American Association for Cancer Research
15417786mcr190726-sup-225628_2_supp_6090701_q5m3by.docx (36.93 kB)

Supplementary Figure Legend from Cdc42 Mediates Cancer Cell Chemotaxis in Perineural Invasion

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journal contribution
posted on 2023-04-03, 17:09 authored by Natalya Chernichenko, Tatiana Omelchenko, Sylvie Deborde, Richard L. Bakst, Shizhi He, Chun-Hao Chen, Laxmi Gusain, Efsevia Vakiani, Nora Katabi, Alan Hall, Richard J. Wong

A.Immunofluorescence microscopy was performed on control or shCdc42 MiaPaCa2 murine sciatic nerve tumors. Slides were stained with DAPI (blue) nuclear staining and primary antibodies (green) targeting total Cdc42, �-Pix, RET, and phospho-RET. B. Hematoxylin and eosin staining and GTP-Cdc42 immunohistochemistry of a control MiaPaCa2 murine sciatic nerve tumor.


American Head and Neck Society

Memorial Sloan-Kettering Cancer Center



Perineural invasion (PNI) is an ominous form of cancer progression along nerves associated with poor clinical outcome. Glial derived neurotrophic factor (GDNF) interacts with cancer cell RET receptors to enable PNI, but downstream events remain undefined. We demonstrate that GDNF leads to early activation of the GTPase Cdc42 in pancreatic cancer cells, but only delayed activation of RhoA and does not affect Rac1. Depletion of Cdc42 impairs pancreatic cancer cell chemotaxis toward GDNF and nerves. An siRNA library of guanine nucleotide exchange factors was screened to identify activators of Cdc42. ARHGEF7 (β-Pix) was required for Cdc42 activation and chemotaxis toward nerves, and also colocalizes with RET under GDNF stimulation. Cdc42 enables PNI in an in vitro dorsal root ganglia coculture model, and controls the directionality of migration but does not affect cell speed or cell viability. In contrast, Rac1 was necessary for cell speed but not directionality, while the RhoA was not necessary for either cell speed or directionality. Cdc42 was required for PNI in an in vivo murine sciatic nerve model. Depletion of Cdc42 significantly diminished the length of PNI, volume of PNI, and motor nerve paralysis resulting from PNI. Activated Cdc42 is expressed in human salivary ductal cancer cells invading nerves. These findings establish the GDNF–RET–β-Pix–Cdc42 pathway as a directional regulator of pancreatic cancer cell migration toward nerves, highlight the importance of directional migration in PNI, and offer novel targets for therapy. Cdc42 regulates cancer cell directional migration toward and along nerves in PNI.

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