Modeling collective cell behavior in cancer: Perspectives from an interdisciplinary conversation.

Collective cell behavior contributes to all stages of cancer progression. Understanding how collective behavior emerges through cell-cell interactions and decision-making will advance our understanding of cancer biology and provide new therapeutic approaches. Here, we summarize an interdisciplinary discussion on multicellular behavior in cancer, draw lessons from other scientific disciplines, and identify future directions.

Epigenetics and genome stability.

Maintaining genome stability is essential to an organism's health and survival. Breakdown of the mechanisms protecting the genome and the resulting genome instability are an important aspect of the aging process and have been linked to diseases such as cancer. Thus, a large network of interconnected pathways is responsible for ensuring genome integrity in the face of the continuous challenges that induce DNA damage. While these pathways are diverse, epigenetic mechanisms play a central role in many of them. DNA modifications, histone variants and modifications, chromatin structure, and non-coding RNAs all carry out a variety of functions to ensure that genome stability is maintained. Epigenetic mechanisms ensure the functions of centromeres and telomeres that are essential for genome stability. Epigenetic mechanisms also protect the genome from the invasion by transposable elements and contribute to various DNA repair pathways. In this review, we highlight the integral role of epigenetic mechanisms in the maintenance of genome stability and draw attention to issues in need of further study.

Rho Kinase Inhibition as a Therapeutic for Progressive Supranuclear Palsy and Corticobasal Degeneration.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative four-repeat tauopathies with no cure. Mitigating pathogenic tau levels is a rational strategy for tauopathy treatment, but therapeutic targets with clinically available drugs are lacking. Here, we report that protein levels of the Rho-associated protein kinases (ROCK1 and ROCK2), p70 S6 kinase (S6K), and mammalian target of rapamycin (mTOR) were increased in PSP and CBD brains. RNAi depletion of ROCK1 or ROCK2 reduced tau mRNA and protein level in human neuroblastoma cells. However, additional phenotypes were observed under ROCK2 knockdown, including decreased S6K and phosphorylated mTOR levels. Pharmacologic inhibition of Rho kinases in neurons diminished detergent-soluble and -insoluble tau through a combination of autophagy enhancement and tau mRNA reduction. Fasudil, a clinically approved ROCK inhibitor, suppressed rough eye phenotype and mitigated pathogenic tau levels by inducing autophagic pathways in a Drosophila model of tauopathy. Collectively, these findings highlight the Rho kinases as rational therapeutic targets to combat tau accumulation in PSP and CBD. SIGNIFICANCE STATEMENT: Studies of progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) suggest that mitigating pathogenic tau levels is a rational strategy for tauopathy treatment. In this report, the Rho-associated protein kinases (ROCK1 and ROCK2) are identified as novel drug targets for PSP and CBD. We show that elevated insoluble tau levels are associated with increased ROCK1 and ROCK2 in PSP and CBD brains, whereas experiments in cellular and animal models identify pharmacologic inhibition of ROCKs as a mechanism-based approach to reduce tau levels. Our study correlates bona fide changes in PSP and CBD brains with cellular models, identifies drug targets, and tests the therapeutic in vivo.

Gene expression analysis at the intersection of ploidy and hybridity in maize.

Heterosis and polyploidy are two important aspects of plant evolution. To examine these issues, we conducted a global gene expression study of a maize ploidy series as well as a set of tetraploid inbred and hybrid lines. This gene expression analysis complements an earlier phenotypic study of these same materials. We find that ploidy change affects a large fraction of the genome, albeit at low levels; gene expression changes rarely exceed 2-fold and are typically not statistically significant. The most common gene expression profile we detected is greater than linear increase from monoploid to diploid, and reductions from diploid to triploid and from triploid to tetraploid, a trend that mirrors plant stature. When examining heterosis in tetraploid maize lines, we found a large fraction of the genome impacted but the majority of changes were not statistically significant at 2-fold or less. Non-additive expression was common in the hybrids, and the extent of non-additivity increased both in number and magnitude from duplex to quadruplex hybrids. Overall, we find that gene expression trends mirror observations from the phenotypic studies; however, obvious mechanistic connections remain unknown.

Comparative analysis of inbred and hybrid maize at the diploid and tetraploid levels.

Heterosis often occurs in offspring derived from a cross between inbred or divergent parents and can be observed as the superior performance of these hybrids for a wide variety of characters. Heterosis was compared in maize lines at two ploidy levels, diploid and tetraploid, to gain a better understanding of the interaction of heterosis and ploidy level. Employing genetically identical diploid and tetraploid maize derived from four different inbred lines, we investigated heterosis for 11 morphological traits, including several plant height measures, as well as flowering time for both silks and anthers. We find that the heterotic response of a certain hybrid differs between diploid and tetraploid lines, and that the response at one ploidy cannot serve as a predictor for the other. Also, progressive heterosis was found for several of the characters in the tetraploid double-cross hybrid, which can have four different alleles at one locus, compared to the double-cross diploid hybrids, which can only possess two alleles per locus. Overall, the results indicate that the heterotic response of tetraploid maize lines differs significantly from that of the diploid.

Genetic variation for the response to ploidy change in Zea mays L.

Polyploidization is an important process in the evolutionary history of most eukaryotic species. It oftentimes causes large-scale genomic reorganizations and is accompanied by a wide variety of phenotypic alterations in morphology, niche preference and fitness characteristics. Despite their importance, the morphological effects of alterations in ploidy are not well understood. We investigated these changes in four diverse maize inbred lines, using monoploid, diploid, triploid and tetraploid derivatives, measuring 13 characters in a randomized field study. Employing several analysis of variance approaches, we find that all characters investigated strongly respond to alterations in ploidy. This response appears to have two sources: one source is shared by all inbred lines and constitutes a common response to ploidy change. The other source is genotype specific and results in a response to ploidy change that varies among inbred lines. This finding demonstrates the existence of genetic variation for the morphological response to ploidy change in Zea mays.