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Updated: Jun 29, 2025
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Published on: December 12, 2019
DDR2 signaling and mechanosensing orchestrate neuroblastoma cell fate through different transcriptome mechanisms
Theadora Vessella1, Steven Xiang2, Cong Xiao3,4
1Department of Chemical Engineering, Worcester Polytechnic Institute, MA, USA.
Abstract:
The extracellular matrix (ECM) regulates carcinogenesis by interacting with cancer cells via cell surface receptors. Discoidin Domain Receptor 2 (DDR2) is a collagen-activated receptor implicated in cell survival, growth, and differentiation. Dysregulated DDR2 expression has been identified in various cancer types, making it as a promising therapeutic target. Additionally, cancer cells exhibit mechanosensing abilities, detecting changes in ECM stiffness, which is particularly important for carcinogenesis given the observed ECM stiffening in numerous cancer types. Despite these, whether collagen-activated DDR2 signaling and ECM stiffness-induced mechanosensing exert similar effects on cancer cell behavior and whether they operate through analogous mechanisms remain elusive. To address these questions, we performed bulk RNA sequencing (RNA-seq) on human SH-SY5Y neuroblastoma cells cultured on collagen-coated substrates. Our results show that DDR2 downregulation induces significant changes in the cell transcriptome, with changes in expression of 15% of the genome, specifically affecting the genes associated with cell division and differentiation. We validated the RNA-seq results by showing that DDR2 knockdown redirects the cell fate from proliferation to senescence. Like DDR2 knockdown, increasing substrate stiffness diminishes cell proliferation. Surprisingly, RNA-seq indicates that substrate stiffness has no detectable effect on the transcriptome. Furthermore, DDR2 knockdown influences cellular responses to substrate stiffness changes, highlighting a crosstalk between these two ECM-induced signaling pathways. Based on our results, we propose that the ECM could activate DDR2 signaling and mechanosensing in cancer cells to orchestrate their cell fate through distinct mechanisms, with or without involving gene expression, thus providing novel mechanistic insights into cancer progression.
Insights
Extracellular matrix (ECM) signaling via Discoidin Domain Receptor 2 (DDR2) and ECM stiffness both impact cancer cell proliferation. DDR2 downregulation alters gene expression, while stiffness affects cell fate through distinct, potentially non-transcriptional, mechanisms.
Area of Science:
- Cell Biology
- Cancer Research
- Biophysics
Background:
- The extracellular matrix (ECM) plays a crucial role in regulating cancer progression through cell surface receptors like Discoidin Domain Receptor 2 (DDR2).
- Cancer cells possess mechanosensing capabilities, detecting ECM stiffness, a factor often altered during carcinogenesis.
- The interplay between DDR2 signaling and ECM mechanosensing in cancer cell behavior remains largely unexplored.
Purpose of the Study:
- To investigate whether collagen-activated DDR2 signaling and ECM stiffness-induced mechanosensing elicit similar effects on cancer cell behavior.
- To determine if these two ECM-mediated pathways operate through analogous molecular mechanisms.
- To elucidate the potential crosstalk between DDR2 signaling and mechanosensing in cancer cells.
Main Methods:
- Bulk RNA sequencing (RNA-seq) was performed on human SH-SY5Y neuroblastoma cells cultured on collagen-coated substrates.
- Experimental manipulations included DDR2 downregulation (knockdown) and varying substrate stiffness.
- Cellular responses, including proliferation, senescence, and transcriptomic changes, were analyzed.
Main Results:
- DDR2 downregulation significantly altered the cell transcriptome, affecting genes involved in cell division and differentiation, and redirected cell fate from proliferation to senescence.
- Increased substrate stiffness reduced cell proliferation, but surprisingly, did not induce detectable transcriptomic changes via RNA-seq.
- DDR2 knockdown modulated cellular responses to substrate stiffness, indicating a crosstalk between DDR2 signaling and mechanosensing.
Conclusions:
- The ECM can activate DDR2 signaling and mechanosensing in cancer cells to orchestrate cell fate.
- These pathways may operate through distinct mechanisms, potentially independent of gene expression changes, offering new insights into cancer progression.
- Understanding this crosstalk provides novel mechanistic insights into how the ECM influences cancer cell behavior.
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