Abstract 3246: TMS1 / ASC is critical for primary ciliogenesis and participates in cell migration

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 8_Supplement; p. 3246
• Main Authors: Abreu, Eladio, Patel, Pritty, Kline, Erik, Marcus, Adam, Vertino, Paula
• Format: Journal Article
• Language: English
• Published: 15.04.2012
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-3246

Abstract TMS1/ ASC encodes a bipartite signaling protein that functions in programmed cell death and proinflammatory response. Loss of function of TMS1/ASC through epigenetic silencing has been implicated in the pathogenesis of several malignancies, including breast and prostate cancer, although the precise mechanism by which TMS1 loss promotes tumorigenesis remains unclear. Recently, we showed that, in breast epithelial cells, TMS1/ASC silencing promotes resistance to detachment induced apoptosis or ‘anoikis’ through a mechanism that involves the inhibition of procaspase-8 cleavage and Bim upregulation. Here, we further characterized the role of TMS1 in breast epithelial cell adhesion and motility. We found that while TMS1 was dispensable for adhesion to fibronectin, it was necessary for efficient migration across a transwell chamber towards a chemoattractant and in wound-closure. siRNA mediated silencing of TMS1 inhibited breast cell invasion through a Matrigel matrix. Subcellular localization studies showed that adhesion of breast epithelial cells to a fibronectin substratum induced the aggregation of TMS1 into barrel-like structures that formed at the apical cell surface. Primary cilia are solitary, sensory organelles that serve as platforms for multiple signaling pathways. Signalling from these organelles plays an important role in linking environmental cues to cell growth control. Interestingly, primary cilia are observed at much lower frequencies on cancer cells. Physical and temporal similarities between the observed TMS1 barrel-like structures and the basal structures of primary cilia suggest that TMS1 may be linked to adhesion and migration activities by regulating the function and/or biogenesis of primary cilia. To test this hypothesis, we used HEK293 kidney epithelial cells expressing an inducible myc-tagged TMS1 and TMS1-/- MEFs to explore the role of TMS1 in primary ciliogenesis. We found that in the absence of TMS1, HEK293 cells were unable to produce primary cilia, but cilia formation could be induced upon TMS1 induction. Taken together, our studies provide evidence of a novel non-apoptotic, inflammasome-independent role for TMS1 in epithelial cell biology. Furthermore, TMS1 silencing may contribute to carcinogenesis by conferring a tumor suppression disadvantage resulting from primary ciliogenesis deficiencies. Supported by Department of Defense/CDMRP Breast cancer grant W81XWH-08-1-0390 and NIH Institutional Research and Academic Career Development Award (IRACDA) K12GM000680. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3246. doi:1538-7445.AM2012-3246