Trop-2 inactivates E-cadherin and drives colon cancer metastasis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15576-e15576
Author(s):  
Saverio Alberti ◽  
Emanuela Guerra ◽  
Donato F. Altomare ◽  
Raffaella Depalo ◽  
Marco Trerotola
Keyword(s):  
Colon Cancer ◽  
Cell Adhesion ◽  
Cancer Metastasis ◽  
Case Series ◽  
Cancer Therapies ◽  
Primary Tumors ◽  
Metastatic Relapse ◽  
E Cadherin ◽  
Cell Cell

e15576 Background: Metastatic diffusion is the biggest hurdle for colon cancer (CRC) cure and the identification of decisive drivers of CRC metastasis is an urgent need in CRC care. Methods: The expression of target molecules in primary tumors and metastases was systematically assessed by DNA array and IHC analysis. Cell-cell adhesion capacity was quantified in 2D cell cultures and in HCT116 CRC cell spheroids. Pro-metastatic impact of wtTrop-2 and activated, tail-less Trop-2 (Δcyto) was assessed in vivo in orthotopic diffusion models of KM12SM CRC cells. Primary CRC and metastasis transcriptomes were analyzed for differential induction of EMT determinants. Kaplan–Meier plots were used to illustrate survival and metastatic relapse in independent case series of CRC patients. Results: Trop-2 was identified as uniquely upregulated in CRC models by transcriptome analysis. wtTrop-2 and ΔcytoTrop-2 were shown to induce cell migration, wound-healing and resistance to apoptosis induction . wtTrop-2 increased the metastatic capacity of KM12SM cells, raising metastasis diffusion from 45% for control cells to 90% for wtTrop-2 transfectants. The constitutively-active ΔcytoTrop-2 further boosted metastatic spreading, with metastatic livers reaching up to four times their normal size. Constitutive high expression of E-cadherin was revealed in cancer metastases. No evidence was obtained for transcriptional down-regulation of epithelial differentiation biomarkers. No induction of EMT transcription factors was observed in Trop-2-activated cells. Trop-2 tightly bound E-cadherin and caused its release from the cytoskeleton, for loss of cell-cell adhesion and activation of β-catenin. The Trop-2/E-cadherin/β-catenin-driven pro-metastatic program was recapitulated in CRC patients and was shown to impact on CRC metastatic relapse and overall patient survival. Conclusions: We identify Trop-2-driven functional inactivation of E-cadherin as a key driver of metastatic diffusion in CRC. These findings may pave the way for novel multi-marker personalized diagnostics and anti-cancer therapies. [Table: see text]

Inactivation of E-cadherin by Trop-2 drives colon cancer metastasis.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 105-105
Author(s):  
Saverio Alberti ◽  
Emanuela Guerra ◽  
Donato F. Altomare ◽  
Raffaella Depalo ◽  
Marco Trerotola
Keyword(s):  
Colon Cancer ◽  
Cell Adhesion ◽  
Cancer Patients ◽  
Cancer Metastasis ◽  
Colon Cancer Metastasis ◽  
Metastatic Relapse ◽  
Metastatic Spreading ◽  
E Cadherin ◽  
Cell Cell

105 Background: Tumor metastasis is the main cause of death of colon cancer patients and the biggest hurdle for cancer cure. We set to identify decisive drivers and of pivotal therapy targets for colon cancer metastasis. Methods: IHC analysis quantified the expression of target molecules in primary tumors and metastases. Cell-cell adhesion capacity was assessed in vitro and in HCT116 colon cancer cell spheroids. Pre-clinical models of orthotopic growth of KM12SM colon cancer cells and metastatic diffusion to the liver were utilized to assess metastatic spreading force of wtTrop-2 and of the constitutively-active, tail-less form of Trop-2 (Δcyto). Xenotransplant and metastasis transcriptomes were analyzed for differential induction of EMT determinants. Kaplan–Meier plots were used to illustrate survival and metastatic relapse in independent case series of colon cancer patients. Results: wtTrop-2 was shown to induce wound-healing. ΔcytoTrop-2 further increased cell migration ability. Both wtTrop-2 and ΔcytoTrop-2 induced resistance to apoptosis in vitro and in vivo. wtTrop-2 strikingly increased the metastatic capacity of KM12SM cells, raising metastasis rates from 45% for control cells to 90% for wtTrop-2 transfectants. The constitutively-active ΔcytoTrop-2 further boosted metastatic spreading, with metastatic livers reaching up to four times their normal size. Cancer metastases revealed high levels of E-cadherin, in the absence of transcriptional down-regulation. EMT transcription factors were largely missing from Trop-2-activated cells. Rather, binding to Trop-2 was shown to cause the release of E-cadherin from the cytoskeleton, loss of cell-cell adhesion and activation of β-catenin. This global, Trop-2/E-cadherin/β-catenin-driven pro-metastatic program was recapitulated in colon cancer patients and was shown to impact on colon cancer metastatic relapse and overall patient survival. Conclusions: We identify Trop-2-driven functional inactivation of E-cadherin as a widespread driver of metastatic diffusion in colon cancer, opening novel avenues for personalized diagnostic procedures and anti-cancer therapies. [Table: see text]

