E-cadherin interacts with EGFR resulting in hyper-activation of ERK in multiple models of breast cancer

Russo, Gabriella; Karl, Michelle; Clark, D.D.; Cui, Julie; Carney, Ryan M.; Su, Boyang; Starich, Bartholomew; Lih, Tung Shing Mamie; Zhang, Qiming; Wu, Pei Hsun; Lee, Meng Horng; Leong, Hon S.; Zhang, Hui; Wirtz, Denis

doi:10.1101/2020.11.04.368746

Cited by 9 publications

(31 citation statements)

References 62 publications

(137 reference statements)

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“…1c). This enhanced E-cad dependent proliferation is maintained at all collagen concentrations, supporting the previously reported hyper-proliferation observed in 3D cultures [27]. Regarding the effects of the ECM on cancer cell proliferation, we observe that softer matrices (1 mg/mL) promote higher proliferation rates than stiffer matrices regardless of E-cad expression (Fig.…”

Section: Cancer Cell Proliferation Is Promoted By E-cad and Limited B...supporting

confidence: 90%

“…E-cad is a transmembrane protein that is ubiquitously expressed in non-invasive epithelial and tumor cells prior to their epithelial-mesenchymal transition (EMT) [19]. For this reason, it was believed to be a tumor-suppressor gene, and its loss a prerequisite for tumor metastasis; however, this hypothesis has been recently questioned [25, 26, 27]. We showed that E-cad expression results in hyper-proliferation of breast cancer cells by promoting activation of the ERK cascade utilizing a similar 3D organoid model.…”

Section: Resultsmentioning

confidence: 99%

“…When modulating propulsion force or spheroid-ECM friction, altering extracellular conditions has a greater effect on collective invasion than spheroid proliferation. We consider proliferation rate an intercellular condition in our spheroid system due to its dependence on E-cad expression and the requirement for formation of cell-cell adherens junctions to activate the ERK hyperproliferation cascade [27]. Therefore, to analyze the impact of intercellular conditions, we alter the stiffness of the cell aggregate and the proliferation rate, which are both modulated experimentally by E-cad expression.…”

Section: Parametric Analysis Of the Continuum Modelmentioning

confidence: 99%

“…The transition to a mesenchymal phenotype and decrease in cell-cell adhesion associated with the loss of E-cad expression encourage single-cell invasion, while E-cad expression favors collective cell invasion [15]. More recent studies on E-cad expression in invasive ductal carcinoma (IDC) have provided evidence that E-cad also alters the proliferative phenotype of breast cancer cells through EGFR/MEK activation [16]. E-cad positive (E-cad+) cells are hyper-proliferative compared to E-cad negative (E-cad-) cells.…”

Section: Introductionmentioning

confidence: 99%

“…E-cad positive (E-cad+) cells are hyper-proliferative compared to E-cad negative (E-cad-) cells. IDC patients with tumors that are E-cad+ have a lower survival rate than those with E-cad-tumors and suffer from metastatic disease more frequently [16, 17]. Thus, this paradoxical role of E-cad in the clinical setting has led to a re-examination of its classification and a focus on the interactions between the tumor and its microenvironment.…”

Section: Introductionmentioning

confidence: 99%

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Tumor proliferation and invasion are coupled through cell-extracellular matrix friction

Crawford

Gomez-Cruz

Russo

et al. 2022

Preprint

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Cell proliferation and invasion are two key drivers of tumor progression and are traditionally considered two independent cellular processes regulated by distinct pathways. Throughin vitroandin silicomethods, we provide evidence that these two processes are intrinsically coupled through matrix-adhesion friction. Using novel tumor spheroids, we show that both tumor cell proliferation and invasion are limited by a volumetric carrying capacity of the system, i.e. maximum spatial cell concentration supported by the system’s total cell count, nutrient consumption rate, and collagen gel mechanical properties. To manipulate these phenotypes in breast cancer cells, we modulate the expression of E-cadherin and its associated role in adhesion, invasion, and proliferation. We integrate these results into a mixed-constitutive formulation to computationally delineate the contributions of cellular and extracellular adhesion, stiffness, and mechanical properties of the extracellular matrix (ECM) to the proliferative and invasive fates of breast cancer tumor spheroids. Both approaches conclude that the dominant drivers of tumor fate are system properties modulating cell-ECM friction, such as E-cadherin dependent cell-ECM adhesion and matrix pore size.

