Adaptor proteins mediate CXCR4 and PI4KA crosstalk in prostate cancer cells and the significance of PI4KA in bone tumor growth.

The chemokine receptor, CXCR4 signaling regulates cell growth, invasion, and metastasis to the bone-marrow niche in prostate cancer (PCa). Previously, we established that CXCR4 interacts with phosphatidylinositol 4-kinase IIIα (PI4KIIIα encoded by PI4KA) through its adaptor proteins and PI4KA overexpressed in the PCa metastasis. To further characterize how the CXCR4-PI4KIIIα axis promotes PCa metastasis, here we identify CXCR4 binds to PI4KIIIα adaptor proteins TTC7 and this interaction induce plasma membrane PI4P production in prostate cancer cells. Inhibiting PI4KIIIα or TTC7 reduces plasma membrane PI4P production, cellular invasion, and bone tumor growth. Using metastatic biopsy sequencing, we found PI4KA expression in tumors correlated with overall survival and contributes to immunosuppressive bone tumor microenvironment through preferentially enriching non-activated and immunosuppressive macrophage populations. Altogether we have characterized the chemokine signaling axis through CXCR4-PI4KIIIα interaction contributing to the growth of prostate cancer bone metastasis.

Adaptor proteins mediate CXCR4 and PI4KA crosstalk in prostate cancer cells and the significance of PI4KA in bone tumor growth.

The chemokine receptor, CXCR4 signaling regulates cell growth, invasion, and metastasis to the bone-marrow niche in prostate cancer (PCa). Previously, we established that CXCR4 interacts with phosphatidylinositol 4-kinase IIIα (PI4KIIIα encoded by PI4KA) through its adaptor proteins and PI4KA overexpressed in the PCa metastasis. To further characterize how the CXCR4-PI4KIIIα axis promotes PCa metastasis, here we identify CXCR4 binds to PI4KIIIα adaptor proteins TTC7 and this interaction induce plasma membrane PI4P production in prostate cancer cells. Inhibiting PI4KIIIα or TTC7 reduces plasma membrane PI4P production, cellular invasion, and bone tumor growth. Using metastatic biopsy sequencing, we found PI4KA expression in tumors correlated with overall survival and contributes to immunosuppressive bone tumor microenvironment through preferentially enriching non-activated and immunosuppressive macrophage populations. Altogether we have characterized the chemokine signaling axis through CXCR4-PI4KIIIα interaction contributing to the growth of prostate cancer bone metastasis.

Association of lymph node yield with overall survival in patients with pathologically node negative prostate cancer.

We investigated the association between lymph node yield (LNY) with overall survival (OS) and post-radical prostatectomy (RP) secondary treatments among men with pathologically node negative (pN0) prostate cancer. We reviewed the National Cancer Database for men with Gleason Grade Group 2 or higher prostate cancer treated with RP and had pathologically node-negative disease. LNY was modeled as a continuous and categorical variable grouped by quartiles of LNY. Secondary treatment was defined as the use of radiation or systemic therapy post-RP. Multivariable Cox proportional hazards and logistic regression models were used to test for an association of LNY with OS and secondary treatments, respectively. We identified 89,416 men with pN0 prostate cancer treated with RP from 2010-2015. LNY was associated with improved OS when modeled as a categorical and continuous variable. The third (6-9 nodes) and fourth (≥10 nodes) quartiles of LNY were associated with improved OS (HR 0.87, 95% CI 0.79-0.96, P = 0.006 and HR 0.88, 95% CI 0.79-0.98, P= 0.017, respectively) when compared with the lowest quartile of LNY (≤3 nodes) and the hazard of death decreased by 1% for each benign lymph node removed (HR 0.99, 95% CI 0.98-0.99, P= 0.022). Additionally, categorical and continuous LNY was associated with significantly less use of post-RP secondary treatments. Removal of additional negative lymph nodes was associated with improved OS and less secondary treatments in patients with pN0 prostate cancer. These data suggest that removing a higher quantity of lymph nodes provides more accurate staging and prognosis.

Cell dynamics in fetal intestinal epithelium: implications for intestinal growth and morphogenesis.

The cellular mechanisms that drive growth and remodeling of the early intestinal epithelium are poorly understood. Current dogma suggests that the murine fetal intestinal epithelium is stratified, that villi are formed by an epithelial remodeling process involving the de novo formation of apical surface at secondary lumina, and that radial intercalation of the stratified cells constitutes a major intestinal lengthening mechanism. Here, we investigate cell polarity, cell cycle dynamics and cell shape in the fetal murine intestine between E12.5 and E14.5. We show that, contrary to previous assumptions, this epithelium is pseudostratified. Furthermore, epithelial nuclei exhibit interkinetic nuclear migration, a process wherein nuclei move in concert with the cell cycle, from the basal side (where DNA is synthesized) to the apical surface (where mitosis takes place); such nuclear movements were previously misinterpreted as the radial intercalation of cells. We further demonstrate that growth of epithelial girth between E12.5 and E14.5 is driven by microtubule- and actinomyosin-dependent apicobasal elongation, rather than by progressive epithelial stratification as was previously thought. Finally, we show that the actin-binding protein Shroom3 is crucial for the maintenance of the single-layered pseudostratified epithelium. In mice lacking Shroom3, the epithelium is disorganized and temporarily stratified during villus emergence. These results favor an alternative model of intestinal morphogenesis in which the epithelium remains single layered and apicobasally polarized throughout early intestinal development.