Endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases

AbstractPatients who have had their primary pancreatic ductal adenocarcinoma (PDA) surgically resected often develop metastatic disease, exemplifying the problem of latent metastases. Livers from patients and mice with PDA contained single, disseminated cancer cells (DCCs) with an unusual phenotype of being cytokeratin-19 (CK19)- and MHC class I (MHCI)-. We created a mouse model to determine how DCCs develop, their relationship to metastatic latency, and the role of immunity. Intra-portal injection of immunogenic PDA cells into pre-immunized mice seeded livers only with single, non-replicating DCCs lacking MHCI and CK19; naïve recipients had macro-metastases. Transcriptomic analysis of PDA cells with the DCC phenotype demonstrated an endoplasmic reticulum (ER) stress response. Relieving ER stress with a chemical chaperone, in combination with T cell-depletion, stimulated outgrowth of macro-metastatic lesions containing PDA cells expressing MHCI and CK19. The ER stress response is the cell-autonomous reaction that enables DCCs to escape immunity and establish latent metastases.One sentence summary:Latent pancreatic cancer metastases are created when T cells select disseminated cancer cells in which immune resistance and quiescence have been imposed by endoplasmic stress.

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Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases

Science ◽

10.1126/science.aao4908 ◽

2018 ◽

Vol 360 (6394) ◽

pp. eaao4908 ◽

Cited By ~ 51

Author(s):

Arnaud Pommier ◽

Naishitha Anaparthy ◽

Nicoletta Memos ◽

Z. Larkin Kelley ◽

Alizée Gouronnec ◽

...

Keyword(s):

Pancreatic Cancer ◽

Endoplasmic Reticulum ◽

Transcription Factor ◽

Er Stress ◽

Ductal Adenocarcinoma ◽

Cytokeratin 19 ◽

Complex Class ◽

Er Stress Response ◽

Histocompatibility Complex ◽

Cancer Metastases

The majority of patients with pancreatic ductal adenocarcinoma (PDA) develop metastatic disease after resection of their primary tumor. We found that livers from patients and mice with PDA harbor single disseminated cancer cells (DCCs) lacking expression of cytokeratin 19 (CK19) and major histocompatibility complex class I (MHCI). We created a mouse model to determine how these DCCs develop. Intraportal injection of immunogenic PDA cells into preimmunized mice seeded livers only with single, nonreplicating DCCs that were CK19– and MHCI–. The DCCs exhibited an endoplasmic reticulum (ER) stress response but paradoxically lacked both inositol-requiring enzyme 1α activation and expression of the spliced form of transcription factor XBP1 (XBP1s). Inducible expression of XBP1s in DCCs, in combination with T cell depletion, stimulated the outgrowth of macrometastatic lesions that expressed CK19 and MHCI. Thus, unresolved ER stress enables DCCs to escape immunity and establish latent metastases.

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Induction of Endoplasmic Reticulum-induced Stress Genes in Panc-1 Pancreatic Cancer Cells Is Dependent on Sp Proteins

Journal of Biological Chemistry ◽

10.1074/jbc.c500030200 ◽

2005 ◽

Vol 280 (16) ◽

pp. 16508-16513 ◽

Cited By ~ 23

Author(s):

Maen Abdelrahim ◽

Shengxi Liu ◽

Stephen Safe

Keyword(s):

Pancreatic Cancer ◽

Endoplasmic Reticulum ◽

Transcription Factors ◽

Stress Response ◽

Er Stress ◽

Cancer Cells ◽

Gene Promoters ◽

Er Stress Response ◽

Pancreatic Cancer Cells ◽

Pharmacologically Active

Endoplasmic reticulum (ER) stress plays a critical role in multiple diseases, and pharmacologically active drugs can induce cell death through ER stress pathways. Stress-induced genes are activated through assembly of transcription factors on ER stress response elements (ERSEs) in target gene promoters. Gel mobility shift and chromatin immunoprecipitation assays have confirmed interactions of NF-Y and YY1 with the distal motifs of the tripartite ERSE from the glucose-related protein 78 (GRP78) gene promoter. The GC-rich nonanucleotide (N9) sequence, which forms the ER stress response binding factor (ERSF) complex binds TFII-I and ATF6; however, we have now shown that in Panc-1 pancreatic cancer cells, this complex also binds Sp1, Sp3, and Sp4 proteins. Sp proteins are constitutively bound to the ERSE; however, activation of GRP78 protein (or reporter gene) by thapsigargin or tunicamycin is inhibited after cotransfection with small inhibitory RNAs for Sp1, Sp3, and Sp4. This study demonstrates that Sp transcription factors are important for stress-induced responses through their binding to ERSEs.

