mTOR Inhibition Mitigates Enhanced mRNA Translation Associated with the Metastatic Phenotype of Osteosarcoma Cells In Vivo
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Abstract
Purpose: To successfully metastasize, tumor cells must respond appropriately to biological stressors encountered during metastatic progression. We sought to test the hypothesis that enhanced efficiency of mRNA translation during periods of metastatic stress is required for metastatic competence of osteosarcoma and that this metastasis-specific adaptation is amenable to therapeutic intervention. Experimental Design: We employ novel reporter and proteomic systems that enable tracking of mRNA translation efficiency and output in metastatic osteosarcoma cells as they colonize the lungs. We test the potential to target mRNA translation as an antimetastatic therapeutic strategy through pharmacokinetic studies and preclinical assessment of the prototypic mTOR inhibitor, rapamycin, across multiple models of metastasis. Results: Metastatic osteosarcoma cells translate mRNA more efficiently than nonmetastatic cells during critical stressful periods of metastatic colonization of the lung. Rapamycin inhibits translational output during periods of metastatic stress, mitigates lung colonization, and prolongs survival. mTOR-inhibiting exposures of rapamycin are achievable in mice using treatment schedules that correspond to human doses well below the MTDs defined in human patients, and as such are very likely to be tolerated over long exposures alone and in combination with other agents. Conclusions: Metastatic competence of osteosarcoma cells is dependent on efficient mRNA translation during stressful periods of metastatic progression, and the mTOR inhibitor, rapamycin, can mitigate this translation and inhibit metastasis in vivo. Our data suggest that mTOR pathway inhibitors should be reconsidered in the clinic using rationally designed dosing schedules and clinical metrics related to metastatic progression. Clin Cancer Res; 22(24); 6129–41. ©2016 AACR.
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Ex vivo techniques have been adapted to study tumour-host interactions, screen for metastasis-related vulnerabilities, and validate hits from other screens.
“These techniques have been adapted to study tumour-host interactions, to screen for metastasis-related vulnerabilities and to validate hits identified in other screens 74,75,92,216,217,218,219 .”
From Osteosarcoma (2022) · cites this paper as [218]
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Cites
Lorenz, R., Bernhart, S. H., Höner zu Siederdissen, C., Tafer, H., Flamm, C., Stadler, P. F., & Hofacker, I. L. (2011) · Algorithms for Molecular Biology · doi:10.1186/1748-7188-6-26 · Cited by 5,098 · see citing works
Dissemination and growth of cancer cells in metastatic sites
Chambers, A. F., Groom, A. C., & MacDonald, I. C. (2002) · Nature reviews. Cancer · doi:10.1038/nrc865 · Cited by 3,920 · see citing works
Laplante, M., & Sabatini, D. (2009) · Journal of Cell Science · doi:10.1242/jcs.051011 · Cited by 2,317 · see citing works
Structural features in eukaryotic mRNAs that modulate the initiation of translation.
Kozak, M. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)54860-2 · Cited by 1,826 · see citing works
The mechanisms of Hedgehog signalling and its roles in development and disease
Briscoe, J., & Thérond, P. P. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3598 · Cited by 1,751 · see citing works
Regulation of cap-dependent translation by eIF4E inhibitory proteins
Richter, J. D., & Sonenberg, N. (2005) · Nature · doi:10.1038/nature03205 · Cited by 972 · see citing works
The mTOR Signalling Pathway in Human Cancer
Pópulo, H., Lopes, J. M., & Soares, P. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13021886 · Cited by 830 · see citing works
The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis
Khanna, C., Wan, X., Bose, S., Cassaday, R., Olomu, O., Mendoza, A., Yeung, C., Gorlick, R., Hewitt, S. M., & Helman, L. J. (2004) · Nature Medicine · doi:10.1038/nm982 · Cited by 705 · see citing works
Self-citationVanharanta, S., & Massagué, J. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.09.007 · Cited by 563 · see citing works
Tabernero, J. M., Rojo, F., Calvo, E., Burris, H. A., Judson, I. R., Hazell, K., Martinelli, E., y Cajal, S. R., Jones, S. F., Vidal, L., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.5482 · Cited by 537 · see citing works
Perry, J. A., Kiezun, A., Tonzi, P., Van Allen, E. M., Carter, S. L., Baca, S. C., Cowley, G. S., Bhatt, A. S., Rheinbay, E., Pedamallu, C. S., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1419260111 · Cited by 481 · see citing works
Osteosarcoma: a review of diagnosis, management, and treatment strategies.
