BRG1 and BRM, two core catalytic subunits in SWI ⁄ SNF chromatin remodeling complexes, have been suggested as tumor suppressors, yet their roles in carcinogenesis are unclear. Here, we present evidence that loss of BRG1 and BRM is involved in the progression of lung adenocarcinomas. Analysis of 15 lung cancer cell lines indicated that BRG1 mutations correlated with loss of BRG1 expression and that loss of BRG1 and BRM expression was frequent in E-cadherin-low and vimentin-high cell lines. Immunohistochemical analysis of 93 primary lung adenocarcinomas showed loss of BRG1 and BRM in 11 (12%) and 16 (17%) cases, respectively. Loss of expression of BRG1 and BRM was frequent in solid predominant adenocarcinomas and tumors with low thyroid transcription factor-1 (TTF-1, master regulator of lung) and low cytokeratin7 and E-cadherin (two markers for bronchial epithelial differentiation). Loss of BRG1 was correlated with the absence of lepidic growth patterns and was mutually exclusive of epidermal growth factor receptor (EGFR) mutations. In contrast, loss of BRM was found concomitant with lepidic growth patterns and EGFR mutations. Finally, we analyzed the publicly available dataset of 442 cases and found that loss of BRG1 and BRM was frequent in E-cadherin-low, TTF-1-low, and vimentin-high cases and correlated with poor prognosis. We conclude that loss of either or both BRG1 and BRM is involved in the progression of lung adenocarcinoma into solid predominant tumors with features of epithelial mesenchymal transition and loss of the bronchial epithelial phenotype. BRG1 loss was specifically involved in the progression of EGFR wild-type, but not EGFR-mutant tumors. (Cancer Sci 2013; 104: 266-273) L ung cancer is the leading cause of cancer death in many developed countries, including the United States and Japan. (1,2) The identification of genetic abnormalities, such as epidermal growth factor receptor (EGFR) mutations, KRAS mutations, EML4-ALK translocation, and MET amplifications has revolutionized our understanding of the molecular mechanisms in lung cancer development. (3) However, it has become increasingly apparent that epigenetic alternations play equally important roles in tumorigenesis, and among them, chromatin remodeling factors have attracted much attention recently. (4) Indeed, identification of mutations of chromatin remodeling factors in cancer has been a major hot topic in the past 2 years. (5)(6)(7)(8) BRG1 and BRM, two core catalytic ATPase subunits in human SWI ⁄ SNF chromatin remodeling enzymes, have now emerged as bona fide tumor suppressor genes. (9)(10)(11)(12) Inactivating mutations of BRG1 have been identified in 35% of non-small cell lung cancer cell lines and a subset of primary lung cancer. (9) In a mouse model of lung cancer, targeted knockout of BRG1 can affect tumor development. (10) In contrast to BRG1, mutations of BRM have rarely been identified and epigenetic silencing of BRM plays a contributory role in some cancers. (4,11) However, whether loss of BRG1 and BRM affects phenotype and...

Rearranged during transfection (RET) fusions have been newly identified in approximately 1% of patients with primary lung tumors. However, patient-derived lung cancer cell lines harboring RET fusions have not yet been established or identified, and therefore, the effectiveness of an RET inhibitor on lung tumors with endogenous RET fusion has not yet been studied. In this study, we report identification of CCDC6-RET fusion in the human lung adenocarcinoma cell line LC-2/ad. LC-2/ad showed distinctive sensitivity to the RET inhibitor, vandetanib, among 39 non-small lung cancer cell lines. The xenograft tumor of LC-2/ad showed cribriform acinar structures, a morphologic feature of primary RET fusion-positive lung adenocarcinomas. LC-2/ad cells could provide useful resources to analyze molecular functions of RET-fusion protein and its response to RET inhibitors.

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A new cell chip technology in the form of a two-dimensional microarray of HepG2 spheroids was developed by using the microcontact printing technique. The chip consisted of several collagen spots in a triangular arrangement within a 100-mm2 area at the center of a glass plate (24 x 24 mm), which served as the cell adhesion area; the region excluding the collagen spots that was modified with polyethylene glycol (PEG) served as the non-adhesion area. HepG2 cells inoculated onto the chip gradually formed spheroids with smooth surfaces and high circularity on each collagen spot due to cell proliferation; the spheroid diameters remained constant after 10 days of culture. Such a two-dimensional microarray configuration of HepG2 spheroids could be maintained for at least 2 weeks. The spheroid diameter was directly proportional to the pitch between the collagen spots on the chip. This indicates that we can factitiously control the spheroid diameter. In addition, albumin secretion activity of HepG2 spheroids increased with the increase of spheroid diameter. This chip technology may be applicable as a cellular platform for developing two-dimensional spheroid microarrays.