The Cub-Domain Containing Protein - 1, CDCP1, is a transmembrane glycoprotein, which is able to sequester Src and PKCδ into unique microdomains within the plasma membrane. CDCP1 can either promote or suppress tumor metastasis, dependent on the cancer type and experimental system. How the loss of CDCP1 leads to tumor metastasis is not well understood. We demonstrated for the first time in patients with prostate cancer (PCA), a significant reduction of CDCP1 expression in circulating cancer cells (CTC) and tumor metastasis relative to primary tumors and concordant analytical results. To investigate how the loss of CDCP1 facilitates PCA metastasis, we determined the consequences of CDCP1 loss in non-adherent cancer cells, which provide an experimental model system of CTCs. In this system, CDCP1 silenced cells exhibit 3-fold higher proliferation, 4-fold greater anchorage independent growth with colonies exceeding 5 microns in diameter, and a 2-fold reduction in migration ability. In 10% human plasma, these cells up-regulate p-FAK, p-SRC, p-AKT and p-MAPK expression, and at the same time loose expression of activated β1-integrin. The loss of inside-out activation of β1-integrin occurs through prevention of TALIN phosphorylation. Upon loss of CDCP1, Talin is no longer phosphorylated by CDK5 and this causes the disassembly of the β1 integrin - Talin complex. In addition, β1-integrin dissociates from CDK5 and from the CDK5-regulatory subunit, p35, but remains bound to p-FAK. We determined the pathway by which the loss of CDCP1 arrests CDK5 kinase activity. Upon loss of CDCP1, SRC phosphorylates p35. This generates a binding site for the C2 domain of PKCδ and phosphorylation of CDK5-T77 by PKCδ. The subsequent dissociation of the regulatory subunit abolishes the activity of CDK5. We show that both SRC inhibition and silencing of PKCδ reestablish the inside-out activation of β1-integrin. Altogether we discovered a new mechanism of regulation of CDK5 in prostate cancer cells, which leads to the uncoupling of β1-integrin and FAK. The potential biological and clinical consequences of this mechanism are (1) a switch from cell-matrix to cell-cell adhesion, (2) increased sensitivity of CTCs to FAK inhibitors and (3) improved adaptation and survival of cancer cells in the circulation and at the metastatic sites.

Citation Format: Sara G. Pollan, Fangjin Huang, Joshua M. Lang, Jamie M. Sperger, Kavita Shah, Beatrice S. Knudsen. Loss of CDCP1 in patient prostate cancer metastasis leads to uncoupling of beta-1 integrin from its cytoplasmic signaling through FAK [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5795. doi:10.1158/1538-7445.AM2017-5795