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Section: Cancer Cell Proliferation Is Promoted By E-cad and Limited B...supporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Parametric Analysis Of the Continuum Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Tumor proliferation and invasion are coupled through cell-extracellular matrix friction

Crawford

Gomez-Cruz

Russo

et al. 2022

Preprint

Self Cite

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Tumor dormancy: EMT beyond invasion and metastasis

Aouad,

Quinn,

Berger

et al. 2023

Genesis

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SummaryMore than two‐thirds of cancer‐related deaths are attributable to metastases. In some tumor types metastasis can occur up to 20 years after diagnosis and successful treatment of the primary tumor, a phenomenon termed late recurrence. Metastases arise from disseminated tumor cells (DTCs) that leave the primary tumor early on in tumor development, either as single cells or clusters, adapt to new environments, and reduce or shut down their proliferation entering a state of dormancy for prolonged periods of time. Dormancy has been difficult to track clinically and study experimentally. Recent advances in technology and disease modeling have provided new insights into the molecular mechanisms orchestrating dormancy and the switch to a proliferative state. A new role for epithelial‐mesenchymal transition (EMT) in inducing plasticity and maintaining a dormant state in several cancer models has been revealed. In this review, we summarize the major findings linking EMT to dormancy control and highlight the importance of pre‐clinical models and tumor/tissue context when designing studies. Understanding of the cellular and molecular mechanisms controlling dormant DTCs is pivotal in developing new therapeutic agents that prevent distant recurrence by maintaining a dormant state.

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ERα/LKB1 complex upregulates E‐cadherin expression and stimulates breast cancer growth and progression upon adiponectin exposure

Naimo

Forestiero

Paolì

et al. 2023

Intl Journal of Cancer

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Adiponectin is the major adipocytes‐secreted protein involved in obesity‐related breast cancer growth and progression. We proved that adiponectin promotes proliferation in ERα‐positive breast cancer cells, through ERα transactivation and the recruitment of LKB1 as ERα‐coactivator. Here, we showed that adiponectin‐mediated ERα transactivation enhances E‐cadherin expression. Thus, we investigated the molecular mechanism through which ERα/LKB1 complex may modulate the expression of E‐cadherin, influencing tumor growth, progression and distant metastasis. We demonstrated that adiponectin increases E‐cadherin expression in ERα‐positive 2D and higher extent in 3D cultures. This occurs through a direct activation of E‐cadherin gene promoter by ERα/LKB1‐complex. The impact of E‐cadherin on ERα‐positive breast cancer cell proliferation comes from the evidence that in the presence of E‐cadherin siRNA the proliferative effects of adiponectin is no longer noticeable. Since E‐cadherin connects cell polarity and growth, we investigated if the adiponectin‐enhanced E‐cadherin expression could influence the localization of proteins cooperating in cell polarity, such as LKB1 and Cdc42. Surprisingly, immunofluorescence showed that, in adiponectin‐treated MCF‐7 cells, LKB1 and Cdc42 mostly colocalize in the nucleus, impairing their cytosolic cooperation in maintaining cell polarity. The orthotopic implantation of MCF‐7 cells revealed an enhanced E‐cadherin‐mediated breast cancer growth induced by adiponectin. Moreover, tail vein injection of MCF‐7 cells showed a higher metastatic burden in the lungs of mice receiving adiponectin‐treated cells compared to control. From these findings it emerges that adiponectin treatment enhances E‐cadherin expression, alters cell polarity and stimulates ERα‐positive breast cancer cell growth in vitro and in vivo, sustaining higher distant metastatic burden.

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E-cadherin interacts with EGFR resulting in hyper-activation of ERK in multiple models of breast cancer

Cited by 9 publications

References 62 publications

Tumor proliferation and invasion are coupled through cell-extracellular matrix friction

Tumor proliferation and invasion are coupled through cell-extracellular matrix friction

Tumor dormancy: EMT beyond invasion and metastasis

ERα/LKB1 complex upregulates E‐cadherin expression and stimulates breast cancer growth and progression upon adiponectin exposure

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