Amir Tirosh Lab
Research
Here are some research projects we are currently working on!
Adipose tissue provides key stromal support for cancer
Recent evidence suggests a growing role for adipocytes in tumor growth and development. In many cancers, tumor-surrounding adipocytes support the growing tumor by various secreted factors. Indeed, adipose tissue dysfunction in obesity is an established risk factor not only for cardio-metabolic abnormalities, but also, as becoming increasingly evident, for increased cancer incidence and aggressiveness. Yet, the molecular mechanisms underlying the cancer-obesity link are not fully understood. We have identified one adipokine as a key mediator of adipocyte-cancer crosstalk. We found that this adipokine, normally secreted from adipose tissue in response to metabolic cues, facilitates tumor growth by promoting cancer cell proliferation and migration. We are currently interested exploring the specific molecular mechanism(s) of action by which this adipokine promotes tumor growth. As the obesity-attributable cancer burden is likely to continue and rise, identifying novel stromal secreted factors supporting tumor growth underscores their inhibition as an exciting target for cancer treatment.
Melanoma spheroids incubated with adipose tissue CM
Bodipy staining of cultured adipocytes
H&E staining of melanoma tumor
The effect of nutrition on metabolic health
Environmental and nutritional factors have been demonstrated to affect metabolic health and act as 'endocrine disruptors'. These factors can either act as agonists or antagonists to certain receptors in a wide variety of biological systems. We have previously identified a common food preservative, propionic acid (PA), with distinct metabolic effects that increases hepatic glucose production and cause changes in glucagon and insulin levels leading to liver insulin resistance. Chronic exposure to PA results in weight gain, increase adiposity and systemic insulin resistance in mouse models. We are currently working in in-vitro and in-vivo animal models to assess the effects of several other micronutrients in modern nutrition on the pathophysiology of obesity and diabetes.
Cellular mechanism linking over-nutrition with metabolic diseases
Chronic inflammation and cellular stress are central features of obesity and associated metabolic diseases such as insulin resistance and diabetes. The inflammatory response in obesity is distinct, appears to respond to intrinsic cues, and does not resemble the classical inflammatory paradigm. Significant data have emerged in recent years on the molecular mechanisms leading to the development of these inflammatory and stress responses and how they are linked to metabolic homeostasis. Our research is focused on the regulation and adaptation to inflammation and stress within the tissue milieu in metabolically relevant tissues such as liver and adipose tissue. More specifically, we study cell-cell communication via gap junctions and the propagation of inflammatory and stress signals between cells within a tissue and the potential role of such communication in mediating insulin resistance and metabolic abnormalities. Gap Junctions (GJ) are one of the most common forms of intercellular communication developed by multicellular organisms. GJs form a channel between the cytoplasm of adjacent cells, allowing the exchange of ions, signaling molecules and many metabolites between cells of most tissues. GJ channels are made up of connexin (Cx).Connexin43 (Cx43), a 43-kDa protein, is a ubiquitous and critical GJ protein, playing an important regulatory and developmental roles in many tissues. Our research is aimed to explore the potential role of Cx43 in the adipose tissue under conditions of obesity and insulin resistance. We study how Cx43 mediate cell-cell communication under obese conditions using advanced methods that combine mice models, in-vivo imaging as well as in-vitro cell-cell communication assays.
Dye microinjection to adipose tissue
Parachute assay:
co-culture of adipocytes and SVF
Cx43-mediated inter-cellular communication in liver - illustration
Deciphering transcriptional networks changes in different feeding conditions
The glycation process in the liver
Dysregulation of transcriptional networks in obesity and diabetes
The liver is a highly specialized tissue that regulates a wide variety of biochemical reactions, many of which are necessary for normal vital functions. Feeding and fasting constitute major metabolic cues controlling liver biochemical processes and gene expression, yet the molecular mechanisms regulating these processes in liver are not fully elucidated. Among other processes, we study glycation, the process of non-enzymatic covalent attachment of monosaccharides, such as glucose, to basic amino acids. Diabetes in general, and specifically in the context of obesity, is characterized by hyperglycemia leading to increased glycation of proteins, responsible for chronic complications. Examples for the role of glycation in regulation of cellular proteins are recently emerging but the full scope of molecular targets for glycation, particularly in liver, is incompletely understood. Importantly, little is known about the regulation of protein glycation by monosaccharide sugars. Glycation is reversible by a process termed de-glycation. In the lab, we are exploring mechanisms of glycation and de-glycation, their potential regulation, targets and consequences.