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PERK signaling through C/EBPδ contributes to ER stress-induced expression of immunomodulatory and tumor promoting chemokines by cancer cells.

ABSTRACT: Expression of the transcription factor CEBPD is induced at early stages of the endoplasmic reticulum (ER) stress response. In order to identify the genes modulated by CEBPD during the ER stress response, we transiently silenced CEBPD expression in MDA-MB-435 melanoma cells and isolated mRNA at 6 h of treatment with Thapsigargin or DMSO control. As control, cells were transfected with two different control siRNA oligonucleotides. Results provide insights into which genes are modulated by CEBPD and/or Thapsigargin in MDA-MB-435 cell

ORGANISM(S): Homo sapiens

PROVIDER: GSE131048 | GEO | 2021/11/01

REPOSITORIES: GEO

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Project description:We previously proposed a clinically meaningful intermediate metastatic state defined by a limited number of new metastases (≤5) after 3 months of follow-up, termed oligometastasis that has the curative potential by local cancer treatments as in contrast to the incurable widespread polymetastatic dissemination. While animal models of polymetastasis exist and this phenotype can be further enhanced upon serial in vivo passage, animal models of oligometastasis are not available. Here, we report the creation of an oligometastasis model of MDA-MB-435 human tumor in nude mice in which the oligometastatic phenotype exhibits stability during successive in vivo testing, and satisfies the criteria of ≤ 5 total body macroscopic metastases definition of the human cancer oligometastatic state. In parallel, we also developed an MDA-MB-435 polymetastatic model in which the polymetastatic dissemination pattern was either poly-foci at lung, or involved multiple anatomic sites including lung, heart, muscle, ovaries, kidney, brain and pleura. We have conducted microRNA expression profiling of cell lines derived from distinct lungs of oligo- and poly-metastatic animals. Animal model-derived microRNA expression features that discriminate oligometastatic cell lines from those of polymetastases accurately identify oligometastatic patients who failed to develop widespread metastases (P=0.005). These results demonstrate the clinical relevance of the oligo- and polymetastatic animal models we have developed and their potential in elucidating the molecular underpinnings of oligometastasis progression. We developed a stable human tumor (MDA-MB-435-GFP) xenograft model of oligometastatic and polymetastatic progression by conducting three consecutive rounds of experimental lung colonization assays. In the first round, we generated oligometastases-like lung derivative MDA-MB-435-L1-GFP (L1) or polymetastases-like MDA-MB-435-L1Mic-GFP (L1Mic) cell lines. We subsequently generated three oligometastatic L1 lung cell lines as well as four polymetastatic L1Mic lung cell lines from seven distinct animals of the second in vivo passage for further biological characterization and for microRNA expression analysis.

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PERK signaling through C/EBPδ contributes to ER stress-induced expression of immunomodulatory and tumor promoting chemokines by cancer cells.

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