Multiomic Analyses Unveil Mechanisms of Chemotherapy-Induced Polyneuropathy in iPSC-Sensory Neurons

Background & Aims

The microtubule-stabilizing drug paclitaxel remains standard of care for various solid malignancies, but frequently leads to chemotherapy-induced peripheral neuropathy (CIPN) with a significantly reduced quality of life in long-term cancer survivors [1, 2]. The molecular underpinnings of toxic neurodegeneration, neuroinflammation and pain in patients remain incompletely understood, and there are no predictive biomarkers nor clinically tested preventive treatments yet [3].

Methods

Induced pluripotent stem cell-derived sensory neurons [4, 5] were exposed to paclitaxel. Neurotoxicity was assessed by viability assays, multielectrode arrays (MEA) and sequential RNA sequencing at seven different timepoints from 2h to 48h and after washout of the drug, as well as deep proteome and lipidomic analyses at incipient neurodegeneration (48h).

Results

We observed electrophysiological dysfunction assessed in MEA and a time and dose-dependent decline of cell viability in clinically relevant paclitaxel dosages. Sequential RNA sequencing revealed the early upregulation of the transcription factor JUN followed by a shift towards pro-apoptotic genes (HRK, BBC3, DDIT3, CASP3) and typical transcriptomic signatures of neuroinflammation and pain (CALCB, PIRT, MMP10, IL6R, IL31RA, EGR1, CSF1) that plateaued at 24-48h of paclitaxel exposure. Deep proteome analyses at 48h largely confirmed these findings and additionally revealed a marked degradation of essential axonal transport proteins such as kinesins, stathmins and scaffold proteins (STMN2, STMN3, KIF5A, JIP3, JIP4). In line with a downregulation of rate-limiting enzymes of the lipid biosynthesis, lipidome analysis confirmed neuronal lipid homeostasis deregulation.

Conclusions

In summary, this study comprehensively characterizes neurodegenerative and neuroinflammatory cascades of paclitaxel-induced neurotoxicity enabling the development of biomarkers and new neuroprotective treatment strategies for CIPN.

References

1.Staff NP, Fehrenbacher JC, Caillaud M, Damaj MI, Segal RA, Rieger S: Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems. Experimental Neurology 2020, 324:113121.
2.Boehmerle W, Huehnchen P, Endres M: Chemotherapieinduzierte Neuropathien. Der Nervenarzt 2015, 86(2):156-160.
3.Huehnchen P, Schinke C, Bangemann N, Dordevic AD, Kern J, Maierhof SK, Hew L, Nolte L, Körtvelyessy P, Göpfert JC et al: Neurofilament proteins as potential biomarker in chemotherapy-induced polyneuropathy. JCI Insight 2022.
4.Chambers SM, Qi Y, Mica Y, Lee G, Zhang X-J, Niu L, Bilsland J, Cao L, Stevens E, Whiting P et al: Combined small-molecule inhibition accelerates developmental timing and converts human pluripotent stem cells into nociceptors. Nature biotechnology 2012, 30(7):715-720.
5.Schinke C, Fernandez Vallone V, Ivanov A, Peng Y, Körtvelyessy P, Nolte L, Huehnchen P, Beule D, Stachelscheid H, Boehmerle W et al: Modeling chemotherapy induced neurotoxicity with human induced pluripotent stem cell (iPSC) -derived sensory neurons. Neurobiology of disease 2021, 155:105391.

Presenting Author

Christian Schinke

Poster Authors

Christian Schinke

Dr.

Charité Universitätsmedizin Berlin

Lead Author

Multiomic Analyses Unveil Mechanisms of Chemotherapy-Induced Polyneuropathy in iPSC-Sensory Neurons

Background & Aims

Methods

Results

Conclusions

References

Presenting Author

Christian Schinke

Poster Authors

Christian Schinke

Smilla Maierhof

Lois Hew

Valeria Fernandez Vallone

Silke Frahm

Narasimha Swamy Telugu

Sebastian Diecke

Andranik Ivanov

Richard Kovács

Dieter Beule

Marieluise Kirchner

Philipp Mertins

Ulrike Brüning

Jennifer Kirwan

Harald Stachelscheid

Matthias Endres

Petra Huehnchen

Wolfgang Boehmerle

Topics

IASP 2024 World Congress on Pain