STIM1 Mediates Calcium-Dependent Epigenetic Reprogramming in Pancreatic Cancer

Cancer Res. 2021 Jun 1;81(11):2943-2955. doi: 10.1158/0008-5472.CAN-20-2874. Epub 2021 Jan 12.


Pancreatic ductal adenocarcinoma (PDAC) displays a dismal prognosis due to late diagnosis and high chemoresistance incidence. For advanced disease stages or patients with comorbidities, treatment options are limited to gemcitabine alone or in combination with other drugs. While gemcitabine resistance has been widely attributed to the levels of one of its targets, RRM1, the molecular consequences of gemcitabine resistance in PDAC remain largely elusive. Here we sought to identify genomic, epigenomic, and transcriptomic events associated with gemcitabine resistance in PDAC and their potential clinical relevance. We found that gemcitabine-resistant cells displayed a coamplification of the adjacent RRM1 and STIM1 genes. Interestingly, RRM1, but not STIM1, was required for gemcitabine resistance, while high STIM1 levels caused an increase in cytosolic calcium concentration. Higher STIM1-dependent calcium influx led to an impaired endoplasmic reticulum stress response and a heightened nuclear factor of activated T-cell activity. Importantly, these findings were confirmed in patient and patient-derived xenograft samples. Taken together, our study uncovers previously unknown biologically relevant molecular properties of gemcitabine-resistant tumors, revealing an undescribed function of STIM1 as a rheostat directing the effects of calcium signaling and controlling epigenetic cell fate determination. It further reveals the potential benefit of targeting STIM1-controlled calcium signaling and its downstream effectors in PDAC. SIGNIFICANCE: Gemcitabine-resistant and some naïve tumors coamplify RRM1 and STIM1, which elicit gemcitabine resistance and induce a calcium signaling shift, promoting ER stress resistance and activation of NFAT signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / pharmacology
  • Apoptosis
  • Calcium / metabolism*
  • Calcium Signaling
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Nucleus / metabolism
  • Cell Proliferation
  • Cytosol / metabolism
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm*
  • Endoplasmic Reticulum Stress
  • Epigenesis, Genetic*
  • Gemcitabine
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology*
  • Ribonucleoside Diphosphate Reductase / genetics
  • Ribonucleoside Diphosphate Reductase / metabolism
  • Stromal Interaction Molecule 1 / genetics
  • Stromal Interaction Molecule 1 / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Antimetabolites, Antineoplastic
  • Neoplasm Proteins
  • STIM1 protein, human
  • Stromal Interaction Molecule 1
  • Deoxycytidine
  • RRM1 protein, human
  • Ribonucleoside Diphosphate Reductase
  • Calcium
  • Gemcitabine