RESUMEN
Extracellular vesicles secreted from tumor cells are functional vehicles capable of contributing to intercellular communication and metastasis. A growing number of studies have focused on elucidating the role that tumor-derived extracellular vesicles play in spreading pancreatic cancer to other organs, due to the highly metastatic nature of the disease. We recently showed that small extracellular vesicles secreted from pancreatic cancer cells could initiate malignant transformation of healthy cells. Here, we analyzed the protein cargo contained within these vesicles using mass spectrometry-based proteomics to better understand their makeup and biological characteristics. Three different human pancreatic cancer cell lines were compared to normal pancreatic epithelial cells revealing distinct differences in protein cargo between cancer and normal vesicles. Vesicles from cancer cells contain an enrichment of proteins that function in the endosomal compartment of cells responsible for vesicle formation and secretion in addition to proteins that have been shown to contribute to oncogenic cell transformation. Conversely, vesicles from normal pancreatic cells were shown to be enriched for immune response proteins. Collectively, results contribute to what we know about the cargo contained within or excluded from cancer cell-derived extracellular vesicles, supporting their role in biological processes including metastasis and cancer progression.
Asunto(s)
Transformación Celular Neoplásica/genética , Neoplasias Pancreáticas/genética , Proteómica , Microambiente Tumoral/genética , Comunicación Celular/genética , Línea Celular Tumoral , Exosomas/genética , Vesículas Extracelulares/genética , Vesículas Extracelulares/patología , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Neoplasias Pancreáticas/patologíaRESUMEN
Cancer evolves through a multistep process that occurs by the temporal accumulation of genetic mutations. Tumor-derived exosomes are emerging contributors to tumorigenesis. To understand how exosomes might contribute to cell transformation, we utilized the classic two-step NIH/3T3 cell transformation assay and observed that exosomes isolated from pancreatic cancer cells, but not normal human cells, can initiate malignant cell transformation and these transformed cells formed tumors in vivo. However, cancer cell exosomes are unable to transform cells alone or to act as a promoter of cell transformation. Utilizing proteomics and exome sequencing, we discovered cancer cell exosomes act as an initiator by inducing random mutations in recipient cells. Cells from the pool of randomly mutated cells are driven to transformation by a classic promoter resulting in foci, each of which encode a unique genetic profile. Our studies describe a novel molecular understanding of how cancer cell exosomes contribute to cell transformation. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that major issues remain unresolved (see decision letter).
