Stromal KITL/SCF maintains pancreas tissue homeostasis and restrains tumor progression Journal Article
| Authors: | Kathrina Oñate, M.; Oon, C.; Bhattacharyya, S.; Low, V.; Chen, C.; Zhao, X.; Arnold, F.; Yan, Z.; Pramod, S.; Hang, Y.; Ho, Y. J.; Lowe, S. W.; Kim, S. K.; Xia, Z.; Sherman, M. H. |
| Article Title: | Stromal KITL/SCF maintains pancreas tissue homeostasis and restrains tumor progression |
| Abstract: | Components of normal tissue architecture serve as barriers to tumor progression. Inflammatory and wound-healing programs are requisite features of solid tumorigenesis, wherein alterations to immune and nonimmune stromal elements enable loss of homeostasis during tumor onset. The precise mechanisms by which normal stromal cell states limit tissue plasticity and tumorigenesis, and which are lost during tumor progression, remain largely unknown. In this study, we show that healthy pancreatic mesenchyme expresses the paracrine signaling molecule KITL, also known as stem cell factor, and identify the loss of stromal KITL during tumorigenesis as tumor promoting. Genetic inhibition of mesenchymal KITL in the contexts of health, injury, and cancer together indicates a role for KITL signaling in the maintenance of pancreas tissue architecture, such that the loss of the stromal KITL pool increased tumor growth and reduced survival of tumor-bearing mice. Together, these findings implicate the loss of mesenchymal KITL as a mechanism for establishing a tumor-permissive microenvironment. Significance: By analyzing transcriptional programs in healthy and tumor-associated pancreatic mesenchyme, we find that a subpopulation of mesenchymal cells in healthy pancreas tissue expresses the paracrine signaling factor KITL. The loss of mesenchymal KITL is an accompanying and permissive feature of pancreas tumor evolution, with potential implications for cancer interception. © 2025 The Authors. |
| Keywords: | immunohistochemistry; signal transduction; vasculotropin; controlled study; human tissue; protein expression; unclassified drug; human cell; genetics; histopathology; nonhuman; pancreas cancer; pancreatic neoplasms; flow cytometry; pancreas; cell proliferation; animal cell; mouse; phenotype; animal; metabolism; animals; mice; animal tissue; gene; stem cell factor; metastasis; apoptosis; gene expression; cell infiltration; transforming growth factor beta; animal experiment; animal model; inflammation; cell differentiation; antineoplastic activity; immunofluorescence; pathology; cancer research; cancer therapy; histology; carcinogenesis; alpha smooth muscle actin; extracellular matrix; disease progression; diabetes mellitus; pancreas tumor; western blotting; transforming growth factor beta1; fibroblast; mesenchymal stem cell; real time polymerase chain reaction; upregulation; tumor growth; macrophage; homeostasis; fluorescence activated cell sorting; disease exacerbation; amylase; biomedical engineering; mesenchymal stem cells; tumor microenvironment; epithelial mesenchymal transition; pancreatic ductal carcinoma; tissue homeostasis; humans; human; article; rna sequencing; immunofluorescence assay; antibiotic g 418; single cell rna seq; ceruletide; stromal kitl; hcol1a1; hfabp4; hkitlg; hpdgfra |
| Journal Title: | Cancer Discovery |
| Volume: | 15 |
| Issue: | 5 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-05-01 |
| Start Page: | 913 |
| End Page: | 929 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-24-1079 |
| PUBMED: | 39918337 |
| PROVIDER: | scopus |
| PMCID: | PMC12046321 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Mara H. Sherman -- Source: Scopus |
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