scholarly journals A theoretical approach to coupling the epithelial-mesenchymal transition (EMT) to extracellular matrix (ECM) stiffness via LOXL2

2021 ◽  
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

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.

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

Cancers ◽  
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.

scholarly journals AKR1B1 promotes basal-like breast cancer progression by a positive feedback loop that activates the EMT program

2017 ◽  
Vol 214 (4) ◽  
pp. 1065-1079 ◽  
Author(s):  
Xuebiao Wu ◽  
Xiaoli Li ◽  
Qiang Fu ◽  
Qianhua Cao ◽  
Xingyu Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Progression ◽  
Positive Feedback ◽  
Poor Prognosis ◽  
Feedback Loop ◽  
Epithelial Mesenchymal Transition ◽  
Breast Cancer Patients ◽  
Positive Feedback Loop ◽  
Mesenchymal Transition ◽  
Basal Like Breast Cancer

Basal-like breast cancer (BLBC) is associated with high-grade, distant metastasis and poor prognosis. Elucidating the determinants of aggressiveness in BLBC may facilitate the development of novel interventions for this challenging disease. In this study, we show that aldo-keto reductase 1 member B1 (AKR1B1) overexpression highly correlates with BLBC and predicts poor prognosis in breast cancer patients. Mechanistically, Twist2 transcriptionally induces AKR1B1 expression, leading to nuclear factor κB (NF-κB) activation. In turn, NF-κB up-regulates Twist2 expression, thereby fulfilling a positive feedback loop that activates the epithelial–mesenchymal transition program and enhances cancer stem cell (CSC)–like properties in BLBC. AKR1B1 expression promotes, whereas AKR1B1 knockdown inhibits, tumorigenicity and metastasis. Importantly, epalrestat, an AKR1B1 inhibitor that has been approved for the treatment of diabetic complications, significantly suppresses CSC properties, tumorigenicity, and metastasis of BLBC cells. Together, our study identifies AKR1B1 as a key modulator of tumor aggressiveness and suggests that pharmacologic inhibition of AKR1B1 has the potential to become a valuable therapeutic strategy for BLBC.

scholarly journals Persistent activation of STAT 3 by PIM 2‐driven positive feedback loop for epithelial‐mesenchymal transition in breast cancer

2015 ◽  
Vol 106 (6) ◽  
pp. 718-725 ◽  
Author(s):  
Nizam Uddin ◽  
Rae‐Kwon Kim ◽  
Ki‐Chun Yoo ◽  
Young‐Heon Kim ◽  
Yan‐Hong Cui ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Epithelial Mesenchymal Transition ◽  
Positive Feedback Loop ◽  
Mesenchymal Transition

scholarly journals The paracrine induction of prostate cancer progression by caveolin-1

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Chun-Jung Lin ◽  
Eun-Jin Yun ◽  
U-Ging Lo ◽  
Yu-Ling Tai ◽  
Su Deng ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cell ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Neuroendocrine Differentiation ◽  
Small Subset ◽  
Castration Resistant Prostate Cancer ◽  
Mesenchymal Transition ◽  
The Impact

Abstract A subpopulation of cancer stem cells (CSCs) plays a critical role of cancer progression, recurrence, and therapeutic resistance. Many studies have indicated that castration-resistant prostate cancer (CRPC) is associated with stem cell phenotypes, which could further promote neuroendocrine transdifferentiation. Although only a small subset of genetically pre-programmed cells in each organ has stem cell capability, CSCs appear to be inducible among a heterogeneous cancer cell population. However, the inductive mechanism(s) leading to the emergence of these CSCs are not fully understood in CRPC. Tumor cells actively produce, release, and utilize exosomes to promote cancer development and metastasis, cancer immune evasion as well as chemotherapeutic resistance; the impact of tumor-derived exosomes (TDE) and its cargo on prostate cancer (PCa) development is still unclear. In this study, we demonstrate that the presence of Cav-1 in TDE acts as a potent driver to induce CSC phenotypes and epithelial–mesenchymal transition in PCa undergoing neuroendocrine differentiation through NFκB signaling pathway. Furthermore, Cav-1 in mCRPC-derived exosomes is capable of inducing radio- and chemo-resistance in recipient cells. Collectively, these data support Cav-1 as a critical driver for mCRPC progression.

MYOCD and SMAD3/SMAD4 form a positive feedback loop and drive TGF-β-induced epithelial–mesenchymal transition in non-small cell lung cancer

Oncogene ◽  
2020 ◽  
Vol 39 (14) ◽  
pp. 2890-2904 ◽  
Author(s):  
Xin Tong ◽  
Shengjie Wang ◽  
Zhe Lei ◽  
Chang Li ◽  
Cuijuan Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Epithelial Mesenchymal Transition ◽  
Small Cell ◽  
Small Cell Lung ◽  
Positive Feedback Loop ◽  
Mesenchymal Transition

scholarly journals LINC00511 contributes to glioblastoma tumorigenesis and epithelial‐mesenchymal transition via LINC00511/miR‐524‐5p/YB1/ZEB1 positive feedback loop

2019 ◽  
Vol 24 (2) ◽  
pp. 1474-1487 ◽  
Author(s):  
Xiaoliu Du ◽  
Yiming Tu ◽  
Shuang Liu ◽  
Pengzhan Zhao ◽  
Zhongyuan Bao ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Epithelial Mesenchymal Transition ◽  
Positive Feedback Loop ◽  
Mesenchymal Transition
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