Host-derived growth factors drive ERK phosphorylation and MCL1 expression to promote osteosarcoma cell survival during metastatic lung colonization.

Publisher: Springer Country of Publication: Netherlands NLM ID: 101552938 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-3436 (Electronic) Linking ISSN: 22113428 NLM ISO Abbreviation: Cell Oncol (Dordr) Subsets: MEDLINE

Original Publication: Dordrecht : Springer

Bone Neoplasms*/pathology ; Lung Neoplasms*/secondary ; Myeloid Cell Leukemia Sequence 1 Protein*/metabolism ; Osteosarcoma*/pathology; Animals ; Dogs ; Humans ; Mice ; Cell Line, Tumor ; Cell Survival ; Lung/metabolism ; Phosphorylation

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 single cell RNA-sequencing (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 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.
(© 2023. The Author(s).)

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UL1 TR002733 United States TR NCATS NIH HHS; K01 OD031811 United States OD NIH HHS; R01 CA260178 United States CA NCI NIH HHS; T32 CA269052 United States CA NCI NIH HHS; K08 CA201638 United States CA NCI NIH HHS

Keywords: MAPK; MCL1; Metastasis; Osteosarcoma; pERK

0 (MCL1 protein, human)
0 (Myeloid Cell Leukemia Sequence 1 Protein)

Date Created: 20230907 Date Completed: 20240228 Latest Revision: 20240326

20240326

PMC10899530

10.1007/s13402-023-00867-w

37676378