Tag Archives: Philosophy and Biology Seminar

Andrew J. Ewald, Ph.D.
Virginia DeAcetis Professor and Director, Department of Cell Biology
Director, Giovanis Institute for Translational Cell Biology
Johns Hopkins Medical School
 

 
Video of the event:

 
Abstract:
Cancer mortality is driven by metastasis, the process by which cells escape from the primary tumor and colonize distant organs. We have shown that luminal breast cancer cells can initiate invasion by expressing basal genes, such as keratin 14 (K14). K14+ luminal breast cancer cells collectively invade and intravasate as adherent clusters. Upon arrival at the distant site, K14+ clusters transition to K14- growing metastases. RNA-seq analysis revealed that K14+ cancer cells exhibit high expression of adhesion proteins (e.g. E-cadherin) and low expression of major histocompatibility complex class I (MHC I). We demonstrated genetically that E-cadherin represses invasion and promotes metastasis by acting as a survival factor. We next demonstrated that loss of MHC I expression sensitized K14+ cancer cells to natural killer (NK) cell attack and that cancer cells can induce NK cells to enter a novel metastasis-promoting cell state. We next tested how metastasis mechanisms differ in triple negative breast cancer (TNBC). We found that TNBC tumors express and require both epithelial and mesenchymal markers, as both E-cadherin and vimentin are required for metastasis. We are currently using genetic, multi-omic, and proteomic techniques to identify molecular regulators of metastatic cell states. We also develop and apply co-culture models to test the constraints imposed by intercellular interactions with both cancer and stromal cells.
 

Uri Alon is Professor, Department of Molecular Cell Biology, Weizmann Institute, Israel. His lab studies biological circuits using a combined experimental and theoretical approach, aiming to uncover general underlying principles that govern their functioning and evolution.
 
Video of the talk:

 
Abstract:
Fibrosis -excess scarring- is a condition that cuts across medicine, causes many diseases, and has no cure. It is a complex process with many cell types and molecules. We will show how a minimal mathematical model can form concepts that explain the basic features of fibrosis. These concepts led to experiments that provide new drug candidates that reduce fibrosis in mice for heart attacks and liver fibrosis. No knowledge of either fibrosis or math is needed to understand this talk.

Steven Frank is Donald Bren Professor & Distinguished Professor, Ecology & Evolutionary Biology
School of Biological Sciences at University of California Irvine (USA)
His main research interests concern evolutionary genetics and host-parasite interactions.
URL: stevefrank.org
 
Video of the talk:

 
Academic Distinctions
Fellow, American Academy of Arts and Sciences, Elected 2012
Fellow, American Association for the Advancement of Science, Elected 2009
John Simon Guggenheim Fellowship, 1995
Theodosius Dobzhansky Prize, Society for the Study of Evolution, 1988
Young Investigator Prize, American Society of Naturalists, 1986

Abstract:
The first part of the talk describes the paradox of robustness. When a system robustly corrects errors in its components, the direct selective pressure on those components declines. Weakened selection on components causes them to become less reliable, maintain more genetic variability, or change in design. Loosened constraint on component-level design allows complexity to creep in arbitrarily, without natural selection to remove unnecessary elaboration. New forms of organismal complexity appear, seemingly without any clear logic. In the second part, I link the paradox of robustness to similar ideas developed by others, such as the theory of constructive neutral evolution. In the third part, I unify previous ideas into a more general perspective. I then link the paradox of robustness to the observation that, in evolution, intermediate stages in development tend to be more strongly constrained than earlier or later stages. This leads us to John Doyle’s discussion of the universal architecture of complex robustly designed systems in engineering and in biology, in which there is an important distinction between hardware and software layers. I link the observations about evolutionary constraints in development to Doyle’s hardware vs software distinction. Finally, I argue that constructive neutral evolution is mainly about genomic hardware, in which neutrality likely dominates, whereas the broader paradox of robustness also includes functional components in the software layer, in which nonneutral economic costs and benefits likely dominate.
This talk will be given via Zoom. Please contact Thomas Pradeu if you’d like to join us for this seminar.

