Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment re... more Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the b...
Proteoglycans are a diverse group of molecules which are characterized by a central protein backb... more Proteoglycans are a diverse group of molecules which are characterized by a central protein backbone that is decorated with a variety of linear sulfated glycosaminoglycan side chains. Proteoglycans contribute significantly to the biochemical and mechanical properties of the interstitial extracellular matrix where they modulate cellular behavior by engaging transmembrane receptors. Proteoglycans also comprise a major component of the cellular glycocalyx to influence transmembrane receptor structure/function and mechanosignaling. Through their ability to initiate biochemical and mechanosignaling in cells, proteoglycans elicit profound effects on proliferation, adhesion and migration. Pathologies including cancer and cardiovascular disease are characterized by perturbed expression of proteoglycans where they compromise cell and tissue behavior by stiffening the extracellular matrix and increasing the bulkiness of the glycocalyx. Increasing evidence indicates that a bulky glycocalyx and...
Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the ... more Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programmed cell death. The biochemical milieu regulates mitochondrial function and contributes to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of ageing. Extracellular matrix stiffness and cytoskeletal tension are also altered in cancer and in aged tissues. We determined that cytoskeletal tension elicits a mitochondrial stress response that modifies mitochondrial function via SLC9A1-dependent ion exchange and HSF1-dependent transcription. Our data indicate that this cytoskeletal tension-induced mitochondrial stress response, termed mitohormesis, adaptively tunes mitochondrial metabolism and facilitates oxidative stress resilience. These findings demonstrate that cytoskeletal tension regulates mitochondrial function and suggests that mechanical forces influence tissue behavior by modulating mitochondrial metabolism.One Sen...
Buffone and Weaver discuss how the structure of the backbones and glycans of the tumor glycocalyx... more Buffone and Weaver discuss how the structure of the backbones and glycans of the tumor glycocalyx governs cell–matrix interactions and directs cancer progression.
Philosophical Transactions of the Royal Society B: Biological Sciences
A growing body of work describes how physical forces in and around cells affect their growth, pro... more A growing body of work describes how physical forces in and around cells affect their growth, proliferation, migration, function and differentiation into specialized types. How cells receive and respond biochemically to mechanical signals is a process termed mechanotransduction. Disease may arise if a disruption occurs within this mechanism of sensing and interpreting mechanics. Cancer, cardiovascular diseases and developmental defects, such as during the process of neural tube formation, are linked to changes in cell and tissue mechanics. A breakdown in normal tissue and cellular forces activates mechanosignalling pathways that affect their function and can promote disease progression. The recent advent of high-resolution techniques enables quantitative measurements of mechanical properties of the cell and its extracellular matrix, providing insight into how mechanotransduction is regulated. In this review, we will address the standard methods and new technologies available to prop...
To address cancer as a multifaceted adaptive system, the increasing momentum for cross-disciplina... more To address cancer as a multifaceted adaptive system, the increasing momentum for cross-disciplinary connectivity between cancer biologists, physical scientists, mathematicians, chemists, biomedical engineers, computer scientists, clinicians, and advocates is fueling the emergence of new scientific frontiers, principles, and opportunities within physical sciences and oncology. In parallel to highlighting the advances, challenges, and acceptance of advocates as credible contributors, we offer recommendations for addressing real world hurdles in advancing equitable partnerships among advocacy stakeholders.
Morphogenesis involves interactions of asymmetric cell populations to form complex multicellular ... more Morphogenesis involves interactions of asymmetric cell populations to form complex multicellular patterns and structures comprised of distinct cell types. However, current methods to model morphogenic events lack control over cell-type co-emergence and offer little capability to selectively perturb specific cell subpopulations. Our system interrogates cell-cell interactions and multicellular organization within human induced pluripotent stem cell (hiPSC) colonies. We examined effects of induced mosaic knockdown of molecular regulators of cortical tension (ROCK1) and cell-cell adhesion (CDH1) with CRISPR interference. Mosaic knockdown of ROCK1 or CDH1 resulted in differential patterning within hiPSC colonies due to cellular self-organization, while retaining an epithelial pluripotent phenotype. Knockdown induction stimulates a transient wave of differential gene expression within the mixed populations that stabilized in coordination with observed self-organization. Mosaic patterning ...