Geller, D. S., & Gorlick, R. G. (2010) · PubMed · Cited by 470 · see citing works
Dieterich, D. C., Lee, J. J., Link, A. J., Graumann, J., Tirrell, D. A., & Schuman, E. M. (2007) · Nature Protocols · doi:10.1038/nprot.2007.52 · Cited by 342 · see citing works
Translational reprogramming in cellular stress response
Liu, B., & Qian, S. (2013) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1212 · Cited by 249 · see citing works
Demetri, G. D., Chawla, S. P., Ray-Coquard, I., Le Cesne, A., Staddon, A. P., Milhem, M. M., Penel, N., Riedel, R. F., Bui-Nguyen, B., Cranmer, L. D., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.45.5766 · Cited by 245 · see citing works
Chawla, S. P., Staddon, A. P., Baker, L. H., Schuetze, S. M., Tolcher, A. W., D’Amato, G. Z., Blay, J., Mita, M. M., Sankhala, K. K., Berk, L., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.35.6329 · Cited by 244 · see citing works
Graff, J. R., & Zimmer, S. G. (2003) · Clinical & Experimental Metastasis · doi:10.1023/a:1022943419011 · Cited by 215 · see citing works
Khanna, C., Prehn, J., Yeung, C., Caylor, J., Tsokos, M., & Helman, L. (2000) · Clinical & Experimental Metastasis · doi:10.1023/a:1006767007547 · Cited by 207 · see citing works
Self-citationYang, H.-S., Cho, M.-H., Zakowicz, H., Hegamyer, G., Sonenberg, N., & Colburn, N. H. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.9.3894-3906.2004 · Cited by 199 · see citing works
Toward a Drug Development Path That Targets Metastatic Progression in Osteosarcoma
Khanna, C., Fan, T. M., Gorlick, R., Helman, L. J., Kleinerman, E. S., Adamson, P. C., Houghton, P. J., Tap, W. D., Welch, D. R., Steeg, P. S., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-2574 · Cited by 178 · see citing works
Self-citationOsteosarcoma Genetics and Epigenetics: Emerging Biology and Candidate Therapies
Morrow, J. J., & Khanna, C. (2015) · Critical Reviews™ in Oncogenesis · doi:10.1615/critrevoncog.2015013713 · Cited by 171 · see citing works
Self-citationThe actin-cytoskeleton linker protein ezrin is regulated during osteosarcoma metastasis by PKC
Ren, L., Hong, S., Cassavaugh, J. M., Osborne, T. S., Chou, A. J., Kim, S. Y., Gorlick, R. G., Hewitt, S. M., & Khanna, C. (2008) · Oncogene · doi:10.1038/onc.2008.437 · Cited by 131 · see citing works
Self-citationStress-mediated translational control in cancer cells
Leprivier, G., Rotblat, B., Khan, D., Jan, E., & Sorensen, P. H. B. (2014) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2014.11.002 · Cited by 122 · see citing works
Characterization of the metastatic phenotype of a panel of established osteosarcoma cells
Ren, L., Mendoza, A., Zhu, J., Briggs, J., Halsey, C., Hong, E. S., Burkett, S. S., Morrow, J. J., Lizardo, M. M., Osborne, T. S., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5177 · Cited by 119 · see citing works
Self-citationRegulation of protein synthesis by mRNA structure
Gray, N. K., & Hentze, M. W. (1994) · Molecular Biology Reports · doi:10.1007/bf00986961 · Cited by 114 · see citing works
Modeling metastasis biology and therapy in real time in the mouse lung
Mendoza, A., Hong, S.-H., Osborne, T., Khan, M. A., Campbell, K., Briggs, J., Eleswarapu, A., Buquo, L., Ren, L., Hewitt, S. M., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci40252 · Cited by 92 · see citing works
Self-citationTranslation factors and ribosomal proteins control tumor onset and progression: how?
