bioRxiv : the preprint server for biology · 2026
Spatially coordinated RTK-ERK signaling dynamics shape osteosarcoma single-cell drug response in the lung microenvironment.
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Makkawi Rawan, Halsey Carol, Murthy Vaibhav, Manalo Elise C, Cros Hugo, Yi Xin, Cartier Jessie May, Chang Matthew, Flory Mark, Guptell Kelly, Gross Amy, Roberts Ryan D, Copperman Jeremy, Davies Alexander E
Аннотация
PURPOSE: Lung metastases are the primary cause of death in osteosarcoma patients and treatment response often vary due to convergence of genetic and phenotypic influences in the context of a dynamic tumor-host tissue environment. The purpose of this study was to determine how dynamic tumor- and host-driven receptor tyrosine kinase (RTK)-ERK signaling interactions contribute to phenotypic drug response heterogeneity.
EXPERIMENTAL DESIGN: Live-cell time-lapse microscopy and data-driven dynamical modeling was used to resolve ERK activity, FOSL1/Fra-1 reporter expression, and spatiotemporal cell fate in living, biosensor-expressing osteosarcoma lung metastases ex vivo following MCL1 inhibitor exposure. RTK inhibitors were then evaluated for their ability to suppress adaptive signaling and enhance MCL1 inhibitor efficacy ex vivo and in vivo .
RESULTS: MCL1 inhibition induced extensive tumor-cell death; however, persistent ERK high /Fra-1 high reporter cells emerged and were enriched at the tumor-lung interface, consistent with adaptive resistance. Experimental and computational approaches revealed that tumor-cell lysis amplified fibroblast growth factor receptor (FGFR)-mediated ERK signaling in neighboring cells, promoting a targetable drug-resistant state marked by adaptive ERK induction, FOSL1/Fra-1 expression, and correlated with upregulation of known drug resistance pathways Nrf2 and HMOX1. Combinatorial inhibition of FGFR with fexagratinib, or broad-spectrum RTK inhibitor, pazopanib, suppressed adaptive ERK activation and enhanced MCL1 inhibitor response resulting in greater efficacy ex vivo and in vivo .
CONCLUSIONS: Tumor-host and tumor-cell-lysis-induced FGFR-ERK signaling contribute to spatiotemporally heterogeneous adaptive resistance in metastatic osteosarcoma. These data support combinatorial targeting of RTK signaling with cytotoxic or targeted agents as a strategy to block adaptive resistance and improve treatment efficacy.
EXPERIMENTAL DESIGN: Live-cell time-lapse microscopy and data-driven dynamical modeling was used to resolve ERK activity, FOSL1/Fra-1 reporter expression, and spatiotemporal cell fate in living, biosensor-expressing osteosarcoma lung metastases ex vivo following MCL1 inhibitor exposure. RTK inhibitors were then evaluated for their ability to suppress adaptive signaling and enhance MCL1 inhibitor efficacy ex vivo and in vivo .
RESULTS: MCL1 inhibition induced extensive tumor-cell death; however, persistent ERK high /Fra-1 high reporter cells emerged and were enriched at the tumor-lung interface, consistent with adaptive resistance. Experimental and computational approaches revealed that tumor-cell lysis amplified fibroblast growth factor receptor (FGFR)-mediated ERK signaling in neighboring cells, promoting a targetable drug-resistant state marked by adaptive ERK induction, FOSL1/Fra-1 expression, and correlated with upregulation of known drug resistance pathways Nrf2 and HMOX1. Combinatorial inhibition of FGFR with fexagratinib, or broad-spectrum RTK inhibitor, pazopanib, suppressed adaptive ERK activation and enhanced MCL1 inhibitor response resulting in greater efficacy ex vivo and in vivo .
CONCLUSIONS: Tumor-host and tumor-cell-lysis-induced FGFR-ERK signaling contribute to spatiotemporally heterogeneous adaptive resistance in metastatic osteosarcoma. These data support combinatorial targeting of RTK signaling with cytotoxic or targeted agents as a strategy to block adaptive resistance and improve treatment efficacy.