Detecting heterogeneity in and between breast cancer cell linesAbstractBackground
Cellular heterogeneity in tumor cells is a well-established phenomenon. Genetic and phenotypic cell-to-cell variability have been observed in numerous studies both within the same type of cancer cells and across different types of cancers. Another known fact for metastatic tumor cells is that they tend to be softer than their normal or non-metastatic counterparts. However, the heterogeneity of mechanical properties in tumor cells are not widely studied.
Results
Here we analyzed single-cell optical stretcher data with machine learning algorithms on three different breast tumor cell lines and show that similar heterogeneity can also be seen in mechanical properties of cells both within and between breast tumor cell lines. We identified two clusters within MDA-MB-231 cells, with cells in one cluster being softer than in the other. In addition, we show that MDA-MB-231 cells and MDA-MB-436 cells which are both epithelial breast cancer cell lines with a mesenchymal-like phenotype derived from metastatic cancers are mechanically more different from each other than from non-malignant epithelial MCF-10A cells.
Conclusion
Since stiffness of tumor cells can be an indicator of metastatic potential, this result suggests that metastatic abilities could vary within the same monoclonal tumor cell line.
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Relationship between hepatocellular carcinoma circulating tumor cells and tumor volumeAbstractBackground
Microfluidic platforms have demonstrated the ability to isolate rare circulating tumor cells from a wide variety of cancers. Our group has recently shown the ability to isolate circulating tumor cells (CTCs) from hepatocellular carcinoma (HCC) patients using a hematopoietic cell depletion microfluidic platform. However, the relationship of CTC generation and HCC progression is still not well understood. Tumor size is often used as a clinical prognostic factor, but there has been an inconsistent relationship of tumor size and metastatic recurrence. Characterizing the relationship of primary tumor size and CTCs would provide a better understanding of HCC tumor size and metastatic potential.
Results
CTCs in a cohort of HCC patients with quantitative tumor volume analysis was performed to determine if there was a relationship of tumor size to CTC generation. A total of 24 tumor volumetric analyses were used in this study, and a cutoff of 25 cc was used to create a low and high tumor volume group (median 5.56 vs 108 cc; p < 0.0001). Using an antigen agnostic microfluidic CTC isolation platform and immunofluorescent staining for cytokeratin and glypican-3, CTCs were detected in 18 of 22 (82%) HCC patients. CTCs/mL of blood did not correlate with either tumor volume or serum AFP. Interestingly, CTCs were found to be significantly higher in small compared to large volume tumors (median 18.5 vs 5 CTCs/mL; p = 0.0454).
Conclusion
Altogether, HCC CTCs provide additional data about the tumor independent of standard imaging and blood biomarkers, and there may be biological differences in small volume tumors that facilitate CTC entry into the blood stream. This has implications for HCC CTCs as a biomarker for predicting recurrence and as an early detection platform.
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Cancer dormancy and criticality from a game theory perspectiveAbstractBackground
The physics of cancer dormancy, the time between initial cancer treatment and re-emergence after a protracted period, is a puzzle. Cancer cells interact with host cells via complex, non-linear population dynamics, which can lead to very non-intuitive but perhaps deterministic and understandable progression dynamics of cancer and dormancy.
Results
We explore here the dynamics of host-cancer cell populations in the presence of (1) payoffs gradients and (2) perturbations due to cell migration.
Conclusions
We determine to what extent the time-dependence of the populations can be quantitively understood in spite of the underlying complexity of the individual agents and model the phenomena of dormancy.
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A network modeling approach to elucidate drug resistance mechanisms and predict combinatorial drug treatments in breast cancerAbstractBackground
Mechanistic models of within-cell signal transduction networks can explain how these networks integrate internal and external inputs to give rise to the appropriate cellular response. These models can be fruitfully used in cancer cells, whose aberrant decision-making regarding their survival or death, proliferation or quiescence can be connected to errors in the state of nodes or edges of the signal transduction network.
Results
Here we present a comprehensive network, and discrete dynamic model, of signal transduction in ER+ breast cancer based on the literature of ER+, HER2+, and PIK3CA-mutant breast cancers. The network model recapitulates known resistance mechanisms to PI3K inhibitors and suggests other possibilities for resistance. The model also reveals known and novel combinatorial interventions that are more effective than PI3K inhibition alone.
Conclusions
The use of a logic-based, discrete dynamic model enables the identification of results that are mainly due to the organization of the signaling network, and those that also depend on the kinetics of individual events. Network-based models such as this will play an increasing role in the rational design of high-order therapeutic combinations.