Loreni, F., Mancino, M., & Biffo, S. (2013) · Oncogene · doi:10.1038/onc.2013.153 · Cited by 90 · see citing works
Results of a phase II study of sirolimus and cyclophosphamide in patients with advanced sarcoma
Schuetze, S. M., Zhao, L., Chugh, R. K., Thomas, D. G., Lucas, D. R., Metko, G., Zalupski, M. M., & Baker, L. H. (2012) · European Journal of Cancer · doi:10.1016/j.ejca.2012.03.022 · Cited by 52 · see citing works
The Ezrin Metastatic Phenotype Is Associated with the Initiation of Protein Translation
Briggs, J., Ren, L., Nguyen, R., Chakrabarti, K. R., Cassavaugh, J. M., Rahim, S., Bulut, G., Zhou, M., Veenstra, T. D., Chen, Q., et al. (2012) · Neoplasia · doi:10.1593/neo.11518 · Cited by 30 · see citing works
Self-citationApoptosis Resistance and PKC Signaling: Distinguishing Features of High and Low Metastatic Cells
Hong, S.-H., Ren, L., Mendoza, A., Eleswarapu, A. S., & Khanna, C. (2012) · Neoplasia · doi:10.1593/neo.111498 · Cited by 28 · see citing works
Self-citationPreclinical studies of treosulfan demonstrate potent activity in Ewing’s sarcoma
Werner, S., Mendoza, A., Hilger, R. A., Erlacher, M., Reichardt, W., Lissat, A., Konanz, C., Uhl, M., Niemeyer, C. M., Khanna, C., et al. (2007) · Cancer Chemotherapy and Pharmacology · doi:10.1007/s00280-007-0566-9 · Cited by 27 · see citing works
Self-citationEvaluation of eIF4E Expression in an Osteosarcoma-Specific Tissue Microarray
Osborne, T. S., Ren, L., Healey, J. H., Shapiro, L., Chou, A. J., Gorlick, R. G., Hewitt, S. M., & Khanna, C. (2011) · Journal of Pediatric Hematology/Oncology · doi:10.1097/mph.0b013e318223d0c1 · Cited by 25 · see citing works
Self-citationPharmacokinetics of orally administered low-dose rapamycin in healthy dogs
Larson, J. C., Allstadt, S. D., Fan, T. M., Khanna, C., Lunghofer, P. J., Hansen, R. J., Gustafson, D. L., Legendre, A. Μ., Galyon, G. D., LeBlanc, A. K., et al. (2015) · American Journal of Veterinary Research · doi:10.2460/ajvr.77.1.65 · Cited by 21 · see citing works
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Beird, H. C., Bielack, S. S., Flanagan, A. M., Gill, J., Heymann, D., Janeway, K. A., Livingston, J. A., Roberts, R. D., Strauss, S. J., & Gorlick, R. (2022) · Nature Reviews Disease Primers · doi:10.1038/s41572-022-00409-y · Cited by 660 · see citing works
Osteosarcoma: Accelerating Progress Makes for a Hopeful Future
Saraf, A. J., Fenger, J. M., & Roberts, R. D. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00004 · Cited by 237 · see citing works
Sheng, G., Gao, Y., Yong, Y., & Wu, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.780264 · Cited by 202 · see citing works
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Harris, M. A., & Hawkins, C. J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073817 · Cited by 143 · see citing works
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Nomura, M., Rainusso, N., Lee, Y.-C., Dawson, B., Coarfa, C., Han, R., Larson, J. L., Shuck, R., Kurenbekova, L., & Yustein, J. T. (2019) · JNCI: Journal of the National Cancer Institute · doi:10.1093/jnci/djz026 · Cited by 99 · see citing works
Fan, T. M., Roberts, R. D., & Lizardo, M. M. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00013 · Cited by 90 · see citing works
Self-citationHan, Y., Feng, H., Sun, J., Liang, X., Wang, Z., Xing, W., Dai, Q., Yang, Y., Han, A., Wei, Z., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124590 · Cited by 74 · see citing works
RetractedLeBlanc, A. K., Mazcko, C. N., Cherukuri, A., Berger, E. P., Kisseberth, W. C., Brown, M. E., Lana, S. E., Weishaar, K. M., Flesner, B. K., Bryan, J. N., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-0315 · Cited by 55 · see citing works
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Lizardo, M. M., & Sorensen, P. H. (2018) · Journal of Visualized Experiments · doi:10.3791/56332 · Cited by 19 · see citing works
Self-citationZou, T., Liu, W., Wang, Z., Chen, J., Lu, S., Huang, K., & Li, W. (2021) · Frontiers in Medicine · doi:10.3389/fmed.2021.642615 · Cited by 18 · see citing works
Novel role of the dietary flavonoid fisetin in suppressing rRNA biogenesis
Kammerud, S. C., Metge, B. J., Elhamamsy, A. R., Weeks, S. E., Alsheikh, H. A., Mattheyses, A. L., Shevde, L. A., & Samant, R. S. (2021) · Laboratory Investigation · doi:10.1038/s41374-021-00642-1 · Cited by 18 · see citing works
