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Data on the effects of ECM rigidity on actomyosin contractility and invadopodia activity in individual versus pairs of head and neck squamous cell carcinoma cells.

ABSTRACT: Migration through the extracellular matrix (ECM) is essential for cancer cells to escape the primary tumor and invade neighboring tissues with the potential for metastasis [1]. To penetrate tissue barriers, migrating cancer cells degrade the ECM with actin-rich membrane protrusions called invadopodia [2]. We have previously found that invadopodial ECM degradation is regulated by ECM rigidity in a process mediated by contractile forces in individual head and neck squamous cell carcinoma (HNSCC) cells [3], [4]. However, cancer cells often migrate together and interact with each other to alter their actomyosin contractility in response to the biomechanical properties of the ECM [5]. Therefore, we tested whether ECM rigidity promotes biomechanical interactions between cancer cells to enhance proteolytic activity. Using a minimal model of two HNSCC cells in physical contact, we provide data here that actomyosin contractility, invadopodia formation, and ECM degradation increase in response to ECM rigidity when cells are in pairs versus individual cells using traction force and invadopodia assays.

SUBMITTER: Jerrell R

PROVIDER: S-EPMC8671857 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Data on the effects of ECM rigidity on actomyosin contractility and invadopodia activity in individual versus pairs of head and neck squamous cell carcinoma cells.

Jerrell Rachel R Leih Mitchell M Parekh Aron A

Data in brief 20211206

Migration through the extracellular matrix (ECM) is essential for cancer cells to escape the primary tumor and invade neighboring tissues with the potential for metastasis [1]. To penetrate tissue barriers, migrating cancer cells degrade the ECM with actin-rich membrane protrusions called invadopodia [2]. We have previously found that invadopodial ECM degradation is regulated by ECM rigidity in a process mediated by contractile forces in individual head and neck squamous cell carcinoma (HNSCC) c ...[more]

PMID: 34950756

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Project description:Invadopodia are membrane protrusions dynamically assembled by invasive cancer cells in contact with the extracellular matrix (ECM). Invadopodia are enriched by the structural proteins actin and cortactin as well as metalloproteases such as MT1-MMP, whose function is to degrade the surrounding ECM. During metastasis, invadopodia are necessary for cancer cell intravasation and extravasation. Although signaling pathways involved in the assembly and function of invadopodia are well studied, few studies address invadopodia dynamics and how the cell-ECM interactions contribute to cell invasion. Using iterative analysis based on time-lapse microscopy and mathematical modeling of invasive cancer cells, we found that cells oscillate between invadopodia presence and cell stasis-termed the "invadopodia state"-and invadopodia absence during cell translocation-termed the "migration state." Our data suggest that β1-integrin-ECM binding and ECM cross-linking control the duration of each of the two states. By changing the concentration of cross-linkers in two-dimensional and three-dimensional cultures, we generate an ECM in which 0-0.92 of total lysine residues are cross-linked. Using an ECM with a range of cross-linking degrees, we demonstrate that the dynamics of invadopodia-related functions have a biphasic relationship to ECM cross-linking. At intermediate levels of ECM cross-linking (0.39), cells exhibit rapid invadopodia protrusion-retraction cycles and rapid calcium spikes, which lead to more frequent MT1-MMP delivery, causing maximal invadopodia-mediated ECM degradation. In contrast, both extremely high or low levels of cross-linking lead to slower invadopodia-related dynamics and lower ECM degradation. Additionally, β1-integrin inhibition modifies the dynamics of invadopodia-related functions as well as the length of time cells spend in either of the states. Collectively, these data suggest that β1-integrin-ECM binding nonlinearly translates small physical differences in the extracellular environment to differences in the dynamics of cancer cell behaviors. Understanding the conditions under which invadopodia can be reduced by subtle environment-targeting treatments may lead to combination therapies for preventing metastatic spread.

Project description:BackgroundHNSCC presents a significant health challenge due to its high mortality resulting from treatment resistance and locoregional invasion into critical structures in the head and neck region. Understanding the invasion mechanisms of HNSCC has the potential to guide targeted therapies, improving patient survival. Previously, we demonstrated the involvement of doublecortin like kinase 1 (DCLK1) in regulating HNSCC cell invasion. Here, we investigated the hypothesis that DCLK1 modulates proteins within invadopodia, specialized subcellular protrusions that secrete matrix metalloproteinases to degrade the ECM.MethodsWe employed tandem mass tag (TMT)-based proteomics to identify the role of DCLK1 in regulating proteins involved in HNSCC invasion and validated the findings using immunoblotting. The Cancer Genome Atlas (TCGA) database was interrogated to correlate DCLK1 expression with tumor stage, grade, and invasion-associated proteins. In vitro invasion was assessed using a Boyden chamber assay, and immunohistochemistry on patient samples determined DCLK1's distribution within tumors. Gelatin invadopodia assay was used to establish DCLK1 localization to invadopodia related gelatin degradation. Super-resolution confocal microscopy demonstrated colocalization of DCLK1 with invadopodia markers and MMP trafficking proteins. ECM degradation by MMPs in HNSCC cells with wild-type and knockdown DCLK1 was evaluated using a dye-quenched tracer, while gel zymography and MMP array identified secreted proteases. Proximity ligation assay (PLA) and co-immunoprecipitation assays were used to confirm interactions between DCLK1, MMP9, KIF16B, and RAB40B.ResultsProteomic analysis demonstrate DCLK1's role in regulating proteins involved in cytoskeletal and ECM remodeling. Clinically, rising DCLK1 levels correlate with higher histological grade and lymph node metastasis, with heightened expression observed at the leading edge of HNSCC patient tissue. DCLK1 is localized with markers of mature invadopodia including TKS4, TKS5, cortactin, and MT1-MMP. Knockdown of DCLK1 led to reductions in invadopodia numbers and decreased in vitro invasion and ECM degradation. MMP9 colocalizes with DCLK1 within invadopodia structures and its secretion is disrupted by DCLK1 knockdown. Further, PLA and co-immunoprecipitations studies demonstrate DLCK1 complexes with KIF16B and RAB40B enabling trafficking of degradative MMP9 cargo along the invadopodia to degrade local ECM.ConclusionThis work unveils a novel function of DCLK1 in regulating KIF16B and RAB40B to traffic matrix degrading MMP9 cargo to the distal end of the invadopodia facilitating HNSCC invasion.

Project description:BackgroundFerrogenesis was strongly associated with tumorigenesis and development, and activating the ferrogenic process was a novel regimen in treating cancer, especially conventional treatment-resistant cancers. The purpose of the article was to construct a ferroptosis-related long noncoding RNAs (FRlncRNAs) signature, regardless of expression levels to effectively predict prognosis and immunotherapeutic response for head and neck squamous cell carcinoma (HNSCC).MethodsThe RNA-seq data for HNSCC and corresponding clinical information were obtained in the TCGA database, and ferroptosis-related genes (FRGs) were extracted in the ferroptosis database. On this basis, differentially expressed FRlncRNAs (DEFRlncRNAs) pairs were identified through coexpression analysis, differential expression analysis, and a fresh pairing algorithm. Then, a risk assessment model was established with univariate Cox, LASSO, and multivariate Cox regression analysis. Finally, we evaluated the model from various aspects, including survival status, clinicopathological characteristics, infiltration status of immune cells, immune functions, chemotherapeutic sensitivity, immune checkpoint inhibitors (ICIs)-related molecules, and N6-methyladenosine (m6A) mRNA status.ResultWe established a signature of 11-DEFRlncRNA pairs related to the prognosis of HNSCC that had AUC values above 0.75 in the one-, three-, and five-year ROC curves, underscoring the high susceptibility and specifiability of predicting HNSCC prognosis. Survival rates were remarkably higher for the low-risk patients than for the high-risk patients, and the signature was significantly correlated with survival, clinical, T, and N stages. Finally, immune cell infiltration status, immune functions, chemotherapeutic sensitivity, and expression levels of ICIs-related and m6A-related molecules were statistically different among different groups.ConclusionOur study established a novel lncRNA signature, which is independent of specific expression levels, could predict patient prognosis, and might have promising clinical applications in HNCSS.

Dataset Information

Data on the effects of ECM rigidity on actomyosin contractility and invadopodia activity in individual versus pairs of head and neck squamous cell carcinoma cells.

Publications

Data on the effects of ECM rigidity on actomyosin contractility and invadopodia activity in individual versus pairs of head and neck squamous cell carcinoma cells.

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