TY - JOUR
T1 - Human pancreatic cancer cell exosomes, but not human normal cell exosomes, act as an initiator in cell transformation
AU - Stefanius, Karoliina
AU - Servage, Kelly
AU - Santos, Marcela de Souza
AU - Gray, Hillery Fields
AU - Toombs, Jason E.
AU - Chimalapati, Suneeta
AU - Kim, Min S.
AU - Malladi, Venkat S.
AU - Brekken, Rolf
AU - Orth, Kim
N1 - Publisher Copyright:
© Stefanius et al.
PY - 2019/5
Y1 - 2019/5
N2 - 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).
AB - 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).
UR - http://www.scopus.com/inward/record.url?scp=85067036021&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067036021&partnerID=8YFLogxK
U2 - 10.7554/eLife.40226
DO - 10.7554/eLife.40226
M3 - Article
C2 - 31134894
AN - SCOPUS:85067036021
SN - 2050-084X
VL - 8
JO - eLife
JF - eLife
M1 - e40226
ER -