(8) Investigating the function of inflammatory mediators in Cancer-associated-Cachexia: How does inflammation and the immune system impact on muscle and fat loss observed in many cancer patients?

HYPOTHESIS

Inflammatory mediators are early markers for prediction and prevention of Cancer-Associated-Cachexia (CAC) and can also
be of diagnostic/preventive/prognostic value for early stages of cancer development.

Background & Significance

CAC is characterized by weight loss, fat and muscle atrophy, fatigue, weakness and appetite loss; 80% of patients with advanced cancer develop CAC and 1/3 die of it. There are no biomarkers indicating the onset of CAC and few strategies to ameliorate the severe symptoms. The immune reaction is one of the primary responses to the tumor and its dysregulation could be a trigger for the systemic changes observed during CAC development. We have in the past 5y developed powerful GEMMs and cell transplantation models and our data suggest that inflammation and energy expenditure play an important role in CAC development32, 33. Data from our lab suggest that inflammatory mediators, which are deregulated in skin diseases such as psoriasis, might play an important role in CAC. S100A9 and Lipocalin-2 (Lcn-2) proteins are small molecules essential to fight bacteria and are expressed by neutrophils. Increased levels are found in sera of psoriasis and cancer patients and in several of our mouse models34. Importantly, Lcn-2 is a novel hormone linking bone biology to inflammation and appetite control, both hallmarks of CAC35. Preliminary data suggest that Lcn-2 loss delays CAC development in syngeneic models and could therefore be a preventive cancer target.

Objectives

To provide trans-disciplinary training to ESR8 by performing a collaborative research project on evaluating the role of S100A9 and Lipocalin-2 in syngeneic and genetic models of CAC. ESR8 has to determine

if these proteins are expressed and secreted early in CAC development;

if the development of CAC is affected in GEMMs for skin and BC and transplantation models lacking S100A9 and Lcn-2;

dependent on the results of 1+2, initiate inhibitory/activating strategies to modulate the activity of these proteins to prevent/ameliorate CAC;

explore the expression of Lcn-2 in early, i.e. premalignant, versus late stages of skin a cancer using breast GEMMs and patient sections with BC. The GEMMs for CAC and the experimental expertise are present at the host lab and ESR8 will gain relative independence within the first 21 months, which will also allow her/him to fully benefit from visiting the secondments labs.

Enrolment in Doctoral degree(s):

  • Medical University of Vienna