The discoidin domain receptor 1 (DDR1) is overexpressed in breast carcinoma cells. Low DDR1 expre... more The discoidin domain receptor 1 (DDR1) is overexpressed in breast carcinoma cells. Low DDR1 expression is associated with worse relapse-free survival, reflecting its controversial role in cancer progression. We detected DDR1 on luminal cells but not on myoepithelial cells of DDR1 mice. We found that DDR1 loss compromises cell adhesion, consistent with data that older DDR1 mammary glands had more basal/myoepithelial cells. Basal cells isolated from older mice exerted higher traction forces than the luminal cells, in agreement with increased mammary branches observed in older DDR1 mice and higher branching by their isolated organoids. When we crossed DDR1 mice with MMTV-PyMT mice, the PyMT/DDR1 mammary tumors grew faster and had increased epithelial tension and matricellular fibrosis with a more basal phenotype and increased lung metastases. DDR1 deletion induced basal differentiation of CD90CD24 cancer cells, and the increase in basal cells correlated with tumor cell mitoses. K14 bas...
Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including th... more Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including the aggressive primary brain tumor glioblastoma (GBM). It remains unclear how fluid dynamics impacts tumor progression and can be targeted therapeutically. To address this issue, a novel telemetry-based approach was developed to measure changes in IFP during progression of GBM xenografts. Antisecretory factor (AF) is an endogenous protein that displays antisecretory effects in animals and patients. Here, endogenous induction of AF protein or exogenous administration of AF peptide reduced IFP and increased drug uptake in GBM xenografts. AF inhibited cell volume regulation of GBM cells, an effect that was phenocopiedby the sodium-potassium-chloride cotransporter 1 (SLC12A2/NKCC1) inhibitor bumetanide. As a result, AF induced apoptosis and increased survival in GBM models., the ability of AF to reduce GBM cell proliferation was phenocopied by bumetanide and NKCC1 knockdown. Next, AF's abi...
Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment re... more Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the b...
Proteoglycans are a diverse group of molecules which are characterized by a central protein backb... more Proteoglycans are a diverse group of molecules which are characterized by a central protein backbone that is decorated with a variety of linear sulfated glycosaminoglycan side chains. Proteoglycans contribute significantly to the biochemical and mechanical properties of the interstitial extracellular matrix where they modulate cellular behavior by engaging transmembrane receptors. Proteoglycans also comprise a major component of the cellular glycocalyx to influence transmembrane receptor structure/function and mechanosignaling. Through their ability to initiate biochemical and mechanosignaling in cells, proteoglycans elicit profound effects on proliferation, adhesion and migration. Pathologies including cancer and cardiovascular disease are characterized by perturbed expression of proteoglycans where they compromise cell and tissue behavior by stiffening the extracellular matrix and increasing the bulkiness of the glycocalyx. Increasing evidence indicates that a bulky glycocalyx and...
Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the ... more Mitochondria control eukaryotic cell fate by producing the energy needed to support life and the signals required to execute programmed cell death. The biochemical milieu regulates mitochondrial function and contributes to the dysfunctional mitochondrial phenotypes implicated in cancer and the morbidities of ageing. Extracellular matrix stiffness and cytoskeletal tension are also altered in cancer and in aged tissues. We determined that cytoskeletal tension elicits a mitochondrial stress response that modifies mitochondrial function via SLC9A1-dependent ion exchange and HSF1-dependent transcription. Our data indicate that this cytoskeletal tension-induced mitochondrial stress response, termed mitohormesis, adaptively tunes mitochondrial metabolism and facilitates oxidative stress resilience. These findings demonstrate that cytoskeletal tension regulates mitochondrial function and suggests that mechanical forces influence tissue behavior by modulating mitochondrial metabolism.One Sen...
Buffone and Weaver discuss how the structure of the backbones and glycans of the tumor glycocalyx... more Buffone and Weaver discuss how the structure of the backbones and glycans of the tumor glycocalyx governs cell–matrix interactions and directs cancer progression.
