842 research outputs found
Complexity in cancer stem cells and tumor evolution: towards precision medicine
In this review, we discuss recent advances on the plasticity of cancer stem
cells and highlight their relevance to understand the metastatic process and to
guide therapeutic interventions. Recent results suggest that the strict
hierarchical structure of cancer cell populations advocated by the cancer stem
cell model must be reconsidered since the depletion of cancer stem cells leads
the other tumor cells to switch back into the cancer stem cell phenotype. This
plasticity has important implications for metastasis since migrating cells do
not need to be cancer stem cells in order to seed a metastasis. We also discuss
the important role of the immune system and the microenvironment in modulating
phenotypic switching and suggest possible avenues to exploit our understanding
of this process to develop an effective strategy for precision medicine.Comment: 2 Figures, to appear in Seminars in Cancer Biology, Available online
23 February 201
Conformational mechanism for the stability of microtubule-kinetochore attachments
Regulating the stability of microtubule(MT)-kinetochore attachments is
fundamental to avoiding mitotic errors and ensure proper chromosome segregation
during cell division. While biochemical factors involved in this process have
been identified, its mechanics still needs to be better understood. Here we
introduce and simulate a mechanical model of MT-kinetochore interactions in
which the stability of the attachment is ruled by the geometrical conformations
of curling MT-protofilaments entangled in kinetochore fibrils. The model allows
us to reproduce with good accuracy in vitro experimental measurements of the
detachment times of yeast kinetochores from MTs under external pulling forces.
Numerical simulations suggest that geometrical features of MT-protofilaments
may play an important role in the switch between stable and unstable
attachments
Mechanical Properties of Growing Melanocytic Nevi and the Progression to Melanoma
Melanocytic nevi are benign proliferations that sometimes turn into malignant
melanoma in a way that is still unclear from the biochemical and genetic point
of view. Diagnostic and prognostic tools are then mostly based on dermoscopic
examination and morphological analysis of histological tissues. To investigate
the role of mechanics and geometry in the morpholgical dynamics of melanocytic
nevi, we study a computation model for cell proliferation in a layered
non-linear elastic tissue. Numerical simulations suggest that the morphology of
the nevus is correlated to the initial location of the proliferating cell
starting the growth process and to the mechanical properties of the tissue. Our
results also support that melanocytes are subject to compressive stresses that
fluctuate widely in the nevus and depend on the growth stage. Numerical
simulations of cells in the epidermis releasing matrix metalloproteinases
display an accelerated invasion of the dermis by destroying the basal membrane.
Moreover, we suggest experimentally that osmotic stress and collagen inhibit
growth in primary melanoma cells while the effect is much weaker in metastatic
cells. Knowing that morphological features of nevi might also reflect geometry
and mechanics rather than malignancy could be relevant for diagnostic purpose
Cholesterol impairment contributes to neuroserpin aggregation
Intraneural accumulation of misfolded proteins is a common feature of several
neurodegenerative pathologies including Alzheimer's and Parkinson's diseases,
and Familial Encephalopathy with Neuroserpin Inclusion Bodies (FENIB). FENIB is
a rare disease due to a point mutation in neuroserpin which accelerates protein
aggregation in the endoplasmic reticulum (ER). Here we show that cholesterol
depletion induced either by prolonged exposure to statins or by inhibiting the
sterol regulatory binding-element protein (SREBP) pathway also enhances
aggregation of neuroserpin proteins. These findings can be explained
considering a computational model of protein aggregation under non-equilibrium
conditions, where a decrease in the rate of protein clearance improves
aggregation. Decreasing cholesterol in cell membranes affects their biophysical
properties, including their ability to form the vesicles needed for protein
clearance, as we illustrate by a simple mathematical model. Taken together,
these results suggest that cholesterol reduction induces neuroserpin
aggregation, even in absence of specific neuroserpin mutations. The new
mechanism we uncover could be relevant also for other neurodegenerative
