The main focus in our laboratory is the
identification and physiological characterization of
adipocyte-specific gene products and the elucidation of
pathways that are an integral part of the complex set of
reactions that drive adipogenesis. The hope is to unravel
novel mechanisms and identify novel proteins that could serve
as potential links between the adipocyte and the process of
whole body energy homeostasis, thereby defining novel targets
for pharmacological intervention and further define the role
of adipose tissue as an endocrine tissue. Until recently,
adipose tissue has been considered to be a mere storage
compartment of triglycerides. It is now becoming clear that
adipocytes are highly responsive to extracellular stimuli,
play a central role in overall energy homeostasis and are also
essential for certain aspects of the immune system.
Many epidemiological studies currently suggest a positive correlation between the prevalence of obesity and cancer incidence and mortality. Rigorous meta-analysis studies demonstrate strong associations of obesity with esophageal adenocarcinoma, thyroid, colon and renal cancers in males and endometrial, gallbladder, esophageal adeno-carcinoma, ovarian and renal cancers in females. In addition, postmenopausal breast, pancreatic, thyroid and colon cancers also showed strong positive associations in females. While the epidemiological evidence linking obesity with cancer incidence is strong, particularly with breast cancer, the underlying mechanistic connections remain elusive.
Our expertise lies at the level of adipocyte physiology. As adipose tissues becomes dysfunctional, the altered physiological state of obese adipose tissue holds the key to enhanced mitogenic effects on tumor development and progression, in part through altered paracrine and endocrine signals. Evidence supporting growth-stimulatory roles of adipocyte-derived factors (such as adipokines and lipid metabolites) on cancer progression has been highlighted in several of our papers. We have published a number of additional papers over the past 8 years, examining the contributions of specific adipokines, such as adiponectin, leptin and have summarized these observations in many reviews and commentaries.
Our most recent published efforts focus on two important aspects of tumor growth in the context of metabolic dysregulation. A recent study entitled “Neuregulin 1-HER axis as a key mediator of hyperglycemic memory effects in breast cancer” is dealing with the epigenetic consequences of a transient exposure to hyperglycemic conditions with respect to tumor growth. Poor outcomes in diabetic patients are observed across a range of human tumors, suggesting that cancer cells develop unique characteristics under diabetic conditions. Cancer cells exposed to hyperglycemic insults acquire permanent aggressive traits of tumor growth through epigenetic modifications, even after a return to euglycemic conditions. Comparative genome-wide mapping of hyperglycemia-specific open chromatin regions and concomitant mRNA expression profiling revealed that neuregulin-1 gene, an established endogenous ligand for the HER3 receptor, is activated through a putative distal enhancer. Our findings highlight the targeted inhibition of NRG1-HER3 pathways as a target for the treatment breast cancer patients with associated diabetes. Endotrophin, a cleavage product of an abundant extracellular matrix component of adipose tissue, Col VIα3. Col VI is ubiquitously expressed throughout various connective tissues, such as blood vessels, muscle, lung and skin. However, adipose tissue is by far the most abundant COLVI source. COLVI is a large collagenous glycoprotein composed of the 3 chains, α1, α2, and α3. Once secreted into the extracellular space, COLVI tetramers organize into microfibrils. The carboxyl-terminal C5 domain of the α3 chain is subsequently cleaved off from the COLVI microfibrils by proteolytic activity. However, little is known about the functional roles or details of cleavage process for the C5 domain. In our previous studies, we have determined that adipocyte-derived COLVI is a tumor-promoting factor, and COLVI null mice (COL6-/-) display an attenuated formation of early hyperplasia and primary tumor growth. Endotrophin, as the active ColVI moiety, is critically involved in cancer progression. It acts as a potent pro-fibrotic agent, it is a chemokine that attracts macrophages and endothelial precursor cells and potently stimulates endothelial to mesenchymal transition (EMT) of tumor cells. As such, it potently induces chemoresistance.
Additional efforts focus on the role of the innate immune response to tumor invasion in the mammary gland.