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Series GSE234614 Query DataSets for GSE234614
Status Public on May 03, 2024
Title Osteosarcoma uses host-derived growth factors to drive ERK phosphorylation and MCL1 expression to survive in the metastatic environment
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Purpose: For patients with osteosarcoma, disease-related mortality most often results from lung metastasis—a phenomenon shared with many solid tumors. While established metastatic lesions behave aggressively, very few of the tumor cells that reach the lung will survive. By identifying mechanisms that facilitate survival of disseminated tumor cells, we can develop therapeutic strategies that prevent and treat metastasis. Methods: We analyzed scRNAseq data from murine metastasis-bearing lungs to interrogate changes in both host and tumor cells during colonization. We used these data to elucidate pathways that become activated in cells that survive dissemination and identify candidate host-derived signals that drive activation. We validated these findings through live cell reporter systems, immunocytochemistry, and fluorescent immunohistochemistry. We then validated the functional relevance of key candidates using pharmacologic inhibition in models of metastatic osteosarcoma. Results: Expression patterns suggest that the MAPK pathway is significantly elevated in early and (to a lesser degree) established metastases. MAPK activity correlates with expression of anti-apoptotic genes, especially MCL1. Niche cells produce growth factors that increase ERK phosphorylation and MCL1 expression in tumor cells. Both early and established metastases are vulnerable to MCL1 inhibition, but not MEK inhibition in vivo. Combining MCL1 inhibition with chemotherapy both prevented colonization and eliminated established metastases in murine models of osteosarcoma. Conclusion: Niche-derived growth factors drive MAPK activity and MCL1 expression in osteosarcoma, promoting metastatic colonization. Although later metastases produce less MCL1, they remain dependent on it. MCL1 is a promising target for clinical trials in both human and canine patients.
Overall design To study transcriptional changes during metastasis of osteosarcoma, we collected samples from OS17 PDX models at timepoints from primary tumor through 49 days post metastasis. We also include normal lung as a control.
Web link
Contributor(s) McAloney C, Makkawi R, Budhathoki Y, Cannon MV, Franz E, Gross A, Cam M, Vetter T, Davies A, Roberts R
Citation(s) 37676378
Submission date Jun 09, 2023
Last update date May 04, 2024
Contact name Matthew Cannon
Organization name Nationwide Childrens Hospital
Department Center for Childhood Cancer
Street address 700 Childrens Drive
City Columbus
State/province Ohio
ZIP/Postal code 43205
Country USA
Platforms (2)
GPL25431 Illumina HiSeq 4000 (Homo sapiens; Mus musculus)
GPL25526 Illumina NovaSeq 6000 (Homo sapiens; Mus musculus)
Samples (5)
GSM7471912 Day 14 OS17 met
GSM7471913 Day 28 OS17 met
GSM7471914 Day 49 OS17 met
BioProject PRJNA982131

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Supplementary file Size Download File type/resource
GSE234614_RAW.tar 361.5 Mb (http)(custom) TAR (of TAR)
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Raw data are available in SRA
Processed data provided as supplementary file

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