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Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer

Cancers ◽

10.3390/cancers13164173 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4173

Author(s):

Faustino Mollinedo ◽

Consuelo Gajate

Keyword(s):

Pancreatic Cancer ◽

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Cancer Cells ◽

Tumor Cells ◽

Apoptotic Cell ◽

Ether Lipid ◽

Ductal Adenocarcinoma ◽

Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly regulated by different signaling routes that involve a variety of subcellular organelles. Endoplasmic reticulum (ER) stress acts as a double-edged sword at the interface of cell survival and death. Pancreatic cells exhibit high hormone and enzyme secretory functions, and thereby show a highly developed ER. Thus, pancreatic cancer cells display a prominent ER. Solid tumors have to cope with adverse situations in which hypoxia, lack of certain nutrients, and the action of certain antitumor agents lead to a complex interplay and crosstalk between ER stress and autophagy—the latter acting as an adaptive survival response. ER stress also mediates cell death induced by a number of anticancer drugs and experimental conditions, highlighting the pivotal role of ER stress in modulating cell fate. The alkylphospholipid analog prototype edelfosine is selectively taken up by tumor cells, accumulates in the ER of a number of human solid tumor cells—including pancreatic cancer cells—and promotes apoptosis through a persistent ER-stress-mediated mechanism both in vitro and in vivo. Here, we discuss and propose that direct ER targeting may be a promising approach in the therapy of pancreatic cancer, opening up a new avenue for the treatment of this currently incurable and deadly cancer. Furthermore, because autophagy acts as a cytoprotective response to ER stress, potentiation of the triggering of a persistent ER response by combination therapy, together with the use of autophagy blockers, could improve the current gloomy expectations for finding a cure for this type of cancer.

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Hyperthermia Disturbs and Delays Spontaneous Differentiation of Human Embryoid Bodies

Biomedicines ◽

10.3390/biomedicines8060176 ◽

2020 ◽

Vol 8 (6) ◽

pp. 176

Author(s):

Ji Hyun Kwon ◽

Hyun Kyu Kim ◽

Tae Won Ha ◽

Jeong Suk Im ◽

Byung Hoo Song ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Heat Stress ◽

Stress Response ◽

Er Stress ◽

Embryonic Stem ◽

Embryoid Bodies ◽

Chemical Chaperone ◽

Gene Markers ◽

Er Stress Response ◽

Delayed Differentiation

Various types of stress stimuli have been shown to threaten the normal development of embryos during embryogenesis. Prolonged heat exposure is the most common stressor that poses a threat to embryo development. Despite the extensive investigation of heat stress control mechanisms in the cytosol, the endoplasmic reticulum (ER) heat stress response remains unclear. In this study, we used human embryonic stem cells (hESCs) to examine the effect of heat stress on early embryonic development, specifically alterations in the ER stress response. In a hyperthermic (42 °C) culture, ER stress response genes involved in hESC differentiation were induced within 1 h of exposure, which resulted in disturbed and delayed differentiation. In addition, hyperthermia increased the expression levels of activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) genes, which are associated with the protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway. Furthermore, we demonstrated that tauroursodeoxycholic acid, a chemical chaperone, mitigated the delayed differentiation under hyperthermia. Our study identified novel gene markers in response to hyperthermia-induced ER stress on hESCs, thereby providing further insight into the mechanisms that regulate human embryogenesis.

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Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells

Oncogene ◽

10.1038/sj.onc.1205992 ◽

2002 ◽

Vol 21 (57) ◽

pp. 8749-8758 ◽

Cited By ~ 93

Author(s):

Takehiko Segawa ◽

Martin E Nau ◽

Linda L Xu ◽

Rao N Chilukuri ◽

Mazen Makarem ◽

...

Keyword(s):

Prostate Cancer ◽

Endoplasmic Reticulum ◽

Stress Response ◽

Er Stress ◽

Cancer Cells ◽

Prostate Cancer Cells ◽

Induced Expression ◽

Er Stress Response ◽

Stress Response Genes

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Self-delivery of N-hydroxylethyl peptide assemblies to the cytosol inducing endoplasmic reticulum dilation in cancer cells

Chemical Communications ◽

10.1039/c9cc03460a ◽

2019 ◽

Vol 55 (52) ◽

pp. 7474-7477 ◽

Cited By ~ 4

Author(s):

Shijin Zhang ◽

Xunwu Hu ◽

Dingze Mang ◽

Toshio Sasaki ◽

Ye Zhang

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Alcohol Abuse ◽

Er Stress ◽

Cancer Cells ◽

Clinical Studies ◽

Peptide Assembly ◽

Er Stress Response

Inspired by clinical studies on alcohol abuse induced endoplasmic reticulum disruption, we designed a N-hydroxylethyl peptide assembly to regulate the ER stress response in cancer cells.

