Abstract 5181: Forced hemidesmosome assembly blocks pancreatic cancer cell invasiveness

Hemidesmosomes (HDs) play a critical role in epithelia integrity by anchoring epithelial cells to the basement membrane (BM). These structures, present at the basal cell surface, link the intracellular intermediate filament network with the extracellular laminins of the BM. Interestingly, HDs are frequently lost in cancer cells, thereby facilitating epithelial tumor cell detachment from the BM. Surprisingly, we here provide evidence that a strong immunoreactivity for the integrin α6β4 and BP180, two specific hemidesmosomal proteins, is observed in human pancreatic ductal adenocarcinoma cells, where their function served paradoxically to stimulate migration and invasion. Using human pancreatic cancer cells in culture, we described molecular events explaining why these proteins are hijacked from their primary function and, importantly, how to force back the reassembly of HDs, thereby decreasing cancer cell migration and invasion. This is achieved by introducing in these cells the somatostatin receptor sst2, whose expression is lost in 90% of pancreatic cancers, and which we have shown to have oncosuppressive functions including inhibition of tumor progression and metastasis. Cell treatment with somatostatin forced HDs reassembly by stimulating two separate critical events, as demonstrated in pancreatic cancer cells and in migrating keratinocytes: 1- the dephosphorylation of the α6β4 integrin which drives its relocalization from lamellipodia, where it is delocalised upon its phosphorylation by growth factors in migrating cells, to HDs; 2- the inhibition of the cleavage of BP180 into its pro-migratory BP120 form, which is here shown to account for the strong BP180 immunoreactivity observed in human pancreatic tumor samples as compared to normal pancreas where the full-length BP180 form is mostly expressed. BP180 cleavage into BP120 is here shown to rely at least on the activity of the MMP-9 metalloprotease whose activity is inhibited by sst2. Strikingly, knocking-down BP180 expression (siRNA) impairs somatostatin-induced HDs assembly in sst2-expressing cells. Interestingly, BP180 siRNA partially revert sst2 inhibitory role on in vitro and in vivo cell migration and invasion, as demonstrated using the chick chorioallatoic membrane model whereby tumor progression of pancreatic cancer cell xenografts is monitored. We have identified novel and original mechanisms for somatostatin-activated sst2 to revert cancer cell pro-migratory phenotype by facilitating HD assembly and cancer cell anchorage to the BM. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5181.