TY - JOUR
T1 - STIM1 mediates calcium-dependent epigenetic reprogramming in pancreatic cancer
AU - Kutschat, Ana P.
AU - Hamdan, Feda H.
AU - Wang, Xin
AU - Wixom, Alexander Q.
AU - Najafova, Zeynab
AU - Gibhardt, Christine S.
AU - Kopp, Waltraut
AU - Gaedcke, Jochen
AU - Ströbel, Philipp
AU - Ellenrieder, Volker
AU - Bogeski, Ivan
AU - Hessmann, Elisabeth
AU - Johnsen, Steven A.
N1 - Funding Information:
The authors thank M. Dobbelstein, J. Choo, F. Wegwitz, E. Prokakis, and J. Henck for fruitful discussions. They also thank F. Wegwitz and E. Prokakis for assistance in microscopy. This project was funded by grants from the Deutsche Krebshilfe (70112505; PIPAC consortium) to S.A. Johnsen, Z. Najafova, J. Gaedcke, V. Ellenrieder, and E. Hessmann, the Deutsche Forschungsgemeinschaft (SFB1190 and SFB1027) to I. Bogeski, the National Institute of Diabetes and Digestive and Kidney Diseases (T32 DK07198) to A.Q. Wixom, and the NCI (CA 102701) to S.A. Johnsen.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-20-2874
DO - 10.1158/0008-5472.CAN-20-2874
M3 - Article
C2 - 33436389
AN - SCOPUS:85106987876
VL - 81
SP - 2943
EP - 2955
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -