Advocacy spurs innovation: promoting synergy between physical and biomedical sciences

Despite dramatic advances in decoding the genes, proteins, and pathways that drive cancer, the disease has evaded the reductionist approaches to defeat it. Recent work has highlighted cancer’s heterogeneity, complexity, and ability to develop resistance as major barriers to progress. To better understand and control the processes that govern the initiation, behavior, and progression of cancer, the National Cancer Institute (NCI) created the Physical Sciences-Oncology Center (PS-OC) Network in 2009. As a hub for scientific innovation and as an example of the transdisciplinary research model, the twelve centers within the PS-OC strive for the systematic convergence of the physical sciences with cancer biology. Promoting collaboration between biologists, physicists, mathematicians, chemists, biomedical engineers, and oncologists, the program offers a compelling vision of how new frontiers in physical sciences and oncology will permit the emergence of new scientific principles and opportunities, and of how the benefits of the current convergence revolution would be enhanced by vigorous public/advocacy support

Peering from the outside in: viscoelastic properties of the extracellular matrix dictate spatial organization and apoptosis resistance in mammary epithelial cells

The compliance of the extracellular matrix (ECM) differs between tissues and is altered in tumors. We examined the consequence of modifying the viscoelastic properties of the ECM on mammary epithelial cell (MEC) morphogenesis and apoptosis regulation. Results showed that the elastic modulus of the ECM exerts a profound effect on MEC tissue organization and gene expression that correlates with changes in actin organization and apoptosis resistance. Altering the rigidity of the ECM directly influences integrin expression and additionally modifies integrin-induced gene expression in association with actin reorganization. These data suggest that the compliance of the ECM may cooperatively regulate cell behavior by altering integrin function. Studies are now underway to investigate the possibility that these effects are mediated via changes in integrin-actin cytoskeletal dynamics

A bulky glycocalyx fosters metastasis formation by promoting G1 cell cycle progression.

Metastasis depends upon cancer cell growth and survival within the metastatic niche. Tumors which remodel their glycocalyces, by overexpressing bulky glycoproteins like mucins, exhibit a higher predisposition to metastasize, but the role of mucins in oncogenesis remains poorly understood. Here we report that a bulky glycocalyx promotes the expansion of disseminated tumor cells in vivo by fostering integrin adhesion assembly to permit G1 cell cycle progression. We engineered tumor cells to display glycocalyces of various thicknesses by coating them with synthetic mucin-mimetic glycopolymers. Cells adorned with longer glycopolymers showed increased metastatic potential, enhanced cell cycle progression, and greater levels of integrin-FAK mechanosignaling and Akt signaling in a syngeneic mouse model of metastasis. These effects were mirrored by expression of the ectodomain of cancer-associated mucin MUC1. These findings functionally link mucinous proteins with tumor aggression, and offer a new view of the cancer glycocalyx as a major driver of disease progression

The Oral and Skin Microbiomes of Captive Komodo Dragons Are Significantly Shared with Their Habitat.

Examining the way in which animals, including those in captivity, interact with their environment is extremely important for studying ecological processes and developing sophisticated animal husbandry. Here we use the Komodo dragon (Varanus komodoensis) to quantify the degree of sharing of salivary, skin, and fecal microbiota with their environment in captivity. Both species richness and microbial community composition of most surfaces in the Komodo dragon's environment are similar to the Komodo dragon's salivary and skin microbiota but less similar to the stool-associated microbiota. We additionally compared host-environment microbiome sharing between captive Komodo dragons and their enclosures, humans and pets and their homes, and wild amphibians and their environments. We observed similar host-environment microbiome sharing patterns among humans and their pets and Komodo dragons, with high levels of human/pet- and Komodo dragon-associated microbes on home and enclosure surfaces. In contrast, only small amounts of amphibian-associated microbes were detected in the animals' environments. We suggest that the degree of sharing between the Komodo dragon microbiota and its enclosure surfaces has important implications for animal health. These animals evolved in the context of constant exposure to a complex environmental microbiota, which likely shaped their physiological development; in captivity, these animals will not receive significant exposure to microbes not already in their enclosure, with unknown consequences for their health. IMPORTANCE Animals, including humans, have evolved in the context of exposure to a variety of microbial organisms present in the environment. Only recently have humans, and some animals, begun to spend a significant amount of time in enclosed artificial environments, rather than in the more natural spaces in which most of evolution took place. The consequences of this radical change in lifestyle likely extend to the microbes residing in and on our bodies and may have important implications for health and disease. A full characterization of host-microbe sharing in both closed and open environments will provide crucial information that may enable the improvement of health in humans and in captive animals, both of which experience a greater incidence of disease (including chronic illness) than counterparts living under more ecologically natural conditions

