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Rab27a plays a dual role in metastatic propensity of pancreatic cancer.

ABSTRACT: Pancreatic cancer is an aggressive malignancy, often diagnosed at metastatic stages. Several studies have implicated systemic factors, such as extracellular vesicle release and myeloid cell expansion, in the establishment of pre-metastatic niches in cancer. The Rab27a GTPase is overexpressed in advanced cancers, can regulate vesicle trafficking, and has been previously linked to non-cell autonomous control of tumor growth and metastasis, however, the role of Rab27a itself in the metastatic propensity of pancreatic cancer is not well understood. Here, we have established a model to study how Rab27a directs formation of the pre-metastatic niche. Loss of Rab27a in pancreatic cancer cells did not decrease tumor growth in vivo, but resulted in altered systemic myeloid cell expansion, both in the primary tumors and at the distant organ sites. In metastasis assays, loss of Rab27a expression in tumor cells injected into circulation compromised efficient outgrowth of metastatic lesions. However, Rab27a knockdown cells had an unexpected advantage at initial steps of metastatic seeding, suggesting that Rab27a may alter cell-autonomous invasive properties of the tumor cells. Gene expression analysis of gene expression revealed that downregulation of Rab27a increased expression of genes involved in epithelial-to-mesenchymal transition pathways, consistent with our findings that primary tumors arising from Rab27a knockdown cells were more invasive. Overall, these data reveal that Rab27a can play divergent roles in regulating pro-metastatic propensity of pancreatic cancer cells: by generating pro-metastatic environment at the distant organ sites, and by suppressing invasive properties of the cancer cells.

SUBMITTER: Kren N

PROVIDER: S-EPMC7193593 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Rab27a plays a dual role in metastatic propensity of pancreatic cancer.

Kren Nancy N Michaud Daniel D Bagchi Sukriti S Greene Kevin K Pylayeva-Gupta Yuliya Y

Scientific reports 20200430 1

Pancreatic cancer is an aggressive malignancy, often diagnosed at metastatic stages. Several studies have implicated systemic factors, such as extracellular vesicle release and myeloid cell expansion, in the establishment of pre-metastatic niches in cancer. The Rab27a GTPase is overexpressed in advanced cancers, can regulate vesicle trafficking, and has been previously linked to non-cell autonomous control of tumor growth and metastasis, however, the role of Rab27a itself in the metastatic prope ...[more]

PMID: 32355248

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most common malignant pancreatic tumor in western countries, characterized by a low 5-year survival rate of only 11 %. Owing to a lack of early and specific symptoms, most patients are diagnosed at advanced or even me-tastasized stages essentially impairing treatment efficacy. Metastatic outgrowth requires a high plasticity of tumor cells implying phenotypic switching in response to changing envi-ronments. One important process leading to phenotypic switching is the Epithelial-Mesenchymal-Transition (EMT) and its reversion, the Mesenchymal-Epithelial-Transition (MET). This process has been associated with the gain of cancer stem cell (CSC) properties being regarded as drivers of tumor initiation at primary and secondary sites. Still, it is poorly understood whether different CSC phenotypes exist along the EMT/MET axis and how these impact malignancy associated properties. Thus, this study aimed to characterize CSC popula-tions of epithelial and mesenchymal PDAC cells and how these relate to functional pheno-types. Methods: For this purpose, single-cell-cloning of the two PDAC cell lines Panc1 and Panc89 was performed to isolate and expand CSC- (Holoclone cells) and non-CSC (Paraclone cells) clones. Cell variants were characterized regarding cell growth, migration, invasion, cell ad-hesion and tumorigenicity. Results: Panc1 Holoclone cells showed a mesenchymal phenotype dominated by high ex-pression of the stemness marker Nestin, while Panc89 Holoclone cells exhibited an epitheli-al phenotype with elevated expression of the stemness marker SOX2. Moreover, Panc89 Holoclone cells showed enhanced cell growth and colony formation ability compared to Panc1 Holoclone cells. In contrast, slowly proliferating Panc1 Holoclone cells were highly invasive, while Panc89 Holoclone cells showed a slow cluster-like invasion. In line with these findings, a higher number of metastases was formed by Panc1 Holoclone cells in vivo. How-ever, Panc89 Holoclone cells led to formation of larger tumors limiting survival of inoculated mice. Moreover, epithelial and mesenchymal CSC-clones showed clear differences with re-spect to organ manifestation. Conclusion: Overall, these data support the view of different CSC phenotypes in PDAC cells that are linked to distinct EMT/MET phenotypes and that manifest in a different metastatic propensity.

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Rab27a plays a dual role in metastatic propensity of pancreatic cancer.

Publications

Rab27a plays a dual role in metastatic propensity of pancreatic cancer.

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