scholarly journals Biogenesis of Polarized Epithelial Cells During Kidney Development In Situ: Roles of E-Cadherin–mediated Cell–Cell Adhesion and Membrane Cytoskeleton Organization

1998 ◽  
Vol 9 (11) ◽  
pp. 3161-3177 ◽  
Author(s):  
Peter A. Piepenhagen ◽  
W. James Nelson
Keyword(s):  
Cell Adhesion ◽  
Epithelial Cells ◽  
Kidney Development ◽  
Lateral Membrane ◽  
Membrane Cytoskeleton ◽  
Triton X ◽  
E Cadherin ◽  
Cell Cell

Organization of proteins into structurally and functionally distinct plasma membrane domains is an essential characteristic of polarized epithelial cells. Based on studies with cultured kidney cells, we have hypothesized that a mechanism for restricting Na/K-ATPase to the basal-lateral membrane involves E-cadherin–mediated cell–cell adhesion and integration of Na/K-ATPase into the Triton X-100–insoluble ankyrin- and spectrin-based membrane cytoskeleton. In this study, we examined the relevance of these in vitro observations to the generation of epithelial cell polarity in vivo during mouse kidney development. Using differential detergent extraction, immunoblotting, and immunofluorescence histochemistry, we demonstrate the following. First, expression of the 220-kDa splice variant of ankyrin-3 correlates with the development of resistance to Triton X-100 extraction for Na/K-ATPase, E-cadherin, and catenins and precedes maximal accumulation of Na/K-ATPase. Second, expression of the 190-kDa slice variant of ankyrin-3 correlates with maximal accumulation of Na/K-ATPase. Third, Na/K-ATPase, ankyrin-3, and fodrin specifically colocalize at the basal-lateral plasma membrane of all epithelial cells in which they are expressed and during all stages of nephrogenesis. Fourth, the relative immunofluorescence staining intensities of Na/K-ATPase, ankyrin-3, and fodrin become more similar during development until they are essentially identical in adult kidney. Thus, renal epithelial cells in vivo regulate the accumulation of E-cadherin–mediated adherens junctions, the membrane cytoskeleton, and Na/K-ATPase through sequential protein expression and assembly on the basal-lateral membrane. These results are consistent with a mechanism in which generation and maintenance of polarized distributions of these proteins in vivo and in vitro involve cell–cell adhesion, assembly of the membrane cytoskeleton complex, and concomitant integration and retention of Na/K-ATPase in this complex.

‘MCC’ protein interacts with E-cadherin and β-catenin strengthening cell–cell adhesion of HCT116 colon cancer cells

Oncogene ◽  
2017 ◽  
Vol 37 (5) ◽  
pp. 663-672 ◽  
Author(s):  
F A Benthani ◽  
D Herrmann ◽  
P N Tran ◽  
L Pangon ◽  
M C Lucas ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Adhesion ◽  
Cancer Cells ◽  
Colon Cancer Cells ◽  
E Cadherin ◽  
Cell Cell

Rescuing the N-cadherin knockout by cardiac-specific expression of N- or E-cadherin

Development ◽  
2001 ◽  
Vol 128 (4) ◽  
pp. 459-469
Author(s):  
Y. Luo ◽  
M. Ferreira-Cornwell ◽  
H. Baldwin ◽  
I. Kostetskii ◽  
J. Lenox ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Heart Development ◽  
Critical Role ◽  
Embryonic Cells ◽  
Wild Type ◽  
Specific Expression ◽  
Developmental Defects ◽  
E Cadherin ◽  
Cell Cell

