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Intercellular Transfer of Oncogenic KRAS via Tunneling Nanotubes Introduces Intracellular Mutational Heterogeneity in Colon Cancer Cells

1
Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN 55455, USA
2
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA
3
Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN 55455, USA
4
NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
5
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Minnesota, Minneapolis, MN 55455, USA
6
Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
7
Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(7), 892; https://doi.org/10.3390/cancers11070892
Received: 16 May 2019 / Revised: 12 June 2019 / Accepted: 18 June 2019 / Published: 26 June 2019
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Abstract

Mutated forms of the RAS oncogene drive 30% of all cancers, but they cannot be targeted therapeutically using currently available drugs. The molecular and cellular mechanisms that create a heterogenous tumor environment harboring both mutant and wild-type RAS have not been elucidated. In this study, we examined horizontal transfer of mutant KRAS between colorectal cancer (CRC) cells via a direct form of cell-to-cell communication called tunneling nanotubes (TNTs). TNT formation was significantly higher in CRC cell lines expressing mutant KRAS than CRC cell lines expressing wild-type RAS; this effect was most pronounced in metastatic CRC cell lines with both mutant KRAS and deficiency in mismatch repair proteins. Using inverted and confocal fluorescence time-lapse and fluorescence recovery after photobleaching (FRAP)-based microscopy, we observed GFP-tagged mutant KRASG12D protein trafficking between CRC cells through TNTs within a span of seconds to several minutes. Notably, acquisition of mutant KRAS increased Extracellular Signal-regulated Kinase (ERK) phosphorylation and upregulated tunneling nanotube formation in recipient wildtype CRC cells. In conclusion, these findings suggest that intercellular horizontal transfer of RAS can occur by TNTs. We propose that intercellular transfer of mutant RAS can potentially induce intratumoral heterogeneity and result in a more invasive phenotype in recipient cells. View Full-Text
Keywords: tunneling nanotubes; intercellular communication; KRAS; oncogene; cellular reprogramming; intercellular transfer; colon cancer; colorectal cancer; confocal microscopy tunneling nanotubes; intercellular communication; KRAS; oncogene; cellular reprogramming; intercellular transfer; colon cancer; colorectal cancer; confocal microscopy
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Desir, S.; Wong, P.; Turbyville, T.; Chen, D.; Shetty, M.; Clark, C.; Zhai, E.; Romin, Y.; Manova-Todorova, K.; Starr, T.K.; Nissley, D.V.; Steer, C.J.; Subramanian, S.; Lou, E. Intercellular Transfer of Oncogenic KRAS via Tunneling Nanotubes Introduces Intracellular Mutational Heterogeneity in Colon Cancer Cells. Cancers 2019, 11, 892.

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