Integrin-linked kinase tunes cell–cell and cell-matrix adhesions to regulate the switch between apoptosis and EMT downstream of TGFβ1

Kilinc, Ayse Nihan; Han, Sang-Ok; Barrett, Lena A.; Anandasivam, Niroshan; Nelson, Celeste M.

doi:10.1091/mbc.e20-02-0092

Cited by 27 publications

(23 citation statements)

References 39 publications

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“…, 2018 ). Furthermore, we recently found that ILK is required for induction of EMT in mammary epithelial cells cultured on stiff substrata ( Kilinc et al. , 2021 ).…”

Section: Resultsmentioning

confidence: 99%

“…The focal adhesion component integrin-linked kinase (ILK) is upregulated in NMuMG cells cultured on stiff substrata (Han et al, 2018). Furthermore, we recently found that ILK is required for induction of EMT in mammary epithelial cells cultured on stiff substrata (Kilinc et al, 2021).…”

Section: The Stiffness Of the Microenvironment Regulates Mnc In Part Through Integrin-linked Kinase (Ilk)mentioning

confidence: 99%

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Substratum stiffness signals through integrin-linked kinase and β1-integrin to regulate midbody proteins and abscission during EMT

Rabie

Zhang

Dunn

et al. 2021

MBoC

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Abscission is the final stage of cytokinesis during which the parent cell physically separates to yield two identical daughters. Failure of abscission results in multinucleation, a sign of genomic instability and a precursor to aneuploidy, enabling characteristics of neoplastic progression. Induction of epithelial-mesenchymal transition (EMT) causes multinucleation in mammary epithelial cells cultured on stiff microenvironments that have mechanical properties similar to those found in breast tumors, but not on soft microenvironments reminiscent of the normal mammary gland. Here, we report that on stiff microenvironments, EMT signaling through Snail upregulates the midbody-associated proteins septin-6, Mklp1, and anillin, leading to abscission failure and multinucleation. To uncover the mechanism by which stiff microenvironments promote multinucleation in cells undergoing EMT, we investigated the role of cell-matrix adhesion through β1-integrin and integrin-linked kinase (ILK). We found that ILK expression, but not kinase activity, is required for EMT-associated multinucleation in cells on stiff microenvironments. Conversely, increasing focal adhesions by expressing an autoclustering β1-integrin promotes multinucleation in cells on soft microenvironments. Our data suggest that signaling through focal adhesions causes failure of cytokinesis in cells actively undergoing EMT. These results highlight the importance of tissue mechanics and adhesion in regulating the cellular response to EMT inducers.

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“…, 2018 ). Furthermore, we recently found that ILK is required for induction of EMT in mammary epithelial cells cultured on stiff substrata ( Kilinc et al. , 2021 ).…”

Section: Resultsmentioning

confidence: 99%

Section: The Stiffness Of the Microenvironment Regulates Mnc In Part Through Integrin-linked Kinase (Ilk)mentioning

confidence: 99%

Substratum stiffness signals through integrin-linked kinase and β1-integrin to regulate midbody proteins and abscission during EMT

Rabie

Zhang

Dunn

et al. 2021

MBoC

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“…ILK promotes phosphorylation of and subsequent inactivation of GSK3β, resulting in regulation of cyclin D1 and activation of transcription factors (TF), including activator protein-1 (AP-1), β-catenin/T-cell factor (Tcf), and cAMP response element-binding protein (CREB). β-catenin stabilization results in the regulation The ILK-PINCH-Parvin (IPP) complex acts as a structural and signaling hub downstream of integrin-mediated engagement with collagen-rich, stiff ECM [12] to promote processes critical for metastasis, including cytoskeletal dynamics, EMT, migration, and invasion. ILK also promotes phosphorylation of key target proteins essential to processes critical for cancer progression, including survival, proliferation, migration, invasion, and EMT.…”

Section: Ilk Functions As a Signaling Node Within Focal Adhesionsmentioning

confidence: 99%

“…The substrata of primary solid tumors are generally stiffer than adjacent normal tissue, while breast cancer metastases often develop in tissues of less stiff composition, such as the lung, liver, and brain. A series of studies employing engineered synthetic culture substrata that emulate the mechanical properties of relatively soft, compliant tissue matrices and stiff matrices common in solid tumors have revealed a critical role of ILK as a mechanotransducer in promoting metastatic progression (Figure 1) [12,[27][28][29][30][31].…”

