et al. Proteogenomic characterization of pancreatic ductal adenocarcinoma. Cell 184, 5031–5052 (2021).
Google Scholar
Hayashi, A. et al. A unifying paradigm for transcriptional heterogeneity and squamous features in pancreatic ductal adenocarcinoma. Nat. Cancer 1, 59–74 (2020).
Google Scholar
Rasti, A. et al. Cytoplasmic expression of Twist1, an EMT-related transcription factor, is associated with higher grades renal cell carcinomas and worse progression-free survival in clear cell renal cell carcinoma. Clin. Exp. Med. 18, 177–190 (2018).
Google Scholar
Parajuli, P. et al. Twist1 activation in muscle progenitor cells causes muscle loss akin to cancer cachexia. Dev. Cell 45, 712–725 (2018).
Google Scholar
Razzaque, M. S. & Atfi, A. Regulatory role of the transcription factor Twist1 in cancer-associated muscle cachexia. Front. Physiol. 11, 662 (2020).
Google Scholar
Wang, X. et al. TWIST1 regulates HK2 ubiquitination degradation to promote pancreatic cancer invasion and metastasis. Cancer Cell Int. 25, 37 (2025).
Google Scholar
Chen, S. et al. Hypoxia induces TWIST-activated epithelial–mesenchymal transition and proliferation of pancreatic cancer cells in vitro and in nude mice. Cancer Lett. 383, 73–84 (2016).
Google Scholar
Li, T. et al. S100A16 induces epithelial–mesenchymal transition in human PDAC cells and is a new therapeutic target for pancreatic cancer treatment that synergizes with gemcitabine. Biochem. Pharmacol. 189, 114396 (2021).
Google Scholar
Kawai, M. et al. Polybromo 1/vimentin axis dictates tumor grade, epithelial–mesenchymal transition, and metastasis in pancreatic cancer. J. Clin. Invest. 135, e177533 (2025).
Google Scholar
Hwang, W. L. et al. Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment. Nat. Genet. 54, 1178–1191 (2022).
Google Scholar
Stein-O’Brien, G. L. et al. Enter the matrix: factorization uncovers knowledge from omics. Trends Genet. 34, 790–805 (2018).
Google Scholar
Sharma, G., Conlantuoni, C., Goff, L. A., Fertig, E. J. & Stein-O’Brien, G. projectR: an R/Bioconductor package for transfer learning via PCA, NMF, correlation and clustering. Bioinformatics 36, 3592–3593 (2020).
Google Scholar
Aung, K. L. et al. Genomics-driven precision medicine for advanced pancreatic cancer: early results from the COMPASS trial. Clin. Cancer Res. 24, 1344–1354 (2018).
Google Scholar
Martinelli, P. et al. The acinar regulator Gata6 suppresses KrasG12V-driven pancreatic tumorigenesis in mice. Gut 65, 476–486 (2016).
Google Scholar
Kalisz, M. et al. HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer. EMBO J. 39, e102808 (2020).
Google Scholar
Martinelli, P. et al. GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer. Gut 66, 1665–1676 (2017).
Google Scholar
Real, F. X., Vilá, M. R., Skoudy, A., Ramaekers, F. C. S. & Corominas, J. M. Intermediate filaments as differentiation markers of exocrine pancreas. II. Expression of cytokeratins of complex and stratified epithelia in normal pancreas and in pancreas cancer. Int. J. Cancer 54, 720–727 (1993).
Google Scholar
Hamdan, F. H. & Johnsen, S. A. DeltaNp63-dependent super enhancers define molecular identity in pancreatic cancer by an interconnected transcription factor network. Proc. Natl Acad. Sci. USA 115, E12343–E12352 (2018).
Google Scholar
Somerville, T. D. D. et al. TP63-mediated enhancer reprogramming drives the squamous subtype of pancreatic ductal adenocarcinoma. Cell Rep. 25, 1741–1755 (2018).
Google Scholar
Ying, H. et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012).
Google Scholar
Biondani, G. et al. Extracellular matrix composition modulates PDAC parenchymal and stem cell plasticity and behavior through the secretome. FEBS J. 285, 2104–2124 (2018).
Google Scholar
Leca, J. et al. Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness. J. Clin. Invest. 126, 4140–4156 (2016).
Google Scholar
Olivares, O. et al. Collagen-derived proline promotes pancreatic ductal adenocarcinoma cell survival under limited nutrient conditions. Nat. Commun. 8, 16031 (2017).
Google Scholar
Sun, L. et al. Transcription factor Twist1 drives fibroblast activation to promote kidney fibrosis via signaling proteins Prrx1/TNC. Kidney Int. 106, 840–855 (2024).
Google Scholar
Sung, C. et al. Twist1 is up-regulated in gastric cancer-associated fibroblasts with poor clinical outcomes. Am. J. Pathol. 179, 1827–1838 (2011).
Google Scholar
Yeo, S. et al. Twist1 is highly expressed in cancer-associated fibroblasts of esophageal squamous cell carcinoma with a prognostic significance. Oncotarget 8, 65265–65280 (2017).
