Shyama Nandakumar - Academia.edu (original) (raw)

Uploads

Papers by Shyama Nandakumar

Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with th... more Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with the accumulation of damage over the course of an animal’s lifespan. How long-lived cells deal with ageing-related damage is poorly understood. Here we show that polyploid cells accumulate in the adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid in the adult Drosophila brain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in adult Drosophila melanogaster brains.

Frontiers in Cell and Developmental Biology, 2021

Terminally differentiated cells of the nervous system have long been considered to be in a stable... more Terminally differentiated cells of the nervous system have long been considered to be in a stable non-cycling state and are often considered to be permanently in G0. Exit from the cell cycle during development is often coincident with the differentiation of neurons, and is critical for neuronal function. But what happens in long lived postmitotic tissues that accumulate cell damage or suffer cell loss during aging? In other contexts, cells that are normally non-dividing or postmitotic can or re-enter the cell cycle and begin replicating their DNA to facilitate cellular growth in response to cell loss. This leads to a state called polyploidy, where cells contain multiple copies of the genome. A growing body of literature from several vertebrate and invertebrate model organisms has shown that polyploidy in the nervous system may be more common than previously appreciated and occurs under normal physiological conditions. Moreover, it has been found that neuronal polyploidization can pl...

Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with th... more Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with the accumulation of damage over the course of an animal’s lifespan. How long-lived cells deal with ageing-related damage is poorly understood. Here we show that polyploid cells accumulate in the ageing adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid with age in the adult Drosophila brain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region with age. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in ageing Drosophila melanogaster brains.

The Drosophila melanogaster accessory gland is a functional analog of the mammalian prostate made... more The Drosophila melanogaster accessory gland is a functional analog of the mammalian prostate made up of two secretory epithelial cell types, termed main and secondary cells. This tissue is responsible for making and secreting seminal fluid proteins and other molecules that contribute to successful reproduction. Here, we show that similar to the mammalian prostate, this tissue grows with age. We find that the adult accessory gland grows in part via endocycles to increase DNA content and cell size. The differentiated, bi-nucleated main cells remain poised to endocycle in the adult gland, and tissue damage or upregulation of signals that promote growth are sufficient to trigger dramatic endocycling leading to increases in cell size and ploidy, independent of mating status. Our data establishes that the adult accessory gland is not quiescent, but instead uses endocycles to maintain accessory gland function throughout the fruit fly lifespan.

Scientific Reports

Intravasation and extravasation of cancer cells through blood/lymph vessel endothelium are essent... more Intravasation and extravasation of cancer cells through blood/lymph vessel endothelium are essential steps during metastasis. Successful invasion requires coordinated tumor-endothelial crosstalk, utilizing mechanochemical signaling to direct cytoskeletal rearrangement for transmigration of cancer cells. However, mechanisms underlying physical interactions are difficult to observe due to the lack of experimental models easily combined with theoretical models that better elucidate these pathways. We have previously demonstrated that an engineered 3D in vitro endothelial-epithelial co-culture system can be used to isolate both molecular and physical tumor-endothelial interactions in a platform that is easily modeled, quantified, and probed for experimental investigation. Using this platform with mathematical modeling, we show that breast metastatic cells display unique behavior with the endothelium, exhibiting a 3.2-fold increase in interaction with the endothelium and a 61-fold increase in elongation compared to normal breast epithelial cells. our mathematical model suggests energetic favorability for cellular deformation prior to breeching endothelial junctions, expending less energy as compared to undeformed cells, which is consistent with the observed phenotype. Finally, we show experimentally that pharmacological inhibition of the cytoskeleton can disrupt the elongatation and alignment of metastatic cells with endothelial tubes, reverting to a less invasive phenotype. Mathematical models are useful tools to simplify complex systems in order to better understand physiological dynamics of biological processes. Cancer metastasis is a complex and multifaceted process that involves changes at genetic, mechanochemical, and environmental levels. As a result of this complexity, coupling experimental models with mathematical models presents a robust way to mimic, quantify, and describe tumor behavior. Furthermore, mathematical models can be used to support and validate hypotheses and experimental results. Using mathematical models, we can better understand the factors governing complex processes by stripping them down to the most influential variables. Mathematical and computational models are used widely in cell biology on scales ranging from gene expression to cell population dynamics 1-4. Several properties intrinsic to the tumor 5,6 , as well as factors governed by reciprocal signaling 7-10 between the extra cellular matrix and the tumor, have been implicated in increased invasiveness. However, metastasis also involves the interaction between the endothelium and tumor cells. It has been observed that both metastatic cells and the endothelium undergo physical changes that are essential to metastasis. For example, metastatic breast epithelial cells decrease the stiffness of endothelial cells which is believed to enhance epithelial cell transmigration 11. Similarly, metastatic cells have been found to be 80% more compliant than benign cells, and this decrease in cell stiffness may also enhance the ability of these cells to successfully cross the endothelial cell barrier 12,13. It is clear that reciprocal interactions between the two cell types is critical for invasion 14. Successful invasion of metastatic cells into an endothelial vessel requires a coordinated dance of chemical and mechanical signals that control dynamic cellular processes such as cellular membrane extension 15,16 , membrane adhesion, and cellular migration 17. Biological processes have been previously described using hyperelastic and viscoelastic models to mathematically characterize the physical behavior of tissue, cells, and biopolymers 18,19. Characterizing biomaterials as such

Nature Communications, 2015

2015. "Physical nanoscale conduitmediated communication between tumour cells and the endothelium ... more 2015. "Physical nanoscale conduitmediated communication between tumour cells and the endothelium modulates endothelial phenotype." Nature communications 6 (1): 8671.

Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with th... more Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with the accumulation of damage over the course of an animal’s lifespan. How long-lived cells deal with ageing-related damage is poorly understood. Here we show that polyploid cells accumulate in the adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid in the adult Drosophila brain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in adult Drosophila melanogaster brains.

Frontiers in Cell and Developmental Biology, 2021

Terminally differentiated cells of the nervous system have long been considered to be in a stable... more Terminally differentiated cells of the nervous system have long been considered to be in a stable non-cycling state and are often considered to be permanently in G0. Exit from the cell cycle during development is often coincident with the differentiation of neurons, and is critical for neuronal function. But what happens in long lived postmitotic tissues that accumulate cell damage or suffer cell loss during aging? In other contexts, cells that are normally non-dividing or postmitotic can or re-enter the cell cycle and begin replicating their DNA to facilitate cellular growth in response to cell loss. This leads to a state called polyploidy, where cells contain multiple copies of the genome. A growing body of literature from several vertebrate and invertebrate model organisms has shown that polyploidy in the nervous system may be more common than previously appreciated and occurs under normal physiological conditions. Moreover, it has been found that neuronal polyploidization can pl...

Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with th... more Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with the accumulation of damage over the course of an animal’s lifespan. How long-lived cells deal with ageing-related damage is poorly understood. Here we show that polyploid cells accumulate in the ageing adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid with age in the adult Drosophila brain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region with age. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in ageing Drosophila melanogaster brains.

The Drosophila melanogaster accessory gland is a functional analog of the mammalian prostate made... more The Drosophila melanogaster accessory gland is a functional analog of the mammalian prostate made up of two secretory epithelial cell types, termed main and secondary cells. This tissue is responsible for making and secreting seminal fluid proteins and other molecules that contribute to successful reproduction. Here, we show that similar to the mammalian prostate, this tissue grows with age. We find that the adult accessory gland grows in part via endocycles to increase DNA content and cell size. The differentiated, bi-nucleated main cells remain poised to endocycle in the adult gland, and tissue damage or upregulation of signals that promote growth are sufficient to trigger dramatic endocycling leading to increases in cell size and ploidy, independent of mating status. Our data establishes that the adult accessory gland is not quiescent, but instead uses endocycles to maintain accessory gland function throughout the fruit fly lifespan.

Scientific Reports

Intravasation and extravasation of cancer cells through blood/lymph vessel endothelium are essent... more Intravasation and extravasation of cancer cells through blood/lymph vessel endothelium are essential steps during metastasis. Successful invasion requires coordinated tumor-endothelial crosstalk, utilizing mechanochemical signaling to direct cytoskeletal rearrangement for transmigration of cancer cells. However, mechanisms underlying physical interactions are difficult to observe due to the lack of experimental models easily combined with theoretical models that better elucidate these pathways. We have previously demonstrated that an engineered 3D in vitro endothelial-epithelial co-culture system can be used to isolate both molecular and physical tumor-endothelial interactions in a platform that is easily modeled, quantified, and probed for experimental investigation. Using this platform with mathematical modeling, we show that breast metastatic cells display unique behavior with the endothelium, exhibiting a 3.2-fold increase in interaction with the endothelium and a 61-fold increase in elongation compared to normal breast epithelial cells. our mathematical model suggests energetic favorability for cellular deformation prior to breeching endothelial junctions, expending less energy as compared to undeformed cells, which is consistent with the observed phenotype. Finally, we show experimentally that pharmacological inhibition of the cytoskeleton can disrupt the elongatation and alignment of metastatic cells with endothelial tubes, reverting to a less invasive phenotype. Mathematical models are useful tools to simplify complex systems in order to better understand physiological dynamics of biological processes. Cancer metastasis is a complex and multifaceted process that involves changes at genetic, mechanochemical, and environmental levels. As a result of this complexity, coupling experimental models with mathematical models presents a robust way to mimic, quantify, and describe tumor behavior. Furthermore, mathematical models can be used to support and validate hypotheses and experimental results. Using mathematical models, we can better understand the factors governing complex processes by stripping them down to the most influential variables. Mathematical and computational models are used widely in cell biology on scales ranging from gene expression to cell population dynamics 1-4. Several properties intrinsic to the tumor 5,6 , as well as factors governed by reciprocal signaling 7-10 between the extra cellular matrix and the tumor, have been implicated in increased invasiveness. However, metastasis also involves the interaction between the endothelium and tumor cells. It has been observed that both metastatic cells and the endothelium undergo physical changes that are essential to metastasis. For example, metastatic breast epithelial cells decrease the stiffness of endothelial cells which is believed to enhance epithelial cell transmigration 11. Similarly, metastatic cells have been found to be 80% more compliant than benign cells, and this decrease in cell stiffness may also enhance the ability of these cells to successfully cross the endothelial cell barrier 12,13. It is clear that reciprocal interactions between the two cell types is critical for invasion 14. Successful invasion of metastatic cells into an endothelial vessel requires a coordinated dance of chemical and mechanical signals that control dynamic cellular processes such as cellular membrane extension 15,16 , membrane adhesion, and cellular migration 17. Biological processes have been previously described using hyperelastic and viscoelastic models to mathematically characterize the physical behavior of tissue, cells, and biopolymers 18,19. Characterizing biomaterials as such

Nature Communications, 2015

2015. "Physical nanoscale conduitmediated communication between tumour cells and the endothelium ... more 2015. "Physical nanoscale conduitmediated communication between tumour cells and the endothelium modulates endothelial phenotype." Nature communications 6 (1): 8671.