Section: Mechanotransduction Matrix Stiffness and Invasionmentioning

confidence: 99%

New Perspectives on the Role of Integrin-Linked Kinase (ILK) Signaling in Cancer Metastasis

McDonald¹,

Dedhar

2022

Cancers

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Cancer metastasis is a major barrier to the long-term survival of cancer patients. In cancer cells, integrin engagement downstream of cell-extracellular matrix (ECM) interactions results in the recruitment of cytoskeletal and signaling molecules to form multi-protein complexes to promote processes critical for metastasis. One of the major functional components of these complexes is Integrin Linked Kinase (ILK). Here, we discuss recent advances in our understanding of the importance of ILK as a signaling effector in processes linked to tumor progression and metastasis. New mechanistic insights as to the role of ILK in cellular plasticity, epithelial mesenchymal transition (EMT), migration, and invasion, including the impact of ILK on the formation of invadopodia, filopodia-like protrusions (FLPs), and Neutrophil Extracellular Trap (NET)-induced motility are highlighted. Recent findings detailing the contribution of ILK to therapeutic resistance and the importance of ILK as a potentially therapeutically tractable vulnerability in both solid tumors and hematologic malignancies are discussed. Indeed, pharmacologic inhibition of ILK activity using specific small molecule inhibitors is effective in curtailing the contribution of ILK to these processes, potentially offering a novel therapeutic avenue for inhibiting critical steps in the metastatic cascade leading to reduced drug resistance and increased therapeutic efficacy.

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“…The similarity between EMT and de-differentiation programs extends beyond cell-intrinsic alterations and impacts cell-extrinsic changes as well. EMT often leads to varied extracellular matrix (ECM) stiffness and density (Deng et al, 2021; Fattet et al, 2020; Kumar et al, 2014) and altered cell-matrix and cell-cell interactions (Bianchi et al, 2010; Kilinc et al, 2021). In melanoma, acquisition of de-differentiated and invasive phenotypes is often accompanied with changes in composition and physical properties of ECM, and modified cell-matrix interactions and cell morphology (Kaur et al, 2019; Long et al, 2019; Spoerri et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis

Pillai

Rajaram

Thakur

et al. 2022

Preprint

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Epithelial to mesenchymal transition (EMT) is a well-studied hallmark of epithelial-like cancers that is characterized by loss of epithelial markers and gain of mesenchymal markers. Interestingly, melanoma, which is derived from melanocytes of the skin, also undergo phenotypic plasticity toward mesenchymal-like phenotypes under the influence of various micro-environmental cues. Our study connects EMT to the phenomenon of de-differentiation (i.e., transition from proliferative to more invasive phenotypes) observed in melanoma cells during drug treatment. By analyzing 78 publicly available transcriptomic melanoma datasets, we found that de-differentiation in melanoma is accompanied by upregulation of mesenchymal genes, but not necessarily a concomitant loss of an epithelial program, suggesting a more 'one-dimensional' EMT that leads to a hybrid epithelial/ mesenchymal phenotype. Samples lying in the hybrid epithelial/mesenchymal phenotype also correspond to the intermediate phenotypes in melanoma along the proliferative-invasive axis - neural crest and transitory ones. Interestingly, as melanoma cells progress along the invasive axis, the mesenchymal signature does not increase monotonically. Instead, we observe a peak in mesenchymal scores followed by a decline, as cells further de-differentiate. This biphasic response recapitulates the dynamics of melanocyte development, suggesting close interactions among genes controlling differentiation and mesenchymal programs in melanocytes. Similar trends were noted for metabolic changes often associated with EMT in carcinomas in which progression along mesenchymal axis correlates with the downregulation of oxidative phosphorylation, while largely maintaining glycolytic capacity. Overall, these results provide an explanation for how EMT and de-differentiation axes overlap with respect to their transcriptional and metabolic programs in melanoma.

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Integrin-linked kinase tunes cell–cell and cell-matrix adhesions to regulate the switch between apoptosis and EMT downstream of TGFβ1

Cited by 27 publications

References 39 publications

Substratum stiffness signals through integrin-linked kinase and β1-integrin to regulate midbody proteins and abscission during EMT

Substratum stiffness signals through integrin-linked kinase and β1-integrin to regulate midbody proteins and abscission during EMT

New Perspectives on the Role of Integrin-Linked Kinase (ILK) Signaling in Cancer Metastasis

Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis

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