Role of intratumoural heterogeneity in cancer drug resistance : molecular and clinical perspectives

Drug resistance continues to be a major barrier to the delivery of curative therapies in cancer. Historically, drug resistance has been associated with over-expression of drug transporters, changes in drug kinetics or amplification of drug targets. However, the emergence of resistance in patients treated with new-targeted therapies has provided new insight into the complexities underlying cancer drug resistance. Recent data now implicate intratumoural heterogeneity as a major driver of drug resistance. Single cell sequencing studies that identified multiple genetically distinct variants within human tumours clearly demonstrate the heterogeneous nature of human tumours. The major contributors to intratumoural heterogeneity are (i) genetic variation, (ii) stochastic processes, (iii) the microenvironment and (iv) cell and tissue plasticity. Each of these factors impacts on drug sensitivity. To deliver curative therapies to patients, modification of current therapeutic strategies to include methods that estimate intratumoural heterogeneity and plasticity will be essential.

Cancer gene signatures in risk stratification: use in personalized medicine

Cancer is a complex disease which arises due to a series of genetic changes related to cell division and growth control. Cancer remains the second leading cause of death in humans next to heart diseases. As a testimony to our progress in understanding the biology of cancer and developments in cancer diagnosis and treatment methods, the overall median survival time of all cancers has increased six fold one year to six years during the last four decades. However, while the median survival time has increased dramatically for some cancers like breast and colon, there has been only little change for other cancers like pancreas and brain. Further, not all patients having a single type of tumour respond to the standard treatment. The differential response is due to genetic heterogeneity which exists not only between tumours, which is called intertumour heterogeneity, but also within individual tumours, which is called intratumoural heterogeneity. Thus it becomes essential to personalize the cancer treatment based on a specific genetic change in a given tumour. It is also possible to stratify cancer patients into low- and high-risk groups based on expression changes or alterations in a group of genes gene signatures and choose a more suitable mode of therapy. It is now possible that each tumour can be analysed using various high-throughput methods like gene expression profiling and next-generation sequencing to identify its unique fingerprint based on which a personalized or tailor-made therapy can be developed. Here, we review the important progress made in the recent years towards personalizing cancer treatment with the use of gene signatures.

Expression of E-cadherin repressors SNAIL, ZEB1 and ZEB2 by tumour and stromal cells influences tumour-budding phenotype and suggests heterogeneity of stromal cells in pancreatic cancer.

BACKGROUND There is evidence that tumour-stroma interactions have a major role in the neoplastic progression of pancreatic ductal adenocarcinoma (PDAC). Tumour budding is thought to reflect the process of epithelial-mesenchymal transition (EMT); however, the relationship between tumour buds and EMT remains unclear. Here we characterize the tumour-budding- and stromal cells in PDAC at protein and mRNA levels concerning factors involved in EMT. METHODS mRNA in situ hybridisation and immunostaining for E-cadherin, β-catenin, SNAIL1, ZEB1, ZEB2, N-cadherin and TWIST1 were assessed in the main tumour, tumour buds and tumour stroma on multipunch tissue microarrays from 120 well-characterised PDACs and associated with the clinicopathological features, including peritumoural (PTB) and intratumoural (ITB) budding. RESULTS Tumour-budding cells showed increased levels of ZEB1 (P<0.0001) and ZEB2 (P=0.0119) and reduced E-cadherin and β-catenin (P<0.0001, each) compared with the main tumour. Loss of membranous β-catenin in the main tumour (P=0.0009) and tumour buds (P=0.0053), without nuclear translocation, as well as increased SNAIL1 in tumour and stromal cells (P=0.0002, each) correlated with high PTB. ZEB1 overexpression in the main tumour-budding and stromal cells was associated with high ITB (P=0.0084; 0.0250 and 0.0029, respectively) and high PTB (P=0.0005; 0.0392 and 0.0007, respectively). ZEB2 overexpression in stromal cells correlated with higher pT stage (P=0.03), lymphatic invasion (P=0.0172) and lymph node metastasis (P=0.0152). CONCLUSIONS In the tumour microenvironment of phenotypically aggressive PDAC, tumour-budding cells express EMT hallmarks at protein and mRNA levels underlining their EMT-type character and are surrounded by stromal cells expressing high levels of the E-cadherin repressors ZEB1, ZEB2 and SNAIL1, this being strongly associated with the tumour-budding phenotype. Moreover, our findings suggest the existence of subtypes of stromal cells in PDAC with phenotypical and functional heterogeneity.

