Chemotherapy-Induced Tunneling Nanotubes Mediate Intercellular Drug Efflux in Pancreatic Cancer

Snider Desir, Patrick O'Hare, Rachel I Vogel, William Sperduto, Akshat Sarkari, Elizabeth L Dickson, Phillip Wong, Andrew C Nelson, Yuman Fong, Clifford J Steer, Subree Subramanian, Emil Lou

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Abstract

Intercellular communication plays a critical role in the ever-evolving landscape of invasive cancers. Recent studies have elucidated the potential role of tunneling nanotubes (TNTs) in this function. TNTs are long, filamentous, actin-based cell protrusions that mediate direct cell-to-cell communication between malignant cells. In this study, we investigated the formation of TNTs in response to variable concentrations of the chemotherapeutic drug doxorubicin, which is used extensively in the treatment of cancer patients. Doxorubicin stimulated an increased formation of TNTs in pancreatic cancer cells, and this occurred in a dose-dependent fashion. Furthermore, TNTs facilitated the intercellular redistribution of this drug between connected cells in both pancreatic and ovarian cancer systems in vitro. To provide supportive evidence for the relevance of TNTs in pancreatic cancer in vivo, we performed multiphoton fluorescence microscopy and imaged TNTs in tumor specimens resected from three human patients with pancreatic adenocarcinoma, and one with neuroendocrine carcinoma. In sum, TNT formation was upregulated in aggressive forms of pancreatic carcinoma, was further stimulated after chemotherapy exposure, and acted as a novel method for drug efflux. These findings implicate TNTs as a potential novel mechanism of drug resistance in chemorefractory forms of cancer.

Original languageEnglish (US)
Article number9484
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Nanotubes
Pancreatic Neoplasms
Drug Therapy
Pharmaceutical Preparations
Doxorubicin
Multiphoton Fluorescence Microscopy
Neoplasms
Neuroendocrine Carcinoma
Drug Resistance
Cell Communication
Ovarian Neoplasms
Actins
Adenocarcinoma

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Chemotherapy-Induced Tunneling Nanotubes Mediate Intercellular Drug Efflux in Pancreatic Cancer. / Desir, Snider; O'Hare, Patrick; Vogel, Rachel I; Sperduto, William; Sarkari, Akshat; Dickson, Elizabeth L; Wong, Phillip; Nelson, Andrew C; Fong, Yuman; Steer, Clifford J; Subramanian, Subree; Lou, Emil.

In: Scientific reports, Vol. 8, No. 1, 9484, 01.12.2018.

Research output: Contribution to journalArticle

Desir, Snider ; O'Hare, Patrick ; Vogel, Rachel I ; Sperduto, William ; Sarkari, Akshat ; Dickson, Elizabeth L ; Wong, Phillip ; Nelson, Andrew C ; Fong, Yuman ; Steer, Clifford J ; Subramanian, Subree ; Lou, Emil. / Chemotherapy-Induced Tunneling Nanotubes Mediate Intercellular Drug Efflux in Pancreatic Cancer. In: Scientific reports. 2018 ; Vol. 8, No. 1.
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abstract = "Intercellular communication plays a critical role in the ever-evolving landscape of invasive cancers. Recent studies have elucidated the potential role of tunneling nanotubes (TNTs) in this function. TNTs are long, filamentous, actin-based cell protrusions that mediate direct cell-to-cell communication between malignant cells. In this study, we investigated the formation of TNTs in response to variable concentrations of the chemotherapeutic drug doxorubicin, which is used extensively in the treatment of cancer patients. Doxorubicin stimulated an increased formation of TNTs in pancreatic cancer cells, and this occurred in a dose-dependent fashion. Furthermore, TNTs facilitated the intercellular redistribution of this drug between connected cells in both pancreatic and ovarian cancer systems in vitro. To provide supportive evidence for the relevance of TNTs in pancreatic cancer in vivo, we performed multiphoton fluorescence microscopy and imaged TNTs in tumor specimens resected from three human patients with pancreatic adenocarcinoma, and one with neuroendocrine carcinoma. In sum, TNT formation was upregulated in aggressive forms of pancreatic carcinoma, was further stimulated after chemotherapy exposure, and acted as a novel method for drug efflux. These findings implicate TNTs as a potential novel mechanism of drug resistance in chemorefractory forms of cancer.",
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