Google Scholar
Koenig, A., Mueller, C., Hasel, C., Adler, G. & Menke, A. Collagen type I induces disruption of E-cadherin–mediated cell-cell contacts and promotes proliferation of pancreatic carcinoma cells. Cancer Res. 66, 4662–4671 (2006).
Google Scholar
Chen, Y. et al. Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer. Cancer Cell 39, 548–565 (2021).
Google Scholar
Jain, R., Fischer, S., Serra, S. & Chetty, R. The use of cytokeratin 19 (CK19) immunohistochemistry in lesions of the pancreas, gastrointestinal tract, and liver. Appl. Immunohistochem. Mol. Morphol. 18, 9–15 (2010).
Google Scholar
Apte, M. V., Pirola, R. C. & Wilson, J. S. Pancreatic stellate cells: a starring role in normal and diseased pancreas. Front. Physiol. 3, 344 (2012).
Google Scholar
Ferdek, P. E. & Jakubowska, M. A. Biology of pancreatic stellate cells-more than just pancreatic cancer. Pflugers Arch. 469, 1039–1050 (2017).
Google Scholar
Kusiak, A. A., Szopa, M. D., Jakubowska, M. A. & Ferdek, P. E. Signaling in the physiology and pathophysiology of pancreatic stellate cells – a brief review of recent advances. Front. Physiol. 11, 78 (2020).
Google Scholar
Puleo, F. et al. Stratification of pancreatic ductal adenocarcinomas based on tumor and microenvironment features. Gastroenterology 155, 1999–2013 (2018).
Google Scholar
Miller, B. W. et al. Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol. Med. 7, 1063–1076 (2015).
Google Scholar
Zhou, X. et al. Clinical impact of molecular subtyping of pancreatic cancer. Front. Cell Dev. Biol. 9, 743908 (2021).
Google Scholar
Topham, J. T. et al. Subtype-discordant pancreatic ductal adenocarcinoma tumors show intermediate clinical and molecular characteristics. Clin. Cancer Res. 27, 150–157 (2021).
Google Scholar
Janky, R. et al. Prognostic relevance of molecular subtypes and master regulators in pancreatic ductal adenocarcinoma. BMC Cancer 16, 1–15 (2016).
Google Scholar
Hotz, B. et al. Epithelial to mesenchymal transition: expression of the regulators snail, slug, and twist in pancreatic cancer. Clin. Cancer Res. 13, 4769–4776 (2007).
Google Scholar
Krebs, A. M. et al. The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer. Nat. Cell Biol. 19, 518–529 (2017).
Google Scholar
Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).
Google Scholar
Parajuli, P. et al. TGIF 1 functions as a tumor suppressor in pancreatic ductal adenocarcinoma. EMBO J. 38, e101067 (2019).
Google Scholar
Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).
Google Scholar
Hong, J. et al. Phosphorylation of serine 68 of Twist1 by MAPKs stabilizes Twist1 protein and promotes breast cancer cell invasiveness. Cancer Res. 71, 3980–3990 (2011).
Google Scholar
Zheng, X. et al. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 527, 525–530 (2015).
Google Scholar
Belteki, G. et al. Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline induction. Nucleic Acids Res. 33, e51 (2005).
Google Scholar
Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001).
Google Scholar
Politi, K. et al. Lung adenocarcinomas induced in mice by mutant EGF receptors foundin human lung cancers respondto a tyrosine kinase inhibitor orto down-regulation of the receptors. Genes Dev. 20, 1496–1510 (2006).
Google Scholar
Cardiff, R. D., Miller, C. H. & Munn, R. J. Manual hematoxylin and eosin staining of mouse tissue sections. Cold Spring Harb. Protoc. 2014, pdb-prot073411 (2014).
Google Scholar
Havnar, C. et al. Characterization of tumor-immune microenvironment by high-throughput image analysis of CD8 immunohistochemistry combined with modified Masson’s trichrome. J. Histochem. Cytochem. 69, 611–615 (2021).
Google Scholar
Baidoo, N., Crawley, E., Knowles, C. H., Sanger, G. J. & Belai, A. Total collagen content and distribution is increased in human colon during advancing age. PLoS ONE 17, e0269689 (2022).
Google Scholar
Tran, P. T. et al. Survival and death signals can predict tumor response to therapy after oncogene inactivation. Sci. Transl. Med. 3, 103ra99–103ra99 (2011).
Google Scholar
Wilkerson, M. D. & Hayes, D. N. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinformatics 26, 1572–1573 (2010).
Google Scholar
Kim, D., Langmead, B. & Salzberg, S. L. HISAT: a fast spliced aligner with low memory requirements. Nat. Methods 12, 357–360 (2015).
Google Scholar
Anders, S., Pyl, P. T. & Huber, W. HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166–169 (2015).
Google Scholar
Zhang, Y., Parmigiani, G. & Johnson, W. E. ComBat-seq: batch effect adjustment for RNA-seq count data. NAR Genom. Bioinform. 2, lqaa078 (2020).
Google Scholar
Risso, D., Ngai, J., Speed, T. P. & Dudoit, S. Normalization of RNA-seq data using factor analysis of control genes or samples. Nat. Biotechnol. 32, 896–902 (2014).
Google Scholar