Philosophical Transactions of the Royal Society B: Biological Sciences
A growing body of work describes how physical forces in and around cells affect their growth, pro... more A growing body of work describes how physical forces in and around cells affect their growth, proliferation, migration, function and differentiation into specialized types. How cells receive and respond biochemically to mechanical signals is a process termed mechanotransduction. Disease may arise if a disruption occurs within this mechanism of sensing and interpreting mechanics. Cancer, cardiovascular diseases and developmental defects, such as during the process of neural tube formation, are linked to changes in cell and tissue mechanics. A breakdown in normal tissue and cellular forces activates mechanosignalling pathways that affect their function and can promote disease progression. The recent advent of high-resolution techniques enables quantitative measurements of mechanical properties of the cell and its extracellular matrix, providing insight into how mechanotransduction is regulated. In this review, we will address the standard methods and new technologies available to prop...
To address cancer as a multifaceted adaptive system, the increasing momentum for cross-disciplina... more To address cancer as a multifaceted adaptive system, the increasing momentum for cross-disciplinary connectivity between cancer biologists, physical scientists, mathematicians, chemists, biomedical engineers, computer scientists, clinicians, and advocates is fueling the emergence of new scientific frontiers, principles, and opportunities within physical sciences and oncology. In parallel to highlighting the advances, challenges, and acceptance of advocates as credible contributors, we offer recommendations for addressing real world hurdles in advancing equitable partnerships among advocacy stakeholders.
Morphogenesis involves interactions of asymmetric cell populations to form complex multicellular ... more Morphogenesis involves interactions of asymmetric cell populations to form complex multicellular patterns and structures comprised of distinct cell types. However, current methods to model morphogenic events lack control over cell-type co-emergence and offer little capability to selectively perturb specific cell subpopulations. Our system interrogates cell-cell interactions and multicellular organization within human induced pluripotent stem cell (hiPSC) colonies. We examined effects of induced mosaic knockdown of molecular regulators of cortical tension (ROCK1) and cell-cell adhesion (CDH1) with CRISPR interference. Mosaic knockdown of ROCK1 or CDH1 resulted in differential patterning within hiPSC colonies due to cellular self-organization, while retaining an epithelial pluripotent phenotype. Knockdown induction stimulates a transient wave of differential gene expression within the mixed populations that stabilized in coordination with observed self-organization. Mosaic patterning ...
The discoidin domain receptor 1 (DDR1) is overexpressed in breast carcinoma cells. Low DDR1 expre... more The discoidin domain receptor 1 (DDR1) is overexpressed in breast carcinoma cells. Low DDR1 expression is associated with worse relapse-free survival, reflecting its controversial role in cancer progression. We detected DDR1 on luminal cells but not on myoepithelial cells of DDR1 mice. We found that DDR1 loss compromises cell adhesion, consistent with data that older DDR1 mammary glands had more basal/myoepithelial cells. Basal cells isolated from older mice exerted higher traction forces than the luminal cells, in agreement with increased mammary branches observed in older DDR1 mice and higher branching by their isolated organoids. When we crossed DDR1 mice with MMTV-PyMT mice, the PyMT/DDR1 mammary tumors grew faster and had increased epithelial tension and matricellular fibrosis with a more basal phenotype and increased lung metastases. DDR1 deletion induced basal differentiation of CD90CD24 cancer cells, and the increase in basal cells correlated with tumor cell mitoses. K14 bas...
Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including th... more Interstitial fluid pressure (IFP) presents a barrier to drug uptake in solid tumors, including the aggressive primary brain tumor glioblastoma (GBM). It remains unclear how fluid dynamics impacts tumor progression and can be targeted therapeutically. To address this issue, a novel telemetry-based approach was developed to measure changes in IFP during progression of GBM xenografts. Antisecretory factor (AF) is an endogenous protein that displays antisecretory effects in animals and patients. Here, endogenous induction of AF protein or exogenous administration of AF peptide reduced IFP and increased drug uptake in GBM xenografts. AF inhibited cell volume regulation of GBM cells, an effect that was phenocopiedby the sodium-potassium-chloride cotransporter 1 (SLC12A2/NKCC1) inhibitor bumetanide. As a result, AF induced apoptosis and increased survival in GBM models., the ability of AF to reduce GBM cell proliferation was phenocopied by bumetanide and NKCC1 knockdown. Next, AF's abi...
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