@article{09739d74079e49b98133f1391f3979cf,
title = "HRAS-driven cancer cells are vulnerable to TRPML1 inhibition",
abstract = "By serving as intermediaries between cellular metabolism and the bioenergetic demands of proliferation, endolysosomes allow cancer cells to thrive under normally detrimental conditions. Here, we show that an endolysosomal TRP channel, TRPML1, is necessary for the proliferation of cancer cells that bear activating mutations in HRAS. Expression of MCOLN1, which encodes TRPML1, is significantly elevated in HRAS-positive tumors and inversely correlated with patient prognosis. Concordantly, MCOLN1 knockdown or TRPML1 inhibition selectively reduces the proliferation of cancer cells that express oncogenic, but not wild-type, HRAS. Mechanistically, TRPML1 maintains oncogenic HRAS in signaling-competent nanoclusters at the plasma membrane by mediating cholesterol de-esterification and transport. TRPML1 inhibition disrupts the distribution and levels of cholesterol and thereby attenuates HRAS nanoclustering and plasma membrane abundance, ERK phosphorylation, and cell proliferation. These findings reveal a selective vulnerability of HRAS-driven cancers to TRPML1 inhibition, which may be leveraged as an actionable therapeutic strategy.",
keywords = "HRAS, TRPML1, cancer, cholesterol, endolysosomes",
author = "Jewon Jung and Cho, {Kwang Jin} and Naji, {Ali K.} and Clemons, {Kristen N.} and Wong, {Ching On} and Mariana Villanueva and Steven Gregory and Karagas, {Nicholas E.} and Lingxiao Tan and Hong Liang and Rousseau, {Morgan A.} and Tomasevich, {Kelly M.} and Sikora, {Andrew G.} and Ilya Levental and {van der Hoeven}, Dharini and Yong Zhou and Hancock, {John F.} and Kartik Venkatachalam",
note = "Funding Information: We thank Barbara Diaz-Rohrer, Yufang Chao, Shilpa Narayanan, and Dr. Boyun Kim for technical help; the Bloomington Drosophila Stock Center for fly stocks; Dr. Jeffrey Myers (MDACC) for providing the oral cancer cell lines; Drs. Jeffrey Chang, Ghislain Breton, and Holger K. Eltzschig for use of equipment, and Drs. Jeffrey Chang and Marco Sardiello for helpful discussions. Confocal and live cell microscopy was performed at the Center for Advanced Microscopy, Department of Integrative Biology & Pharmacology at McGovern Medical School, UTHealth. The CAM xenograft experiments were performed at the “Patient-Derived Xenograft and Advanced in vivo Models Core Facility” at Baylor College of Medicine (BCM) with funding from the Cancer Prevention and Research Institute of Texas (CPRIT) grant #170691 and the NCI P30CA125123 Center Grant which supports BCM's Dan L. Duncan Cancer Center shared resources. CAM sections were generated by the Pathology and Histology Core (HTAP) core at BCM (M. “Sayeed” Sayeeduddin, Shahida Salar, Zahida Sayeeduddin, Myoung Kwon, Dr. Patricia Castro, Jami Oritz), which is supported by a P30 Cancer Center Support Grant (NCI-CA125123). This work was supported by a CPRIT grant RP170233 (to J.F.H.); NIH grant R00CA188593 (to K.J.C); and NIH grants R01NS08130 and R21NS094860, and PENN Orphan Disease Center MDBR-18-132-RAS (to K.V.). Funding Information: We thank Barbara Diaz-Rohrer, Yufang Chao, Shilpa Narayanan, and Dr. Boyun Kim for technical help; the Bloomington Drosophila Stock Center for fly stocks; Dr. Jeffrey Myers (MDACC) for providing the oral cancer cell lines; Drs. Jeffrey Chang, Ghislain Breton, and Holger K. Eltzschig for use of equipment, and Drs. Jeffrey Chang and Marco Sardiello for helpful discussions. Confocal and live cell microscopy was performed at the Center for Advanced Microscopy, Department of Integrative Biology & Pharmacology at McGovern Medical School, UTHealth. The CAM xenograft experiments were performed at the “Patient-Derived Xenograft and Advanced in vivo Models Core Facility” at Baylor College of Medicine (BCM) with funding from the Cancer Prevention and Research Institute of Texas (CPRIT) grant #170691 and the NCI P30CA125123 Center Grant which supports BCM{\textquoteright}s Dan L. Duncan Cancer Center shared resources. CAM sections were generated by the Pathology and Histology Core (HTAP) core at BCM (M. “Sayeed” Sayeeduddin, Shahida Salar, Zahida Sayeeduddin, Myoung Kwon, Dr. Patricia Castro, Jami Oritz), which is supported by a P30 Cancer Center Support Grant (NCI-CA125123). This work was supported by a CPRIT grant RP170233 (to J.F.H.); NIH grant R00CA188593 (to K.J.C); and NIH grants R01NS08130 and R21NS094860, and PENN Orphan Disease Center MDBR-18-132-RAS (to K.V.). Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = apr,
doi = "10.15252/embr.201846685",
language = "English (US)",
volume = "20",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Nature Publishing Group",
number = "4",
}