Genome-wide association studies have shown that a gene variant in the Family with Sequence Similarity 13, Member A (FAM13A) is strongly associated with reduced lung function and the appearance of respiratory symptoms in patients with Chronic Obstructive Pulmonary Disease (COPD). A key player in smoking-induced tissue injury and airway remodeling is the transforming growth factor β1 (TGFβ1). To determine the role of FAM13A in TGFβ1 signaling, FAM13A-/- airway epithelial cells were generated using CRISPR-Cas9, while over-expression of FAM13A was achieved using lipid nanoparticles. Wildtype (WT) and FAM13A-/- cells were treated with TGFβ1, followed by gene and/or protein expression analyses. FAM13A-/- cells augmented TGFβ1-induced increase in COL1A1 and MMP2 expression compared to WT cells. This effect was mediated by an increase in CTNNB1 expression in FAM13A-/- cells compared to WT cells after TGFβ1 treatment. FAM13A over-expression was partially protective from TGFβ1-induced COL1A1 expression. Finally, we showed that airway epithelial-specific FAM13A protein expression is significantly increased in patients with severe COPD compared to control non-smokers, and negatively correlated with lung function. In contrast, β-catenin (CTNNB1), which has previously been linked to be regulated by FAM13A, is decreased in the airway epithelium of smokers with COPD compared to non-COPD subjects. Together, our data showed that FAM13A may be protective from TGFβ1-induced fibrotic response in the airway epithelium via sequestering CTNNB1 from its regulation on downstream targets. Therapeutic increase in FAM13A expression in the airway epithelium of smokers at risk for COPD, and those with mild COPD, may reduce the extent of airway tissue remodeling.

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Of the four molecular subgroups, Group 3 MB is the most aggressive and has the worst prognosis. To understand the origins of chemoresistance involving IL-6/STAT3 signaling, we used in vitro co-culture systems to investigate the contribution of microglia as a brain tumor microenvironment cellular source of paracrine cytokines that promotes acquired drug resistance in Group 3 MB. MB cells subjected to co-culture with microglia exhibited increased expression of phosphorylated JAK1 and STAT3, which was correlated with enhanced resistance to vincristine. We found that both microglia and MB cells co-cultured with microglia secreted significant quantities of IL-6, indicating that IL-6 is a paracrine and autocrine cytokine able to initiate and sustain STAT3 activity in MB cells. Surprisingly, IL-6R-/- MB cells, which cannot respond to exogenous IL-6 stimuli, were responsive to microglia co-culture induced activation of STAT3 and chemoresistance. Subsequently, we found that MB cells conditioned in vitro with the IL-6 family cytokines, IL-6, OSM, LIF, or IL-11, exhibited enhanced JAK1/STAT3 activity and chemoresistance. Intriguingly, MB cells conditioned with any one of the IL-6 family cytokine secreted multiple IL-6 family cytokines, implicating a feedback network involving multiple cytokines. The IL-6 family cytokine receptors share a common signal transducing β-subunit, gp130, which may be targeted to mitigate tumor chemoresistance. We showed that microglia co-culture failed to induce chemoresistance of gp130-/- MB cells, and that combination treatment using gp130 inhibitors, or with the JAK inhibitor ruxolitinib, effectively overcame the observed resistance to vincristine in gp130 expressing MB cells. Our in vitro studies highlight the gp130/JAK/STAT pathway as a therapeutic target in combating acquired treatment resistance in Group 3 MB.

The ability of cancer cells to invade into surrounding tissues requires degradation of the extracellular matrix (ECM). Invasive structures, such as invadopodia, form on the plasma membrane of cancer cells and secrete ECM-degrading proteases that play crucial roles in cancer cell invasion. We have previously shown that protein tyrosine phosphatase alpha (PTPα) regulates focal adhesion formation and migration of normal cells. Here we report a novel role for PTPα in promoting triple-negative breast cancer cell invasion in vitro and in vivo. We show that PTPα knockdown reduces ECM degradation and cellular invasion of MDA-MB-231 cells through Matrigel. PTPα is not a component of TKS5-positive structures resembling invadopodia; rather, PTPα localizes with endosomal structures positive for MMP14, caveolin-1, and early endosome antigen 1. Furthermore, PTPα regulates MMP14 localization to plasma membrane protrusions, suggesting a role for PTPα in intracellular trafficking of MMP14. Importantly, we show that orthotopic MDA-MB-231 tumours depleted of PTPα exhibit reduced invasion into the surrounding mammary fat pad. These findings suggest a novel role for PTPα in regulating the invasion of triple-negative breast cancer cells.