Deborah Gordon is Professor of Biology at University of Stanford (USA).
Deborah Gordon is a world-leading specialist of ant colonies and collective behaviors. With her group, she uses ant colonies to investigate systems that operate without central control, and explore analogies with other systems, such as the internet, the immune system, and the brain. She is interested in collective behavior, which can take many forms, such as emergence, self-organization, superorganism, quorum sensing, artificial intelligence, and dynamical networks.
Abstract:
Collective behavior operates without central control, using local interactions among participants to allow groups to respond to changing conditions. It is widespread in nature, not only producing the coordinated movement of bird flocks or fish schools, but also regulating activity in natural systems from cells, as in cancer metastasis or embryonic development, to the social groups of many vertebrates. An ecological perspective on collective behavior examines how collective behavior adjusts to changing environments. Ant colonies function collectively, and the enormous diversity of more than 14K species of ants, in different habitats, provides opportunities to look for general ecological patterns. The collective foraging behavior of harvester ants in the desert adjusts activity to manage water loss, while the trail networks of turtle ants in the canopy of the  tropical forest adjust to rapidly changing resources and vegetation. These examples suggests how systems with similar dynamics in their surroundings have evolved to show similar dynamics in the regulation of collective behavior. An ecological perspective can contribute to new insights in medical research.
See here Deborah Gordon’s TED talk: “What ants teach us about the brain, cancer and the Internet”

 
Publications of Deborah Gordon.

The Bilder Lab (University of Berkeley, USA) studies the molecules and mechanisms that govern the polarity, growth, and morphogenesis of epithelia, the fundamental tissue of all animals and the major constituent of human organs. They also use Drosophila cancer models as a simple system to understand both how epithelial organization prevents tumor formation and how tumors actually kill their hosts.
Example of recent work:
Bilder et al., Tumour-host interactions through the lens of Drosophila, Nature Reviews Cancer (2021)
There is a large gap between the deep understanding of mechanisms driving tumour growth and the reasons why patients ultimately die of cancer. It is now appreciated that interactions between the tumour and surrounding non-tumour (sometimes referred to as host) cells play critical roles in mortality as well as tumour progression, but much remains unknown about the underlying molecular mechanisms, especially those that act beyond the tumour microenvironment. Drosophila has a track record of high-impact discoveries about cell-autonomous growth regulation, and is well suited to now probe mysteries of tumour – host interactions. Here, we review current knowledge about how fly tumours interact with microenvironmental stroma, circulating innate immune cells and distant organs to influence disease progression. We also discuss reciprocal regulation between tumours and host physiology, with a particular focus on paraneoplasias. The fly’s simplicity along with the ability to study lethality directly provide an opportunity to shed new light on how cancer actually kills.

Sarah-Maria Fendt is since 2013 a Principal Investigator at the VIB Center for Cancer Biology and Professor of Oncology at KU Leuven, Belgium. Sarah’s lab is specifically interested in elucidating general regulatory principles in metabolism, and understanding cancer metabolism during metastasis formation as well as during altered whole body physiology. To perform novel research in her fields of interest her group exploits their expertise in metabolomics and fluxomics. The research of Sarah’s lab is currently funded by multiple (inter)national grants and industry, which include an ERC consolidator grant. Sarah received several awards such as the EMBO Gold Medal.
This talk will be given by Zoom. (Please contact Thomas Pradeu for the link).
 
Abstract:
Metastasis formation is the leading cause of death in cancer patients. We find that metabolic rewiring is a liability of metastasizing cancer cells. For example, we discovered that extracellular remodeling of the metastatic niche, a process essential to metastasis formation, requires a transcriptional- independent regulation via the metabolites. Moreover, we provide knowledge on intratumor heterogeneity of metabolism and its role in metastasis formation. Specifically, we discovered that heterogeneity in the metabolic enzyme phosphoglycerate dehydrogenase (PHGDH) predicts in cancer patients the risk for metastasis formation. Strikingly, loss of PHGDH protein expression drives early dissemination of cancer cells due to a novel mechanism leading to the posttranslational modification of cell surface integrins. More recently, we have investigated the nutrient dependencies of metastasis and find a strong organ specific pattern. Thus, we study the metabolism of metastasizing cancer cells with the goal to define novel therapeutic strategies.