Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy

By M. Sherman, R. Yu, Dannielle D. Engle, N. Ding, A. Atkins, H. Tiriac, E. Collisson, F. Connor, Terry Van Dyke, S. Kozlov and 19 more. Cell, 2014

1,024 citations recorded by the source corpus.

Summary The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests Vitamin D priming as an adjunct in PDA therapy.

Subfields: Molecular Biology, Oncology, Surgery

View Paper: https://www.semanticscholar.org/paper/aec6e2574060e238b75cfbe62c501e2c53c4005d

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In Molecular Biology

1. Rakesh K. Jain
2. Lance L. Munn
3. Hadi Tavakoli Nia
4. E. Henke
5. S. Ergün
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7. Giulia Biffi
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In Oncology

1. Rakesh K. Jain
2. Lance L. Munn
3. Giulia Biffi
4. S. Ergün
5. D. Tuveson
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In Surgery

1. Rakesh K. Jain

Citations in the corpus

• IL-1-induced JAK/STAT signaling is antagonized by TGF-β to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. (2018, background): “Among stromal cells, cancer-associated fibroblasts (CAFs) have long been considered pro-tumorigenic components of the PDAC TME, due to their involvement in desmoplasia, immunosuppression and secretion of factors that promote cancer cell proliferation and survival (2,4,11,12).”
• Physical traits of cancer (2020, background): “Other approaches that have shown similar potential in preclinical models include inhibiting the vitamin D receptor (42), sonic hedgehog signaling (43), and C-X-C motif chemokine receptor 4 signaling (44).”
• Tumor microenvironment complexity and therapeutic implications at a glance (2020, background): “An example for the exploitation of CAFs is demonstrated in a study in which the offtarget distribution of anticancer nanoparticles (NPs) to fibroblasts, that creates an obstacle to the effective management of desmoplastic tumors [79] [80] [81] [82] , was exploited to selectively deliver therapeutics”
• Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy (2020, background): “Activated CAFs also express vitamin D receptor (Sherman et al., 2014).”