Biology subjects

Haass, N. K.

Publications and source records attributed to Haass, N. K..

3 recordsLinked to original sources

bioRxiv2020

Synchronised oscillations in growing cell populations are explained by demographic noise

Understanding synchrony in growing populations is important for applications as diverse as epidemiology and cancer treatment. Recent experiments employing fluorescent reporters in melanoma cell lines have uncovered growing subpopulations exhibiting sustained oscillations, with nearby cells appearing to synchronise their cycles. In this study we demonstrate that the behaviour observed is consistent with long-lasting transient phenomenon initiated, and amplified by the finite-sample effects and demographic noise. We present a novel mathematical analysis of a multi-stage model of cell growth which accurately reproduces the synchronised oscillations. As part of the analysis, we elucidate the transient and asymptotic phases of the dynamics and derive an analytical formula to quantify the effect of demographic noise in the appearance of the oscillations. The implications of these findings are broad, such as providing insight into experimental protocols that are used to study the growth of asynchronous populations and, in particular, those investigations relating to anti-cancer drug discovery. Statement of SignificanceRecent experiments have reported strong evidence of periodic oscillations in the proportion of young and old melanoma cells. The biological mechanism generating this synchronisation and the potential impact that can have on commonly used experimental protocols is still unclear. Here we studied a population of melanoma cells for which we found oscillations in the proportions of cells in each phase of the cell cycle. We demonstrate that these observations may be triggered by intrinsic demographic noise alone, rather than any active synchronisation mechanism requiring cell-cell communication. Our findings may have implications for typical experimental protocols which aim to produce asynchronous cell populations.

cell biology↗

bioRxiv2019

Abrogation of RAB27A expression transiently affects melanoma cell proliferation

The role of the small GTPase RAB27A as an essential melanosome trafficking regulator in melanocytes is well-accepted. A decade ago, RAB27A was identified as a tumor dependency gene that promotes melanoma cell proliferation. RAB27A has since been linked to another propeller of cancer progression: exosome secretion. We have recently demonstrated that RAB27A is overexpressed in a subset of melanomas. High RAB27A gene and protein expression correlates with poor prognosis in melanoma patients. Mechanistic investigations revealed that the generation of pro-invasive exosomes was RAB27A-dependent and, therefore, silencing RAB27A reduced melanoma cell invasion in vitro and in vivo. However, previous studies have implicated RAB27A to be involved in both proliferation and invasion of melanoma cells. In this study, we demonstrate that the effects of abrogating RAB27A expression on proliferation are temporary, in contrast to the previously reported persistent effects on tumor invasion and metastasis. Therefore, we assist in the dissection of the short-term versus long-term effects of RAB27A knockdown on melanoma cell proliferation, invasion, and metastasis. We believe that our findings provide novel insights into the effects of RAB27A blockade. SignificanceRAB27A is known to serve as an essential regulator for melanosome trafficking. However, to date its role in melanoma biology has not been completely deciphered. While there are consistent independent reports on the pro-invasive effects of RAB27A, there are conflicting data on its impact on cell proliferation. Here we show that indeed abrogation of RAB27A does reduce cellular proliferation; however, this effect is only transient, while the impact on invasion as reported previously is persistent. This finding offers an explanation for the apparent contradiction in the literature and provides a deeper understanding of RAB27A function in melanoma cell biology.

cancer biology↗

bioRxiv2019

Examining go-or-grow using fluorescent cell-cycle indicators and cell cycle-inhibiting drugs

The go-or-grow hypothesis states that adherent cells undergo reversible phenotype switching between migratory and proliferative states, with cells in the migratory state being more motile than cells in the proliferative state. Here we examine go-or-grow in 2-D in vitro assays using melanoma cells with fluorescent cell-cycle indicators and cell cycle-inhibiting drugs. We analyse the experimental data using single-cell tracking to calculate mean diffusivities, and compare motility between cells in different cell-cycle phases and in cell-cycle arrest. Unequivocally, our analysis does not support the go-or-grow hypothesis. We present clear evidence that cell motility is independent of the cell-cycle phase, and non-proliferative arrested cells have the same motility as cycling cells.

biophysics↗