Cdc42 Mediates Cancer Cell Chemotaxis in Perineural Invasion

Abstract

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 (b-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-b-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.Implications: Cdc42 regulates cancer cell directional migration toward and along nerves in PNI.

Analysis of the signal cross talk via CCL26 in the tumor microenvironment in osteosarcoma

“…Since Rac, RhoA, and Cdc42 are key molecules of cell motility 13 – 15 , we confirmed their protein expression levels in each group (Fig. 4 A).…”

Tumour cell CD99 regulates transendothelial migration via CDC42 and actin remodelling

“…As such, the GEF(s) linking CD99 to CDC42 activity remains to be identified. Interestingly, a β-Pix-CDC42 pathway has recently been identified to regulate perineural invasion in pancreatic cancer ( Chernichenko et al, 2020 ). The basis of the small increases in total CDC42 detected upon CD99 depletion are unclear, but might result from the altered activity of transcription factors and/or post-translational modifications of CDC42 that occur downstream of CDC42 activation and actin reorganisation ( Corry et al, 2020 ; Haga and Ridley, 2016 ; Hall, 2012 ; Medjkane et al, 2009 ; Perona et al, 1997 ).…”

ssc-miR-185 targets cell division cycle 42 and promotes the proliferation of intestinal porcine epithelial cell

“…These results indicated that CDC42 was a target gene of porcine miR-185. As a chemokine that mediates tumors, CDC42 can participate in the migration and invasion of various cancer cells [33]. Previous research reported that microRNA-384 inhibits proliferation, migration and invasion of glioma by targeting at CDC42 [34].…”