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Invadopodia are chemosensing protrusions that guide cancer cell extravasation to promote brain tropism in metastasis.

Abstract：

:Invadopodia are cell protrusions that mediate cancer cell extravasation but the microenvironmental cues and signaling factors that induce invadopodia formation during extravasation remain unclear. Using intravital imaging and loss of function experiments, we determined invadopodia contain receptors involved in chemotaxis, namely GABA receptor and EGFR. These chemotaxis capabilities are mediated in part by PAK1 which controls invadopodia responsiveness to ligands such as GABA and EGF via assembly, stability, and turnover of invadopodia in vivo. PAK1 knockdown rendered cells unresponsive to chemotactic stimuli present in the stroma, resulting in dramatically lower rates of cancer cell extravasation and metastatic colony formation compared to stimulated cancer cells. In an experimental mouse model of brain metastasis, inhibition of PAK1 significantly reduced overall tumor burden and reduced the average size of brain metastases. In summary, invadopodia contain chemotaxis receptors that can respond to microenvironmental cues to guide cancer cell extravasation, and when PAK1 is depleted, brain tropism of metastatic breast cancer cells is significantly reduced, blocking secondary colony growth at sites otherwise permissive for metastatic outgrowth.

journal_name

Oncogene

journal_title

Oncogene

authors

Williams KC,Cepeda MA,Javed S,Searle K,Parkins KM,Makela AV,Hamilton AM,Soukhtehzari S,Kim Y,Tuck AB,Ronald JA,Foster PJ,Chambers AF,Leong HS

doi

10.1038/s41388-018-0667-4

subject

Has Abstract

pub_date

2019-05-01 00:00:00

pages

3598-3615

issue

19

eissn

0950-9232

issn

1476-5594

pii

10.1038/s41388-018-0667-4

journal_volume

38

pub_type

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