Cell-cell adhesion mediated by some members of the cadherin family is essential for embryonic survival. The N-cadherin-null embryo dies during mid-gestation, with multiple developmental defects. We show that N-cadherin-null embryos expressing cadherins using muscle-specific promoters, alpha- or beta-myosin heavy chain, are partially rescued. Somewhat surprisingly, either N-cadherin or E-cadherin was effective in rescuing the embryos. The rescued embryos exhibited an increased number of somites, branchial arches and the presence of forelimb buds; however, in contrast, brain development was severely impaired. In rescued animals, the aberrant yolk sac morphology seen in N-cadherin-null embryos was corrected, demonstrating that this phenotype was secondary to the cardiac defect. Dye injection studies and analysis of chimeric animals that have both wild-type and N-cadherin-null cells support the conclusion that obstruction of the cardiac outflow tract represents a major defect that is likely to be the primary cause of pericardial swelling seen in null embryos. Although rescued embryos were more developed than null embryos, they were smaller than wild-type embryos, even though the integrity of the cardiovascular system appeared normal. The smaller size of rescued embryos may be due, at least in part, to increased apoptosis observed in tissues not rescued by transgene expression, indicating that N-cadherin-mediated cell adhesion provides an essential survival signal for embryonic cells. Our data provide in vivo evidence that cadherin adhesion is essential for cell survival and for normal heart development. Our data also show that E-cadherin can functionally substitute for N-cadherin during cardiogenesis, suggesting a critical role for cadherin-mediated cell-cell adhesion, but not cadherin family member-specific signaling, at the looping stage of heart development.

scholarly journals Transcriptional suppression of AMPKα1 promotes breast cancer metastasis upon oncogene activation

2020 ◽  
Vol 117 (14) ◽  
pp. 8013-8021 ◽  
Author(s):  
Yong Yi ◽  
Deshi Chen ◽  
Juan Ao ◽  
Wenhua Zhang ◽  
Jianqiao Yi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Adhesion ◽  
Cancer Metastasis ◽  
Kinase Activity ◽  
Critical Role ◽  
Breast Cancer Metastasis ◽  
Transcription Control ◽  
Cell Cell

AMP-activated protein kinase (AMPK) functions as an energy sensor and is pivotal in maintaining cellular metabolic homeostasis. Numerous studies have shown that down-regulation of AMPK kinase activity or protein stability not only lead to abnormality of metabolism but also contribute to tumor development. However, whether transcription regulation of AMPK plays a critical role in cancer metastasis remains unknown. In this study, we demonstrate that AMPKα1 expression is down-regulated in advanced human breast cancer and is associated with poor clinical outcomes. Transcription of AMPKα1 is inhibited on activation of PI3K and HER2 through ΔNp63α. Ablation of AMPKα1 expression or inhibition of AMPK kinase activity leads to disruption of E-cadherin-mediated cell–cell adhesion in vitro and increased tumor metastasis in vivo. Furthermore, restoration of AMPKα1 expression significantly rescues PI3K/HER2-induced disruption of cell–cell adhesion, cell invasion, and cancer metastasis. Together, these results demonstrate that the transcription control is another layer of AMPK regulation and suggest a critical role for AMPK in regulating cell–cell adhesion and cancer metastasis.

Loss of Cell Adhesion in Colon Cancer Cells During In Vitro Metastasis Measured by Bio-MEMS Force Sensor

2012 ◽  
Author(s):  
Xin Tang ◽  
Taher Saif
Keyword(s):  
Colon Cancer ◽  
Cell Adhesion ◽  
Cancer Cells ◽  
Force Sensor ◽  
Human Colon ◽  
Colon Cancer Cells ◽  
Surface Adhesion ◽  
E Cadherin