Proteasome Inhibitors and Their Potential Applicability in Osteosarcoma Treatment
Stiphout, C. M. V., Luu, A. K., & Viloria‐Petit, A. (2022) · Cancers · doi:10.3390/cancers14194544 · Cited by 17 · see citing works
Pharmacologic Inhibition of EIF4A Blocks NRF2 Synthesis to Prevent Osteosarcoma Metastasis
Lizardo, M. M., Hughes, C. S., Huang, Y. Z., Shyp, T., Delaidelli, A., Zhang, H., Shaool, S. S., Renner, A. F., Burwag, F., Sayles, L. C., et al. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-24-1317 · Cited by 18 · see citing works
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Meuten, T., Dean, G. A., & Thamm, D. H. (2023) · Veterinary Pathology · doi:10.1177/03009858231207021 · Cited by 17 · see citing works
Ren, L., Huang, S., Beck, J. A., & LeBlanc, A. K. (2021) · Scientific Reports · doi:10.1038/s41598-021-04018-9 · Cited by 13 · see citing works
Self-citationUcci, A., Giacchi, L., & Rucci, N. (2024) · Biomedicines · doi:10.3390/biomedicines12112451 · Cited by 14 · see citing works
Luu, A. K., Cadieux, M., Wong, M., Macdonald, R., Jones, R., Choi, D., Oblak, M. L., Brisson, B. A., Sauer, S. J., Chafitz, J., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23063256 · Cited by 11 · see citing works
Wang, H., Tao, Y., Han, J., Shen, J., Mu, H., Wang, Z., Wang, J., Jin, X., Zhang, Q., Yang, Y., et al. (2024) · Cellular Oncology · doi:10.1007/s13402-024-00967-1 · Cited by 9 · see citing works
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Reinecke, J. B., & Roberts, R. D. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-43085-6_7 · Cited by 7 · see citing works
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Sun, C., & Li, S. (2021) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16420 · Cited by 7 · see citing works
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Reed, D. R., Tulpule, A., Metts, J. L., Trucco, M. M., Robertson‐Tessi, M., O’Donohue, T. J., Cardenas, F. I., Isakoff, M. S., Mauguen, A., Shukla, N. N., et al. (2024) · Journal of Clinical Oncology · doi:10.1200/jco.23.02717 · Cited by 6 · see citing works
Chen, H., & Li, M. (2019) · Europe PMC (PubMed Central) · doi:10.12122/j.issn.1673-4254.2019.11.12 · Cited by 3 · see citing works
Fu, Z., Sun, G., Li, J., & Yu, H. (2024) · Medicine · doi:10.1097/md.0000000000038470 · Cited by 3 · see citing works
Gene and proteomic profiling of osteosarcoma
Patiño‐García, A., & Lecanda, F. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-416721-6.00020-0
Genomic and proteomic profiling of osteosarcoma
Patiño‐García, A., & Lecanda, F. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-821666-8.00054-2
McAloney, C. A., Fan, T. M., & Roberts, R. D. (2026) · Springer eBooks · doi:10.1007/978-3-032-04454-9_9
Self-citation
- Authors
- Morrow, J. J., Mendoza, A., Koyen, A., Lizardo, M. M., Ren, L., Waybright, T. J., Hansen, R. J., Gustafson, D. L., Zhou, M., Fan, T. M., Scacheri, P. C., & Khanna, C.
- Affiliations
- National Institutes of Health (US)
- Frederick National Laboratory for Cancer Research (US)
- University of Colorado Cancer Center (US)
- University of Illinois Urbana-Champaign (US)
- Case Comprehensive Cancer Center (US)
- Corresponding author
- Khanna, Chand
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2016-12-15
- Volume
- 22
- Issue
- 24
- Pages
- 6129-6141
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC5161706
- OpenAlex
- W2470037984
- Cited by
- 27
- References
- 33
- Citations by year
- 2026: 1 · 2024: 5 · 2023: 1 · 2022: 4 · 2021: 8 · 2020: 2 · 2019: 3 · 2018: 2 · 2014: 1
- FWCI
- 0.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (CA186633 and GM007250, #15335, R01CA160356 and 1R01CA193677, P30CA046934)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Keywords
- osteosarcoma, metastasis, mTOR inhibition, rapamycin, mRNA translation, translational regulation, lung colonization, anti-metastatic therapy, dosing regimen, pharmacokinetics
- MeSH terms
- Animals, Female, Humans, Mice, Inbred BALB C, Mice, Nude, Phenotype, RNA, Messenger, Osteosarcoma, Signal Transduction, Mice, SCID, Apoptosis, Sirolimus, Xenograft Model Antitumor Assays, Proteomics, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Mice, TOR Serine-Threonine Kinases
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