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PDF - 5142K, CD151 clustering at areas of cell-cell contact in vivo (S1); Cell-cell adhesion in response to CD151 clustering (S2); MAB 1A5 binds to CD151 not engaged with α3 integrin in HEp3 cells (S3); MAb 1A5 recognizes the integrin-binding domain of CD151 (S4); Antibodies that recognize the integrin-binding domain of CD151 mediate clustering at areas of cell-cell contact (S5); CD151 expression in normal and prostate cancer tissue (S6); Expression of integrin α3 is not altered in cancers of the bladder or skin (S7); CD151free detectable in benign and normal prostate tissue does not correspond with patient outcome (S8).

MOV - 8452K, CD151 clustering at areas of cell-cell contact in HEp3 tumor cells.

PDf - 92K, Legends for Supplementary Figures S1-S8 as well as Supplementary Movie S1.

PDF - 67K, Demographic information of patients that underwent RRP at the London Regional Cancer Program between 1994 and 1998 (S1); Pathological and clinical outcomes of patients that underwent RRP at the London Regional Cancer Program between 1994 and 1998 (S2); Demographic information of patients that developed metastasis during follow up at the London Regional Cancer Program between 1994 and 1998 (S3).

Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma (RCC) with distinctive morphologic and cytogenetic features. Here, we carry out whole-exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n = 22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor suppressor genes (TSG) and/or evidence of alteration of Hippo pathway genes in 85% of samples. PTPN14 (31%) and NF2 (22%) were the most commonly implicated Hippo pathway genes, whereas other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion. Mutations in the context of recurrent chromosomal losses amounted to biallelic alterations in these TSGs. As a readout of Hippo pathway inactivation, a majority of cases (90%) exhibited increased nuclear YAP1 protein expression. Taken together, nearly all cases of MTSCC exhibit some evidence of Hippo pathway dysregulation. Significance: MTSCC is a rare and relatively recently described subtype of RCC. Next-generation sequencing of a multi-institutional MTSCC cohort revealed recurrent chromosomal losses and somatic mutations in the Hippo signaling pathway genes leading to potential YAP1 activation. In virtually all cases of MTSCC, there was evidence of Hippo pathway dysregulation, suggesting a common mechanistic basis for this disease. Cancer Discov; 6(11); 1258–66. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 1197

The clear-cell renal cell carcinoma (ccRCC) is the most prevalent and malignant type of kidney cancer, for which there are no effective treatment. Moreover, the incidence of ccRCC has been increasing steadily. Disruption of epithelial cell polarity, assisted by tight junction (TJ) deregulation, facilitates rewiring of oncogene and tumor suppressor signaling pathways. In this regard, proximal tubular epithelium (PTE), where ccRCC originates is the sole nephron segment that expresses claudin-2 (hereon Cldn2), a TJ- protein. However, role of Cldn2 in ccRCC remains unknown despite well-recognized role of Cldn2 in regulating other cancers. We here report a novel role for Cldn2 in maintaining epithelial differentiation among PTE cells as its loss induces mesenchymal traits and associates with ccRCC progression. In specific, we found a specific (among claudin proteins) loss of Cldn2 expression in PTE cells subjected to stimuli, like EGF, TGF-ß and hypoxia, known to induce EMT in PTE cells as well as in a murine model of spontaneous renal tumorigenesis. Further analysis of a large renal cancer patient cohort revealed a significant decrease in Cldn2 levels in the ccRCC, and its positive association with cancer metastasis. In vitro, genetic ablation of claudin-2 expression in HK-2 or MDCK-II cells potentiated mesenchymal traits (upregulated Vimentin and Fibronectin; p Citation Format: Balawant Kumar, Rizwan Ahmad, Pinelopi Kapitsino, Giovanna A. Giannico, Roy Zent, Raymond Clement Harris, Peter Clark, Punita Dhawan, Amar B. Singh. Rho-GTPase inhibits claudin-2 expression to promote proximal tubular epithelial cell plasticity and renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1767.

Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins α3β1 and α6β1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151free) correlates clinically with tumor progression and metastasis. Clustering CD151free through its integrin-binding domain promotes accumulation in areas of cell–cell contact, leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151free clustering is a strong regulator of motility even in the absence of α3 expression but requires PKCα, suggesting that CD151 can control migration independent of its integrin associations. The histologic detection of CD151free in prostate cancer correlates with poor patient outcome. When CD151free is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151free as an independent predictor of survival. Moreover, the detection of CD151free can stratify survival among patients with elevated prostate-specific antigen levels. Cumulatively, these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151free with prostate cancer progression suggests that it may contribute to the disease and predict cancer progression. Cancer Res; 74(1); 173–87. ©2013 AACR.

The dysregulation of cell migration enables tumor cells to escape their tissue of origin and disseminate. Since cancer-related deaths are primarily caused by the dissemination of tumor cells, mechanisms of migration are both a target for therapy and an indicator of disease progression. The regulation of cell adhesion is widely recognized as a rate-limiting step in metastasis but how tumor cells achieve dynamic control over their adhesion receptors is poorly understood. During an analysis of prostate cancer progression we discovered that α3β1 expression is reduced and that its tetraspanin partner, CD151, is not “integrin-free”. We were able to detect integrin-free CD151 using antibodies specific to the integrin-binding domain of CD151. Dual staining of tumor tissue and normal tissue from prostate cancer patients for total CD151 and integrin-free CD151 revealed that the appearance of integrin-free CD151 corresponds with poor-patient outcome. In fact, the detection of integrin-free CD151 is an independent predictor of prostate cancer progression. Surprisingly, the clustering of integrin-free CD151 immobilizes tumor cells in vivo and prevents metastasis suggesting that the ability of CD151 to control migration does not depend on its α3β1 integrin partner. Indeed, integrin-free CD151 is now associated with non-integrin partners through which it can regulate tumor cell motility. These observations demonstrate that the appearance of integrin-free CD151 reflects the disruption of the CD151/ α3β1/laminin axis and thereby reveals an altered migratory ability in tumor cells. This has clinical as well molecular implications. Integrin-free CD151 can be used as a molecular indicator of disease progression and assist in the distinction between indolent (benign) and advanced disease (Palmer et al. 2013). In addition, the identification of new CD151 partners can provide new therapeutic targets to inhibit the motility of tumor cells that have undergone this change in migratory status. A preliminary evaluation identified a similar appearance of integrin-free CD151 in cancers derived from other tissues, suggesting that this change in molecular status is broadly applicable to most solid tumors. Palmer, et al. (2013). Integrin-free tetraspanin CD151 can inhibit tumor cell motility upon clustering and is a clinical indicator of prostate cancer progression. Cancer Research. Citation Format: Trenis Palmer, Carlos Martinez, Catalina Vasquez, Katie Hebron, Shanna Arnold, Celestial Jones-Paris, Susanne Chan, Venu Chalasani, Jose Gomez-Lemus, Andrew Williams, Joseph Chin, Giovanna Giannico, Tatiana Ketova, John Lewis, Andries Zijlstra. Separation of tetraspanin CD151 from its integrin partner α3β1 reflects an alter migratory state and predicts prostate cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 55. doi:10.1158/1538-7445.AM2014-55