An ADAM12 and FAK positive feedback loop amplifies the interaction signal of tumor cells with extracellular matrix to promote esophageal cancer metastasis

AbstractThe epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, being responsible in many cases for the onset of the metastatic cascade and being integral in the ability of cells to resist drug treatment. Most studies of EMT focus on its induction via chemical signals such as TGF-β or Notch ligands, but it has become increasingly clear that biomechanical features of the microenvironment such as ECM (extracellular matrix) stiffness can be equally important. Here, we introduce a coupled feedback loop connecting stiffness to the EMT transcription factor ZEB1, which acts via increasing the secretion of LOXL2 that leads to increased cross-linking of collagen fibers in the ECM. This increased cross-linking can effectively increase ECM stiffness and increase ZEB1 levels, thus setting a positive feedback loop between ZEB1 and ECM stiffness. To investigate the impact of this non-cell-autonomous effect, we introduce a computational approach capable of connecting LOXL2 concentration to increased stiffness and thereby to higher ZEB1 levels. Our results indicate that this positive feedback loop, once activated, can effectively lock the cells in a mesenchymal state.

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A SMYD3/ITGB6/TGFβ1 Positive Feedback Loop Promotes the Invasion and Adhesion of Ovarian Cancer Spheroids

Frontiers in Oncology ◽

10.3389/fonc.2021.690618 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yahui Jiang ◽

Tianyu Zhou ◽

Yiwen Shi ◽

Weiwei Feng ◽

Tianjiao Lyu

Keyword(s):

Ovarian Cancer ◽

Positive Feedback ◽

Feedback Loop ◽

Cancer Metastasis ◽

Luciferase Reporter ◽

Positive Feedback Loop ◽

Downstream Effectors ◽

Reporter Assays ◽

Cancer Spheroids ◽

E Cadherin

BackgroundImplantation metastasis is the main means of dissemination in ovarian cancer. Our previous studies showed that SET and MYND domain-containing protein 3 (SMYD3) expression was higher in ovarian cancer spheroids than in monolayers. SMYD3 enhancement of spheroid invasion and adhesion is mediated by the downstream effectors ITGB6 and ITGAM. However, the potential mechanisms underlying the SMYD3/integrin-mediated invasion and adhesion of spheroids still need to be explored.MethodsWestern blotting was used to examine the expression of SMYD3, ITGB6 and downstream molecules under different treatments. Immunofluorescence was used to detect the expression of F-actin, E-cadherin and N-cadherin. Anti-ITGB6 antibody-based inhibition and dual-luciferase reporter assays were used to confirm the binding between ITGB6 and latent TGFβ1. Transwell invasion, adherence and 3D tumor spheroid invasion assays were employed to test the effects of TGFβ1 on the invasion and adhesion of ovarian cancer spheroids. ELISA was performed to assess the release of latent TGFβ1 from ovarian cancer spheroids.ResultsSMYD3 and ITGB6 activated the TGFβ1/Smad3 pathway and then induced the upregulation of Snail, Vimentin and N-cadherin and the downregulation of E-cadherin in 3D-cultured ovarian cancer spheroids. In this process, latent TGFβ1 could bind to ITGB6 and become activated to stimulate the Smad3 pathway. Moreover, SMYD3 and ITGB6 could facilitate the release of latent TGFβ1 from 3D-cultured ovarian cancer spheroids. Interestingly, TGFβ1 could promote the expression of SMYD3 and ITGB6 via feedback. This positive feedback loop could further amplify the biological effect and promote the invasion and adhesion of ovarian cancer spheroids.ConclusionOur results demonstrated that the SMYD3/ITGB6/TGFβ1-Smad3 positive feedback loop could promote the invasion and adhesion of ovarian cancer spheroids by upregulating the expression of N-cadherin, Snail, and Vimentin and downregulating the expression of E-cadherin. Thus, our study unmasked the mechanism of SMYD3- and ITGB6-induced ovarian cancer metastasis and provides new ideas for targeted ovarian cancer treatment.

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STX2 promotes colorectal cancer metastasis through a positive feedback loop that activates the NF-κB pathway

Cell Death and Disease ◽

10.1038/s41419-018-0675-x ◽

2018 ◽

Vol 9 (6) ◽

Cited By ~ 8

Author(s):

Yongxia Wang ◽

Honghai Xu ◽

Hongli Jiao ◽

Shuyang Wang ◽

Zhiyuan Xiao ◽

...

Keyword(s):

Colorectal Cancer ◽

Positive Feedback ◽

Feedback Loop ◽

Cancer Metastasis ◽

Positive Feedback Loop ◽

Colorectal Cancer Metastasis

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A positive feedback loop of IL-17B-IL-17RB activates ERK/β-catenin to promote lung cancer metastasis

Cancer Letters ◽

10.1016/j.canlet.2018.02.037 ◽

2018 ◽

Vol 422 ◽

pp. 44-55 ◽

Cited By ~ 5

Author(s):

Yi-Fang Yang ◽

Yi-Chen Lee ◽

Steven Lo ◽

Yi-Ning Chung ◽

Ya-Ching Hsieh ◽

...

Keyword(s):

Lung Cancer ◽

Positive Feedback ◽

Feedback Loop ◽

Cancer Metastasis ◽

Positive Feedback Loop ◽

Lung Cancer Metastasis

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Long noncoding RNA LINC01578 drives colon cancer metastasis through a positive feedback loop with the NF‐κB/YY1 axis

Molecular Oncology ◽

10.1002/1878-0261.12819 ◽

2020 ◽

Vol 14 (12) ◽

pp. 3211-3233 ◽

Cited By ~ 1

Author(s):

Jia Liu ◽

Yang Zhan ◽

Jiefu Wang ◽

Junfeng Wang ◽

Jiansheng Guo ◽

...

