Implications of the hybrid epithelial/mesenchymal phenotype in metastasis

Mohit Kumar Jolly, Marcelo Boareto, Bin Huang, Dongya Jia, Mingyang Lu, Jose N Onuchic, Herbert Levine, Eshel Ben-Jacob

(Submitted on 27 May 2015)

Understanding cell-fate decisions during tumorigenesis and metastasis is a major challenge in modern cancer biology. One canonical cell-fate decision that cancer cells undergo is Epithelial-to-Mesenchymal Transition (EMT) and its reverse Mesenchymal-to-Epithelial Transition (MET). While transitioning between these two phenotypes - epithelial and mesenchymal - cells can also attain a hybrid epithelial/mesenchymal (i.e. partial or intermediate EMT) phenotype. Cells in this phenotype have mixed epithelial (e.g. adhesion) and mesenchymal (e.g. migration) properties, thereby allowing them to move collectively as clusters of Circulating Tumor Cells (CTCs). If these clusters enter the circulation, they can be more apoptosis-resistant and more capable of initiating metastatic lesions than cancer cells moving individually with wholly mesenchymal phenotypes, having undergo a complete EMT. Here, we review the operating principles of the core regulatory network for EMT/MET that acts as a three-way switch giving rise to three distinct phenotypes - epithelial, mesenchymal and hybrid epithelial/mesenchymal. We further characterize this hybrid E/M phenotype in terms of its capabilities in terms of collective cell migration, tumor-initiation, cell-cell communication, and drug resistance. We elucidate how the highly interconnected coupling between these modules coordinates cell-fate decisions among a population of cancer cells in the dynamic tumor, hence facilitating tumor-stoma interactions, formation of CTC clusters, and consequently cancer metastasis. Finally, we discuss the multiple advantages that the hybrid epithelial/mesenchymal phenotype have as compared to a complete EMT phenotype and argue that these collectively migrating cells are the primary 'bad actors' of metastasis.

Multiscale modelling of intestinal crypt organization and carcinogenesis

Alexander G. Fletcher, Philip J. Murray, Philip K. Maini

(Submitted on 16 Jun 2015)

Colorectal cancers are the third most common type of cancer. They originate from intestinal crypts, glands that descend from the intestinal lumen into the underlying connective tissue. Normal crypts are thought to exist in a dynamic equilibrium where the rate of cell production at the base of a crypt is matched by that of loss at the top. Understanding how genetic alterations accumulate and proceed to disrupt this dynamic equilibrium is fundamental to understanding the origins of colorectal cancer. Colorectal cancer emerges from the interaction of biological processes that span several spatial scales, from mutations that cause inappropriate intracellular responses to changes at the cell/tissue level, such as uncontrolled proliferation and altered motility and adhesion. Multiscale mathematical modelling can provide insight into the spatiotemporal organisation of such a complex, highly regulated and dynamic system. Moreover, the aforementioned challenges are inherent to the multiscale modelling of biological tissue more generally. In this review we describe the mathematical approaches that have been applied to investigate multiscale aspects of crypt behaviour, highlighting a number of model predictions that have since been validated experimentally. We also discuss some of the key mathematical and computational challenges associated with the multiscale modelling approach. We conclude by discussing recent efforts to derive coarse-grained descriptions of such models, which may offer one way of reducing the computational cost of simulation by leveraging well-established tools of mathematical analysis to address key problems in multiscale modelling.

http://arxiv.org/abs/1506.05019v1

Commentary: The nature of cancer research

Steven A. Frank

(Submitted on 24 Jun 2015)

Cancer research reflects an implicit conflict. On the one hand, there is an overwhelming desire to control the disease. We all wish that. On the other hand, we would like to understand why cancer follows so many clearly defined yet puzzling patterns. Why is there such regularity in the rates of progression? Why do different tissues vary so much? There should, of course, be no conflict between control and understanding. But the history of cancer research seems to say that those different goals remain oddly estranged. Peto's 1977 article locates the seeds of this conflict most clearly. He describes what is still the most powerful theoretical perspective for analyzing the causes of cancer. He presents many key unsolved puzzles within that context. He also says why most cancer researchers are not interested in these fundamental issues. The subsequent decades of research grew around this rift, blindly, in the way that research disciplines often grow. Let us revisit Peto, almost 40 years ago. We can learn much about the current nature of cancer research.

Link: (here)

The Universality of Cancer

Carson C. Chow, Yanjun Li, Vipul Periwal

Cancer has been characterized as a constellation of hundreds of diseases differing in underlying mutations and depending on cellular environments. Carcinogenesis as a stochastic physical process has been studied for over sixty years, but there is no accepted standard model. We show that the hazard rates of all cancers are characterized by a simple dynamic stochastic process on a half-line, with a universal linear restoring force balancing a universal simple Brownian motion starting from a universal initial distribution. Only a critical radius defining the transition from normal to tumorigenic genomes distinguishes between different cancer types when time is measured in cell–cycle units. Reparametrizing to chronological time units introduces two additional parameters: the onset of cellular senescence with age and the time interval over which this cessation in replication takes place. This universality implies that there may exist a finite separation between normal cells and tumorigenic cells in all tissue types that may be a viable target for both early detection and preventive therapy.

http://arxiv.org/abs/1506.00597v1

A computational modelling approach for deriving biomarkers to predict cancer risk in premalignant disease

Andrew Dhawan, Trevor A Graham, Alexander G Fletcher

doi: http://dx.doi.org/10.1101/020222

Abstract

The lack of effective biomarkers for predicting cancer risk in premalignant disease is a major clinical problem. There is a near-limitless list of candidate biomarkers and it remains unclear how best to sample the tissue in space and time. Practical constraints mean that only a few of these candidate biomarker strategies can be evaluated empirically and there is no framework to determine which of the plethora of possibilities is the most promising. Here we have sought to solve this problem by developing a theoretical platform for in silico biomarker development. We construct a simple computational model of carcinogenesis in premalignant disease and use the model to evaluate an extensive list of tissue sampling strategies and different molecular measures of these samples. Our model predicts that: (i) taking more biopsies improves prognostication, but with diminishing returns for each additional biopsy; (ii) longitudinally-collected biopsies provide only marginally more prognostic information than a single biopsy collected at the latest possible time-point; (iii) measurements of clonal diversity are more prognostic than measurements of the presence or absence of a particular abnormality and are particularly robust to confounding by tissue sampling; and (iv) the spatial pattern of clonal expansions is a particularly prognostic measure. This study demonstrates how the use of a mechanistic framework provided by computational modelling can diminish empirical constraints on biomarker development.

Link