diseases associated with protein aggregation.Comment: 7 figure
Volume changes during active shape fluctuations in cells
Cells modify their volume in response to changes in osmotic pressure but it
is usually assumed that other active shape variations do not involve
significant volume fluctuations. Here we report experiments demonstrating that
water transport in and out of the cell is needed for the formation of blebs,
commonly observed protrusions in the plasma membrane driven by cortex
contraction. We develop and simulate a model of fluid mediated membrane-cortex
deformations and show that a permeable membrane is necessary for bleb formation
which is otherwise impaired. Taken together our experimental and theoretical
results emphasize the subtle balance between hydrodynamics and elasticity in
actively driven cell morphological changes.Comment: Phys. Rev. Lett. in press. 13 pages 4 figures, 9 supplementary
figure
AQP1 Is Not Only a Water Channel: It Contributes to Cell Migration through Lin7/Beta-Catenin
Background: AQP1 belongs to aquaporins family, water-specific, membrane-channel proteins expressed in diverse tissues. Recent papers showed that during angiogenesis, AQP1 is expressed preferentially by microvessels, favoring angiogenesis via the increase of permeability In particular, in AQP1 null mice, endothelial cell migration is impaired without altering their proliferation or adhesion. Therefore, AQP1 has been proposed as a novel promoter of tumor angiogenesis. Methods/Findings: Using targeted silencing of AQP1 gene expression, an impairment in the organization of F-actin and a reduced migration capacity was demonstrated in human endothelial and melanoma cell lines. Interestingly, we showed, for the first time, that AQP1 co-immunoprecipitated with Lin-7. Lin7-GFP experiments confirmed co-immunoprecipitation. In addition, the knock down of AQP1 decreased the level of expression of Lin-7 and b-catenin and the inhibition of proteasome contrasted partially such a decrease. Conclusions/Significance: All together, our findings show that AQP1 plays a role inside the cells through Lin-7/b-catenin interaction. Such a role of AQP1 is the same in human melanoma and endothelial cells, suggesting that AQP1 plays a global physiological role. A model is presented
Bursts of activity in collective cell migration
Dense monolayers of living cells display intriguing relaxation dynamics,
reminiscent of soft and glassy materials close to the jamming transition, and
migrate collectively when space is available, as in wound healing or in cancer
invasion. Here we show that collective cell migration occurs in bursts that are
similar to those recorded in the propagation of cracks, fluid fronts in porous
media and ferromagnetic domain walls. In analogy with these systems, the
distribution of activity bursts displays scaling laws that are universal in
different cell types and for cells moving on different substrates. The main
features of the invasion dynamics are quantitatively captured by a model of
interacting active particles moving in a disordered landscape. Our results
illustrate that collective motion of living cells is analogous to the
corresponding dynamics in driven, but inanimate, systems
CXCR6, a Newly Defined Biomarker of Tissue-Specific Stem Cell Asymmetric Self-Renewal, Identifies More Aggressive Human Melanoma Cancer Stem Cells
Background: A fundamental problem in cancer research is identifying the cell
type that is capable of sustaining neoplastic growth and its origin from normal
tissue cells. Recent investigations of a variety of tumor types have shown that
phenotypically identifiable and isolable subfractions of cells possess the
tumor-forming ability. In the present paper, using two lineage-related human
melanoma cell lines, primary melanoma line IGR39 and its metastatic derivative
line IGR37, two main observations are reported. The first one is the first
phenotypic evidence to support the origin of melanoma cancer stem cells (CSCs)
from mutated tissue-specific stem cells; and the second one is the
identification of a more aggressive subpopulation of CSCs in melanoma that are
CXCR6+. Conclusions/Significance: The association of a more aggressive tumor
phenotype with asymmetric self-renewal phenotype reveals a previously
unrecognized aspect of tumor cell physiology. Namely, the retention of some
tissue-specific stem cell attributes, like the ability to asymmetrically
self-renew, impacts the natural history of human tumor development. Knowledge
of this new aspect of tumor development and progression may provide new targets
for cancer prevention and treatment
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