STIM1 Mediates Calcium-Dependent Epigenetic Reprogramming in Pancreatic Cancer

Abstract

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.

Store-Operated Calcium Entry: Shaping the Transcriptional and Epigenetic Landscape in Pancreatic Cancer

“…Another example of such an occurrence is the co-amplification of WEE1 and ILK on chromosome 11 upon acquired gemcitabine resistance [5]. The overexpression of WEE1 may augment gemcitabine resistance, as gemcitabine targets DNA polymerase triggering replication stress, while WEE1 is known to protect cells from DNA damage by inducing cell cycle arrest [28,29].…”

“…Similarly, other genes amplified upon gemcitabine resistance in pancreatic cancer are RRM1 and STIM1 [5]. The amplification and overexpression of RRM1 was shown to drive gemcitabine resistance, while the upregulation of STIM1 elicits a shift in calcium signaling, promoting ER stress resistance and aberrant transcriptional activation [5].…”

“…Marked by high genomic instability, pancreatic tumors readily adapt to selective pressures, showing high epigenomic and transcriptomic plasticity [2][3][4]. In fact, genomic amplifications of drug-metabolizing enzymes have been observed in pancreatic cancer as well as in other types of cancer as being the main drivers of acquired chemoresistance [5,6]. Interestingly, several other genes are commonly co-amplified during these genomic aberration events, possibly conferring tumors with additional oncogenic properties.…”

“…For example, upon gemcitabine resistance acquisition in pancreatic cancer as well as in non-small-cell lung carcinoma, an amplification of one of the main targets of gemcitabine, ribonucleotide reductase catalytic subunit M1 (RRM1), was observed. This amplification of RRM1 was accompanied by a gain in copy number and overexpression of other genes, such as stromal interaction molecule 1 (STIM1) [5,7]. Interestingly, the co-amplification of STIM1 induced a shift in calcium signaling, leading to aberrant de-regulation of various transcriptional programs [5].…”

“…This amplification of RRM1 was accompanied by a gain in copy number and overexpression of other genes, such as stromal interaction molecule 1 (STIM1) [5,7]. Interestingly, the co-amplification of STIM1 induced a shift in calcium signaling, leading to aberrant de-regulation of various transcriptional programs [5]. In fact, calcium signaling has been described to drive key oncogenic processes such as proliferation, migration, invasion and angiogenesis [8,9], but the effects of its de-regulation in PDAC remain largely unknown.…”