The influence of habitat heterogeneity on patterns of connectivity among rabbit populations in southern Queensland

Patterns of connectivity among local populations influence the dynamics of regional systems, but most ecological models have concentrated on explaining the effect of connectivity on local population structure using dynamic processes covering short spatial and temporal scales. In this study, a model was developed in an extended spatial system to examine the hypothesis that long term connectivity levels among local populations are influenced by the spatial distribution of resources and other habitat factors. The habitat heterogeneity model was applied to local wild rabbit populations in the semi-arid Mitchell region of southern central Queensland (the Eastern system). Species' specific population parameters which were appropriate for the rabbit in this region were used. The model predicted a wide range of long term connectivity levels among sites, ranging from the extreme isolation of some sites to relatively high interaction probabilities for others. The validity of model assumptions was assessed by regressing model output against independent population genetic data, and explained over 80% of the variation in the highly structured genetic data set. Furthermore, the model was robust, explaining a significant proportion of the variation in the genetic data over a wide range of parameters. The performance of the habitat heterogeneity model was further assessed by simulating the widely reported recent range expansion of the wild rabbit into the Mitchell region from the adjacent, panmictic Western rabbit population system. The model explained well the independently determined genetic characteristics of the Eastern system at different hierarchic levels, from site specific differences (for example, fixation of a single allele in the population at one site), to differences between population systems (absence of an allele in the Eastern system which is present in all Western system sites). The model therefore explained the past and long term processes which have led to the formation and maintenance of the highly structured Eastern rabbit population system. Most animals exhibit sex biased dispersal which may influence long term connectivity levels among local populations, and thus the dynamics of regional systems. When appropriate sex specific dispersal characteristics were used, the habitat heterogeneity model predicted substantially different interaction patterns between female-only and combined male and female dispersal scenarios. In the latter case, model output was validated using data from a bi-parentally inherited genetic marker. Again, the model explained over 80% of the variation in the genetic data. The fact that such a large proportion of variability is explained in two genetic data sets provides very good evidence that habitat heterogeneity influences long term connectivity levels among local rabbit populations in the Mitchell region for both males and females. The habitat heterogeneity model thus provides a powerful approach for understanding the large scale processes that shape regional population systems in general. Therefore the model has the potential to be useful as a tool to aid in the management of those systems, whether it be for pest management or conservation purposes.

The mechanical heterogeneity of the hard callus influences local tissue strains during bone healing : a finite element study based on sheep experiments

During secondary fracture healing, various tissue types including new bone are formed. The local mechanical strains play an important role in tissue proliferation and differentiation. To further our mechanobiological understanding of fracture healing, a precise assessment of local strains is mandatory. Until now, static analyses using Finite Elements (FE) have assumed homogenous material properties. With the recent quantification of both the spatial tissue patterns (Vetter et al., 2010) and the development of elastic modulus of newly formed bone during healing (Manjubala et al., 2009), it is now possible to incorporate this heterogeneity. Therefore, the aim of this study is to investigate the effect of this heterogeneity on the strain patterns at six successive healing stages. The input data of the present work stemmed from a comprehensive cross-sectional study of sheep with a tibial osteotomy (Epari et al., 2006). In our FE model, each element containing bone was described by a bulk elastic modulus, which depended on both the local area fraction and the local elastic modulus of the bone material. The obtained strains were compared with the results of hypothetical FE models assuming homogeneous material properties. The differences in the spatial distributions of the strains between the heterogeneous and homogeneous FE models were interpreted using a current mechanobiological theory (Isakson et al., 2006). This interpretation showed that considering the heterogeneity of the hard callus is most important at the intermediate stages of healing, when cartilage transforms to bone via endochondral ossification.

Functional heterogeneity as a two-dimensional concept : empirical evidence for new venture teams

Previous research on entrepreneurial teams has failed to settle the controversy over whether team heterogeneity helps or hinders new venture performance. Reconciling this inconsistency, this paper suggests a new conceptual approach to disentangle differential effects of team heterogeneity by modeling two separate heterogeneity dimensions, namely knowledge scope and knowledge disparity. Analyzing unique data on functional experiences of the members of 337 start-up teams, we find support for our contention of team heterogeneity as a two-dimensional concept. Results suggest that knowledge disparity negatively relates to both start-ups’ entrepreneurial and innovative performance. In contrast, we find knowledge scope to positively affect entrepreneurial performance, while it shows an inverse U-shaped relationship to innovative start-up performance.