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Inactivation of NUPR1 promotes cell death by coupling ER-stress responses with necrosis

10.1101/277384 ◽

2018 ◽

Author(s):

Patricia Santofimia-Castaño ◽

Wenjun Lan ◽

Jennifer Bintz ◽

Odile Gayet ◽

Alice Carrier ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cell Death ◽

Stress Response ◽

Er Stress ◽

Cancer Cells ◽

Necrotic Cell Death ◽

Necrotic Cell ◽

Atp Production ◽

Er Stress Response ◽

Pancreatic Cancer Cells

AbstractGenetic inhibition of NUPR1 induces tumor growth arrest. Inactivation of NUPR1 expression in pancreatic cancer cells results in lower ATP production, higher consumption of glucose with a significant switch from OXPHOS to glycolysis followed by necrotic cell death. Importantly, induction of necrosis is independent of the caspase activity. We demonstrated that NUPR1 inactivation triggers a massive release of Ca2+from the endoplasmic reticulum (ER) to the cytosol and a strong increase in ROS production by mitochondria with a concomitant relocalization of mitochondria to the vicinity of the ER. In addition, transcriptomic analysis of NUPR1-deficient cells shows the induction of an ER stress which is associated to a decrease in the expression of some ER stress response-associated genes. Indeed, during ER stress induced by the treatment with thapsigargin, brefeldin A or tunicamycin, an increase in the mitochondrial malfunction with higher induction of necrosis was observed in NUPR1-defficent cells. Finally, activation of NUPR1 during acute pancreatitis protects acinar cells of necrosis in mice. Altogether, these data enable us to describe a model in which inactivation of NUPR1 in pancreatic cancer cells results in an ER stress that induces a mitochondrial malfunction, a deficient ATP production and, as consequence, the cell death by necrosis.HighlightsNUPR1 expression promotes pancreatic cancer development and progressionNUPR1-depletion is a promising therapeutic strategy to be used for treating cancersNUPR1-depletion induces ER stress, mitochondrial malfunction and a significant switch from OXPHOS to glycolysis followed by necrotic cell deathInactivation of NUPR1 antagonizes cell growth by coupling a defective ER-stress response and a caspase-independent necrosis.

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NOD1/NOD2 and RIP2 Regulate Endoplasmic Reticulum Stress-Induced Inflammation during Chlamydia Infection

mBio ◽

10.1128/mbio.00979-20 ◽

2020 ◽

Vol 11 (3) ◽

Author(s):

Oanh H. Pham ◽

Bokyung Lee ◽

Jasmine Labuda ◽

A. Marijke Keestra-Gounder ◽

Mariana X. Byndloss ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Stress Response ◽

Inflammatory Response ◽

Endoplasmic Reticulum Stress ◽

Er Stress ◽

Young Women ◽

The United States ◽

Chlamydia Infection ◽

Er Stress Response

ABSTRACT The inflammatory response to Chlamydia infection is likely to be multifactorial and involve a variety of ligand-dependent and -independent recognition pathways. We previously reported the presence of NOD1/NOD2-dependent endoplasmic reticulum (ER) stress-induced inflammation during Chlamydia muridarum infection in vitro, but the relevance of this finding to an in vivo context is unclear. Here, we examined the ER stress response to in vivo Chlamydia infection. The induction of interleukin 6 (IL-6) production after systemic Chlamydia infection correlated with expression of ER stress response genes. Furthermore, when tauroursodeoxycholate (TUDCA) was used to inhibit the ER stress response, an increased bacterial burden was detected, suggesting that ER stress-driven inflammation can contribute to systemic bacterial clearance. Mice lacking both NOD1 and NOD2 or RIP2 exhibited slightly higher systemic bacterial burdens after infection with Chlamydia. Overall, these data suggest a model where RIP2 and NOD1/NOD2 proteins link ER stress responses with the induction of Chlamydia-specific inflammatory responses. IMPORTANCE Understanding the initiation of the inflammatory response during Chlamydia infection is of public health importance given the impact of this disease on young women in the United States. Many young women are chronically infected with Chlamydia but are asymptomatic and therefore do not seek treatment, leaving them at risk of long-term reproductive harm due to inflammation in response to infection. Our manuscript explores the role of the endoplasmic reticulum stress response pathway initiated by an innate receptor in the development of this inflammation.

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