Keyword(s):

Colon Cancer ◽

Positive Feedback ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

Feedback Loop ◽

Cancer Metastasis ◽

Positive Feedback Loop ◽

Colon Cancer Metastasis

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A Positive Feedback Loop between Mesenchymal-like Cancer Cells and Macrophages Is Essential to Breast Cancer Metastasis

Cancer Cell ◽

10.1016/j.ccr.2014.03.021 ◽

2014 ◽

Vol 25 (5) ◽

pp. 605-620 ◽

Cited By ~ 327

Author(s):

Shicheng Su ◽

Qiang Liu ◽

Jingqi Chen ◽

Jianing Chen ◽

Fei Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Positive Feedback ◽

Feedback Loop ◽

Cancer Metastasis ◽

Breast Cancer Metastasis ◽

Positive Feedback Loop

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Extracellular matrix proteins: A positive feedback loop in lung fibrosis?

Matrix Biology ◽

10.1016/j.matbio.2013.11.002 ◽

2014 ◽

Vol 34 ◽

pp. 170-178 ◽

Cited By ~ 44

Author(s):

Marjolein E. Blaauboer ◽

Fee R. Boeijen ◽

Claire L. Emson ◽

Scott M. Turner ◽

Behrouz Zandieh-Doulabi ◽

...

Keyword(s):

Extracellular Matrix ◽

Positive Feedback ◽

Lung Fibrosis ◽

Feedback Loop ◽

Extracellular Matrix Proteins ◽

Matrix Proteins ◽

Positive Feedback Loop

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An RFC4/Notch1 signaling feedback loop promotes NSCLC metastasis and stemness

Nature Communications ◽

10.1038/s41467-021-22971-x ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Lei Liu ◽

Tianyu Tao ◽

Shihua Liu ◽

Xia Yang ◽

Xuwei Chen ◽

...

Keyword(s):

Notch Signaling ◽

Positive Feedback ◽

Feedback Loop ◽

Cancer Metastasis ◽

Positive Feedback Loop ◽

Notch1 Signaling ◽

Patient Prognosis ◽

Public Datasets ◽

Nsclc Patients ◽

Transcriptional Target

AbstractNotch signaling represents a key mechanism mediating cancer metastasis and stemness. To understand how Notch signaling is overactivated to couple tumor metastasis and self-renewal in NSCLC cells, we performed the current study and showed that RFC4, a DNA replication factor amplified in more than 40% of NSCLC tissues, directly binds to the Notch1 intracellular domain (NICD1) to competitively abrogate CDK8/FBXW7-mediated degradation of NICD1. Moreover, RFC4 is a functional transcriptional target gene of Notch1 signaling, forming a positive feedback loop between high RFC4 and NICD1 levels and sustained overactivation of Notch signaling, which not only leads to NSCLC tumorigenicity and metastasis but also confers NSCLC cell resistance to treatment with the clinically tested drug DAPT against NICD1 synthesis. Furthermore, together with our study, analysis of two public datasets involving more than 1500 NSCLC patients showed that RFC4 gene amplification, and high RFC4 and NICD1 levels were tightly correlated with NSCLC metastasis, progression and poor patient prognosis. Therefore, our study characterizes the pivotal roles of the positive feedback loop between RFC4 and NICD1 in coupling NSCLC metastasis and stemness properties and suggests its therapeutic and diagnostic/prognostic potential for NSCLC therapy.

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A Theoretical Approach to Coupling the Epithelial-Mesenchymal Transition (EMT) to Extracellular Matrix (ECM) Stiffness via LOXL2

Cancers ◽

10.3390/cancers13071609 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1609

Author(s):

Youyuan Deng ◽

Priyanka Chakraborty ◽

Mohit Kumar Jolly ◽

Herbert Levine

Keyword(s):

Extracellular Matrix ◽

Cancer Progression ◽

Positive Feedback ◽

Feedback Loop ◽

Epithelial Mesenchymal Transition ◽

Critical Role ◽

Cross Linking ◽

Positive Feedback Loop ◽

Mesenchymal Transition ◽

The Impact

The epithelial-mesenchymal transition (EMT) plays a critical role in cancer progression, being responsible in many cases for the onset of the metastatic cascade and being integral in the ability of cells to resist drug treatment. Most studies of EMT focus on its induction via chemical signals such as TGF-β or Notch ligands, but it has become increasingly clear that biomechanical features of the microenvironment such as extracellular matrix (ECM) stiffness can be equally important. Here, we introduce a coupled feedback loop connecting stiffness to the EMT transcription factor ZEB1, which acts via increasing the secretion of LOXL2 that leads to increased cross-linking of collagen fibers in the ECM. This increased cross-linking can effectively increase ECM stiffness and increase ZEB1 levels, thus setting a positive feedback loop between ZEB1 and ECM stiffness. To investigate the impact of this non-cell-autonomous effect, we introduce a computational approach capable of connecting LOXL2 concentration to increased stiffness and thereby to higher ZEB1 levels. Our results indicate that this positive feedback loop, once activated, can effectively lock the cells in a mesenchymal state. The spatial-temporal heterogeneity of the LOXL2 concentration and thus the mechanical stiffness also has direct implications for migrating cells that attempt to escape the primary tumor.

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