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Non-randomness of the anatomical distribution of tumorsAbstractBackground
Why does a tumor start where it does within an organ? Location is traditionally viewed as a random event, yet the statistics of the location of tumors argues against this being a random occurrence. There are numerous examples including that of breast cancer. More than half of invasive breast cancer tumors start in the upper outer quadrant of the breast near the armpit, even though it is estimated that only 35 to 40% of breast tissue is in this quadrant. This suggests that there is an unknown microenvironmental factor that significantly increases the risk of cancer in a spatial manner and that is not solely due to genes or toxins. We hypothesize that tumors are more prone to form in healthy tissue at microvascular ‘hot spots’ where there is a high local concentration of microvessels providing an increased blood flow that ensures an ample supply of oxygen, nutrients, and receptors for growth factors that promote the generation of new blood vessels.
Results
To show the plausibility of our hypothesis, we calculated the fractional probability that there is at least one microvascular hot spot in each region of the breast assuming a Poisson distribution of microvessels in two-dimensional cross sections of breast tissue. We modulated the microvessel density in various regions of the breast according to the total hemoglobin concentration measured by near infrared diffuse optical spectroscopy in different regions of the breast. Defining a hot spot to be a circle of radius 200 μm with at least 5 microvessels, and using a previously measured mean microvessel density of 1 microvessel/mm2, we find good agreement of the fractional probability of at least one hot spot in different regions of the breast with the observed invasive tumor occurrence. However, there is no reason to believe that the microvascular distribution obeys a Poisson distribution.
Conclusions
The spatial location of a tumor in an organ is not entirely random, indicating an unknown risk factor. Much work needs to be done to understand why a tumor occurs where it does.
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Probing three-dimensional collective cancer invasion with DIGMEAbstractBackground
Multicellular pattern formation plays an important role in developmental biology, cancer metastasis and wound healing. While many physical factors have been shown to regulate these multicellular processes, the role of ECM micro-to-meso scale geometry has been poorly understood in 3D collective cancer invasion.
Results
We have developed a mechanical-based strategy, Diskoid In Geometrically Micropatterned ECM (DIGME). DIGME allows easy engineering of the shape of 3D tissue organoid, the mesoscale ECM heterogeneity, and the fiber alignment of collagen-based ECM all at the same time. We have employed DIGME to study the 3D invasion of MDA-MB-231 diskoids in engineered collagen matrix. We find that the collective cancer invasion is closely regulated by the micro-to-meso scale geometry of the ECM.
Conclusions
We conclude that DIGME provides a simple yet powerful tool to probe 3D dynamics of tissue organoids in physically patterned microenvironments.
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Introducing cancer convergence |
Distinguishing mechanisms underlying EMT tristabilityAbstractBackground
The Epithelial-Mesenchymal Transition (EMT) endows epithelial-looking cells with enhanced migratory ability during embryonic development and tissue repair. EMT can also be co-opted by cancer cells to acquire metastatic potential and drug-resistance. Recent research has argued that epithelial (E) cells can undergo either a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype that typically displays collective migration, or a complete EMT to adopt a mesenchymal (M) phenotype that shows individual migration. The core EMT regulatory network - miR-34/SNAIL/miR-200/ZEB1 - has been identified by various studies, but how this network regulates the transitions among the E, E/M, and M phenotypes remains controversial. Two major mathematical models – ternary chimera switch (TCS) and cascading bistable switches (CBS) - that both focus on the miR-34/SNAIL/miR-200/ZEB1 network, have been proposed to elucidate the EMT dynamics, but a detailed analysis of how well either or both of these two models can capture recent experimental observations about EMT dynamics remains to be done.
Results
Here, via an integrated experimental and theoretical approach, we first show that both these two models can be used to understand the two-step transition of EMT - E→E/M→M, the different responses of SNAIL and ZEB1 to exogenous TGF-β and the irreversibility of complete EMT. Next, we present new experimental results that tend to discriminate between these two models. We show that ZEB1 is present at intermediate levels in the hybrid E/M H1975 cells, and that in HMLE cells, overexpression of SNAIL is not sufficient to initiate EMT in the absence of ZEB1 and FOXC2.
Conclusions
These experimental results argue in favor of the TCS model proposing that miR-200/ZEB1 behaves as a three-way decision-making switch enabling transitions among the E, hybrid E/M and M phenotypes.
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ΩτοΡινοΛαρυγγολόγος Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,
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Τρίτη 4 Φεβρουαρίου 2020
Cancer Convergence
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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,
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00302841026182,
00306932607174,
alsfakia@gmail.com,
Anapafseos 5 Agios Nikolaos 72100 Crete Greece,
Medicine by Alexandros G. Sfakianakis,
Telephone consultation 11855 int 1193
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