Human colon carcinoma (HCT-8) cells show metastatic phenotype when cultured on appropriately soft substrates. Here, we studied the surface non-specific adhesion in HCT-8 cells throughout the in vitro metastasis process. A novel bio-MEMS force sensor was used to measure the cell-probe non-specific adhesion. The adhesion characteristics are analyzed using classical Johnson-Kendall-Roberts (JKR) theory. Our results indicate that the post-metastatic HCT-8 cells (dissociated R cells) display remarkably diminished surface adhesion and are potentially more invasive than original pre-metastatic HCT-8 cells (E cells). To the best of our knowledge, this is the first quantitative data on cancer cells adhesion change as in vitro metastasis proceeds. It is well known that, during in vivo cancer metastasis, malignant cancer cells reduce their surface adhesion (both specific and non-specific) [1] as well as modify their extracellular matrix (ECM) ligands [2] to detach from primary tumor and enhance successful invasion into distant healthy organs. Simultaneously, cancer cells down-regulate their surface cell-cell adhesion molecules, i.e. E-Cadherin, to escape from tumor and initiate metastasis [1]. However, there is no quantitative report on cancer cell adhesion throughout the entire metastasis process, since in vivo metastasis is nearly impossible to detect [3]. We had discovered [4] that human colon cancer cells (HCT-8) can consistently display an in vitro metastasis-like phenotype (MLP) within only 7 days of culture on soft hydrogel substrates with appropriate mechanical stiffness (Poly-acrylamide gels with Elastic modulus: 21∼ 47 kPa [14, 15]). We found that MLP is consistent, repeatable and irreversible (Fig. 1a-1c). In addition, the post MLP cancer cells (referred to here as R cells meaning round-shaped in contrast to the E-cells, i.e., the original HCT-8 cells that are epithelial in nature) up-regulate a number of in vivo tissue-destructive proteinases, such as, MMPs [4]. R cells also express remarkably diminished E-Cadherin patterns compared to HCT8 E cells (Fig. 1d, 1e). Using this model system, we are able to study the kinetics of non-specific and specific surface adhesion change on HCT-8 cancer cells. In this paper, we measure the non-specific adhesion of both pre and post metastatic HCT-8 cells (E and R cells respectively) using a novel bio-MEMS force sensor. The adhesion energy and other mechanical properties are analyzed using classical Johnson-Kendall-Roberts (JKR) theory [5]. We find that after undergoing metastasis (or MLP), the dissociated HCT-8 cells (R cells) down-regulate non-specific adhesion, in contrast to their ancestors, HCT-8 E cells. The reduction of non-specific adhesion is coincident with the immuno-fluorescent staining data of cell-cell specific adhesion molecule E-Cadherin, which shows 4 ∼ 6 times down-regulation after MLP (Fig. 1d-1e). The bio-MEMS sensor consists of a micro cantilever beam with spring constant k = 3.48 nN/ μm. A flat probe is attached with the beam which forms adhesive contact with cells. The sensor is made from single crystal silicon, and is coated with a thin layer of native silicon oxide (SiO2). The probe and the sensor are not functionalized. The sensor is manipulated with an x-y-z piezo stage. To measure the cell adhesion, the flat probe is brought in contact with cells’ lateral convex surface at the boundary. After a 2-minute contact, force sensor is pulled away horizontally from the cell island at a constant quasi-static speed of 2.1 ± 0.4 μm/s (Fig. 2a). Due to the cell-probe adhesion, the sensor beam deforms during retraction. Corresponding restoring force of the cell island is given by F = kδ (Fig. 2a-c). Note the probe is non-functionalized (free of any extra-cellular matrix proteins), and only has a coating of SiO2 on the surface due to air exposure. During probe retraction, the cell is continuously stretched while the cell-probe contact area radius Rc remains unchanged (Fig. 3b-e) and the contact angle θ increases (Fig. 3b). At critical value of force, Fc, the cell suddenly detaches from probe (Fig. 3d). The critical Fc at detachment is optically recorded by video camera and was determined as 27.8 ± 2.2 nN. A similar experiment on cells after MLP shows so measurable adhesion, i.e, the force to detach was zero for all the cells tested. Figure shows the measured adhesion in pre and post metastatic cells.

Inhibition of N-linked glycosylation by tunicamycin induces E-cadherin-mediated cell–cell adhesion and inhibits cell proliferation in undifferentiated human colon cancer cells

2010 ◽  
Vol 68 (1) ◽  
pp. 227-238 ◽  
Author(s):  
Julio Cesar Madureira de Freitas Junior ◽  
Bárbara Du Rocher D’Aguiar Silva ◽  
Waldemir Fernandes de Souza ◽  
Wallace Martins de Araújo ◽  
Eliana Saul Furquim Werneck Abdelhay ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cell Proliferation ◽  
Cell Adhesion ◽  
Cancer Cells ◽  
Human Colon ◽  
Colon Cancer Cells ◽  
Human Colon Cancer ◽  
Human Colon Cancer Cells ◽  
E Cadherin ◽  
Cell Cell

622: Von Hippel-Lindau Inactivation Downregulates the Cell-Cell Adhesion Molecule E Cadherin in Renal Cancer Cells

2005 ◽  
Vol 173 (4S) ◽  
pp. 170-170
Author(s):  
Maxine G. Tran ◽  
Miguel A. Esteban ◽  
Peter D. Hill ◽  
Ashish Chandra ◽  
Tim S. O'Brien ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cancer Cells ◽  
Renal Cancer ◽  
Adhesion Molecule ◽  
Cell Adhesion Molecule ◽  
Von Hippel Lindau ◽  
E Cadherin ◽  
Cell Cell
Sign in / Sign up

Export Citation Format

Share Document