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. OurdatasuggestthatmTORpathway inhibitors should be reconsidered in the clinic using rationally designed dosing schedules and clinical metrics related to metastatic progression.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 6129-6141 |
| Number of pages | 13 |
| Journal | Clinical Cancer Research |
| Volume | 22 |
| Issue number | 24 |
| DOIs | |
| State | Published - Dec 15 2016 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
mTOR inhibition mitigates enhanced mRNA translation associated with the metastatic phenotype of osteosarcoma cells in vivo. / Morrow, James J.; Mendoza, Arnulfo; Koyen, Allyson; Lizardo, Michael M.; Ren, Ling; Waybright, Timothy J.; Hansen, Ryan J.; Gustafson, Daniel L.; Zhou, Ming; Fan, Timothy M.; Scacheri, Peter C.; Khanna, Chand.
In: Clinical Cancer Research, Vol. 22, No. 24, 15.12.2016, p. 6129-6141.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - mTOR inhibition mitigates enhanced mRNA translation associated with the metastatic phenotype of osteosarcoma cells in vivo
AU - Morrow, James J.
AU - Mendoza, Arnulfo
AU - Koyen, Allyson
AU - Lizardo, Michael M.
AU - Ren, Ling
AU - Waybright, Timothy J.
AU - Hansen, Ryan J.
AU - Gustafson, Daniel L.
AU - Zhou, Ming
AU - Fan, Timothy M.
AU - Scacheri, Peter C.
AU - Khanna, Chand
PY - 2016/12/15
Y1 - 2016/12/15
N2 - 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. OurdatasuggestthatmTORpathway inhibitors should be reconsidered in the clinic using rationally designed dosing schedules and clinical metrics related to metastatic progression.
AB - 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. OurdatasuggestthatmTORpathway inhibitors should be reconsidered in the clinic using rationally designed dosing schedules and clinical metrics related to metastatic progression.
UR - http://www.scopus.com/inward/record.url?scp=85006983736&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85006983736&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-16-0326
DO - 10.1158/1078-0432.CCR-16-0326
M3 - Article
C2 - 27342399
AN - SCOPUS:85006983736
VL - 22
SP - 6129
EP - 6141
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 24
ER -