Autocrine laminin-5 ligates {alpha}6{beta}4 integrin and activates RAC and NF{kappa}B to mediate anchorange-independent survival of mammary tumors

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express α6β4 integrin. Here, we show that autocrine LM-5 mediates anchorage independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail–truncated α6β4 integrin. α6β4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of β4 integrin is necessary for basal and epidermal growth factor–induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional β1 and β4 integrin through activation of NFκB, and overexpression of NFκB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5–α6β4 integrin–RAC–NFκB signaling

Autocrine laminin-5 ligates α6β4 integrin and activates RAC and NFκB to mediate anchorage-independent survival of mammary tumors

Invasive carcinomas survive and evade apoptosis despite the absence of an exogenous basement membrane. How epithelial tumors acquire anchorage independence for survival remains poorly defined. Epithelial tumors often secrete abundant amounts of the extracellular matrix protein laminin 5 (LM-5) and frequently express α6β4 integrin. Here, we show that autocrine LM-5 mediates anchorage-independent survival in breast tumors through ligation of a wild-type, but not a cytoplasmic tail–truncated α6β4 integrin. α6β4 integrin does not mediate tumor survival through activation of ERK or AKT. Instead, the cytoplasmic tail of β4 integrin is necessary for basal and epidermal growth factor–induced RAC activity, and RAC mediates tumor survival. Indeed, a constitutively active RAC sustains the viability of mammary tumors lacking functional β1 and β4 integrin through activation of NFκB, and overexpression of NFκB p65 mediates anchorage-independent survival of nonmalignant mammary epithelial cells. Therefore, epithelial tumors could survive in the absence of exogenous basement membrane through autocrine LM-5–α6β4 integrin–RAC–NFκB signaling

Asymmetric crowders and membrane morphology at the nexus of intracellular trafficking and oncology.

A definitive understanding of the interplay between protein binding/migration and membrane curvature evolution is emerging but needs further study. The mechanisms defining such phenomena are critical to intracellular transport and trafficking of proteins. Among trafficking modalities, exosomes have drawn attention in cancer research as these nano-sized naturally occurring vehicles are implicated in intercellular communication in the tumor microenvironment, suppressing anti-tumor immunity and preparing the metastatic niche for progression. A significant question in the field is how the release and composition of tumor exosomes are regulated. In this perspective article, we explore how physical factors such as geometry and tissue mechanics regulate cell cortical tension to influence exosome production by co-opting the biophysics as well as the signaling dynamics of intracellular trafficking pathways and how these exosomes contribute to the suppression of anti-tumor immunity and promote metastasis. We describe a multiscale modeling approach whose impact goes beyond the fundamental investigation of specific cellular processes toward actual clinical translation. Exosomal mechanisms are critical to developing and approving liquid biopsy technologies, poised to transform future non-invasive, longitudinal profiling of evolving tumors and resistance to cancer therapies to bring us one step closer to the promise of personalized medicine

18-Beta-Glycyrrhetinic Acid Causes Increased Pigment Production and Decreased Adherence in Methicillin Resistant Staphylococcus Aureus Biofilms

Infections caused by Methicillin Resistant Staphylococcus aureus (MRSA) are an ever growing concern in the health care field.  While MRSA is most known for its resistance to beta-lactams (i.e. penicillin), it has also acquired resistance to a number of other antibiotics.  MRSA plays a major role in chronic wounds due to its ability to form a biofilm, resulting in severe infections.  Biofilms are naturally more resistant to antibiotics than planktonic cells which can be due to their extracellular polymeric substance and slow growing nature, as well as metabolic differences.  This has resulted in biofilms becoming a major focus in the biomedical field.  As MRSA rapidly acquires resistance to currently available antibiotics, there is an urgent need to develop novel antimicrobials. 18?-Glycyrrhetinic acid (GRA) is a compound isolated from Glycyrrhiza glabra and has been shown to be an effective antimicrobial against Staphylococcal planktonic cells; however, investigations on biofilm activity appear to be lacking. Our studies show GRA to have minimal to no effect on biofilm bacterial counts; however, post-treatment observations included an increase in yellow pigment and decreased adherence of biofilms. S. aureus pigments play an important role in virulence, including oxidative stress that may be introduced by antimicrobials like GRA. Crystal violet staining of GRA treated biofilms showed a quantified reduction in adherence compared to controls. This suggests that GRA may cause biofilm dispersal and therefore increased susceptibility to current antimicrobials. 1H NMR metabolomics is being conducted to investigate these results and other metabolic changes in GRA treated biofilms