152 Suppression of p38α promotes fibroblast-led human squamous cell carcinoma (SCC) invasion through p38δ-dependent mechanism

Abstract

Cancer cell invasion is a hallmark of malignancy. Therefore, interfering with key signaling pathways that drive invasion would be expected to provide significant clinical benefits. To evaluate this approach, we are targeting stress-activated p38 kinases p38α and p38δ to modulate cancer cell motility and invasiveness. We recently found that in human squamous carcinoma cell lines SCC9 and SCC12 the rates of scratch wound closure were significantly reduced by pharmacologic or genetic inhibition of p38α alone, or by p38α/p38δ co-inhibition. These data implicated both p38α and p38δ in control of cancer cell motility in two-dimensional (2D) monolayer culture of SCC cells. Here we used pharmacologic inhibitors and RNA interference to investigate the contributions of p38α and p38δ signaling to fibroblast-led SCC invasion in 3D organotypic invasion model in which tumor cells move through collagen matrix remodeled by stromal fibroblasts. In both cell lines inhibition of p38α resulted in a highly invasive SCC tumor cell phenotype that was reversed by a co-inhibition of p38δ. Furthermore, p38α inhibition or depletion led to striking tissue fragility and a marked disruption of tissue architecture, phenotypes which were also largely ameliorated by co-inhibition of p38δ. Weakened E-cadherin-dependent intercellular adhesion likely underlies this fragility as well as increased ability of SCC cells to invade a collagen matrix observed upon p38α inhibition in organotypic, but not in monolayer cultures. Together, our data suggest that while p38α functions to restrict SCC cell invasiveness in 3D organotypic invasion model, p38δ is required for collective invasion of SCC cells. Therefore, blocking p38δ could be a potential strategy to reduce SCC metastasis.