Heterogeneity in auditory alarm sets makes them easier to learn

The primary objective of the experiments reported here was to demonstrate the effects of opening up the design envelope for auditory alarms on the ability of people to learn the meanings of a set of alarms. Two sets of alarms were tested, one already extant and one newly-designed set for the same set of functions, designed according to a rationale set out by the authors aimed at increasing the heterogeneity of the alarm set and incorporating some well-established principles of alarm design. For both sets of alarms, a similarity-rating experiment was followed by a learning experiment. The results showed that the newly-designed set was judged to be more internally dissimilar, and easier to learn, than the extant set. The design rationale outlined in the paper is useful for design purposes in a variety of practical domains and shows how alarm designers, even at a relatively late stage in the design process, can improve the efficacy of an alarm set.

ACE research vignette 001 : benefits and drawbacks of start-up team heterogeneity

This series of research vignettes is aimed at sharing current and interesting research findings from our team of international Entrepreneurship researchers. In this vignette, Dr. Micheal Stuetzer considers some of the benefits and drawbacks associated with team start-up.

4000 years of phenotypic change in an island bird: heterogeneity of selection over three microevolutionary timescales.

Pronounced phenotypic shifts in island populations are typically attributed to natural selection, but reconstructing heterogeneity in long-term selective regimes remains a challenge. We examined a scenario of divergence proposed for species colonizing a new environment, involving directional selection with a rapid shift to a new optimum and subsequent stabilization. We provide some of the first empirical evidence for this model of evolution using morphological data from three timescales in an island bird, Zosterops lateralis chlorocephalus. In less than four millennia since separation from its mainland counterpart, a substantial increase in body size has occurred and was probably achieved in fewer than 500 generations after colonization. Over four recent decades, morphological traits have fluctuated in size but showed no significant directional trends, suggesting maintenance of a relatively stable phenotype. Finally, estimates of contemporary selection gradients indicated generally weak directional selection. These results provide a rare description of heterogeneity in long-term natural regimes, and caution that observations of current selection may be of limited value in inferring mechanisms of past adaptation due to a lack of constancy even over short time-frames.

Revealing performance heterogeneity through knowledge management maturity evaluation : a capability-based approach

The dynamic capabilities view (DCV) focuses on renewal of firms’ strategic knowledge resources so as to sustain competitive advantage within turbulent markets. Within the context of the DCV, the focus of knowledge management (KM) is to develop the KMC through deploying knowledge governance mechanisms that are conducive to facilitating knowledge processes so as to produce superior business performance over time. The essence of KM performance evaluation is to assess how well the KMC is configured with knowledge governance mechanisms and processes that enable a firm to achieve superior performance through matching its knowledge base with market needs. However, little research has been undertaken to evaluate KM performance from the DCV perspective. This study employed a survey study design and adopted hypothesis-testing approaches to develop a capability-based KM evaluation framework (CKMEF) that upholds the basic assertions of the DCV. Under the governance of the framework, a KM index (KMI) and a KM maturity model (KMMM) were derived not only to indicate the extent to which a firm’s KM implementations fulfill its strategic objectives, and to identify the evolutionary phase of its KMC, but also to bench-mark the KMC in the research population. The research design ensured that the evaluation framework and instruments have statistical significance and good generalizabilty to be applied in the research population, namely construction firms operating in the dynamic Hong Kong construction market. The study demonstrated the feasibility of quantitatively evaluating the development of the KMC and revealing the performance heterogeneity associated with the development.

Dealing with heterogeneity problems and causal effect estimation in entrepreneurship research

This paper deals with causal effect estimation strategies in highly heterogeneous empirical settings such as entrepreneurship. We argue that the clearer used of modern tools developed to deal with the estimation of causal effects in combination with our analysis of different sources of heterogeneity in entrepreneurship can lead to entrepreneurship with higher internal validity. We specifically lend support from the counterfactual logic and modern research of estimation strategies for causal effect estimation.

Heterogeneity evidence and linkage studies on Charcot-Marie-Tooth disease

Charcot-Marie-Tooth neuropathy type 1 (CMT1) is an autosomal dominant disorder originally localized to chromosome 1 by linkage to the Duffy blood group. Studies have since shown that the disorder may be heterogeneous, as not all families show this linkage. We tested genetic heterogeneity by the HOMOG computer program in 15 CMT1 pedigrees informative for Duffy. We detected no evidence for heterogeneity in this sample, but when we combined results with previously published lod scores, heterogeneity was statistically significant. Twelve of the 15 families studied did not show linkage to Duffy. We found six of these families to be informative for a chromosome 19 marker, apolipoprotein CII(ApoC2). Despite a previous report showing probable linkage of a non-Duffy-linked CMT1 pedigree to two chromosome 19 markers, we did not detect significant linkage of ApoC2 to CMT1 in these families.