Erwin Wagner – (PI) – Genes and Diseases laboratory – PhD project 7, 8

Chronic inflammation is a key determinant of all cancer types through different modalities and effectors. Here, we will assess the effect of Inflammatory Skin Diseases (ISDs) on skin cancer development (ESR7) and the role of inflammatory mediators in Cancer-Associated-Cachexia (CAC) for diagnostic, prevention and prognosis of early cancer stages (ESR8).

Millions of people suffer from inflammatory skin diseases (ISDs), like psoriasis. However, a connection between psoriasis and cancer risk is not firmly established. By functional and biochemical analyses of genetically engineered mouse models (GEMMs), we will determine whether psoriasis promotes or suppresses specific aspects of skin cancer development, and whether this is of relevance for cancer risk in human populations (ESR7). 80% of patients with advanced cancer develop Cancer-Associated-Cachexia (CAC), a syndrome characterized by weight loss, fat and muscle atrophy, general weakness and appetite loss. CAC is responsible for 1/3 of cancer deaths and a dysregulated immune response to the tumor could be a trigger for the systemic changes observed during CAC development. Using GEMMs and patient samples, we will assess which of the inflammatory mediators of CAC, such as S100A9 and Lipocalin-2, may have diagnostic/preventive/prognostic value early in cancer development (ESR8).

Project 7 – Investigating local skin cancer risk in inflammatory skin diseases

Hypothesis: There is an inflammation-dependent, context-specific effect of Inflammatory Skin Diseases (ISDs) on cancer development.

Background and significance: Millions of people suffer from ISDs like psoriasis and their co-morbidities. However, the connection between psoriasis and cancer risk is far from being established. Depending on cancer type, psoriasis could be promoting cancer development or favouring immune-protection from tumor cells. We established in the past 10y several powerful GEMMs for acute and chronic inflammatory skin diseases to model human diseases. Our data suggest that the skin acts like an endocrine organ keeping epithelial differentiation and inflammation under transcriptional control, e.g. by AP-1 (Fos/Jun) transcription factors. We showed that the loss of JunB/AP-1 expression from epidermal/keratinocytes leads to a multi-organ disease affecting the skin, bones, kidneys, and the hematopoietic system. We have not yet investigated whether a particular inflammatory ‘state’ promotes or inhibits skin cancer.

Objectives: Provide trans-disciplinary training to an ESR through a project evaluating incidence and aggressiveness of non-melanoma skin cancer in the presence of inflammatory skin disease. ESR7 has to (1) determine spontaneous and chemically-induced skin tumor development in mice with a psoriasis-like disease or with an inducible IL-17-dependent inflammatory skin disease (above & unpublished data); (2) determine skin cancer risk in psoriasis patient-derived xenograft models (PDX) upon chemical carcinogenesis protocols; (3) identify mediators of inflammation associated with altered skin cancer rates; (4) validate the findings from GEMMs in human samples.

Project 8 – Investigating the function of inflammatory mediators of Cancer-associated-Cachexia

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

Background and 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 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 models. Importantly, Lcn-2 is a novel hormone linking bone biology to inflammation and appetite control, both hallmarks of CAC. 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 (1) if these proteins are expressed and secreted early in CAC development; (2) if the development of CAC is affected in GEMMs for skin and BC and transplantation models lacking S100A9 and Lcn-2; (3) dependent on the results of 1+2, initiate inhibitory/activating strategies to modulate the activity of these proteins to prevent/ameliorate CAC; (4); 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.

Related readings

[1] Petruzzelli, M. et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab 20, 433-447 (2014).

[2] Petruzzelli, M. & Wagner, E. F. Mechanisms of metabolic dysfunction in cancer-associated cachexia. Genes Dev 30, 489-501 (2016).

[3] Uluckan, O. et al. Chronic skin inflammation leads to bone loss by IL-17-mediated inhibition of Wnt signaling in osteoblasts. Sci Transl Med 8, 330ra (2016).

[4] Mera, P., Ferron, M. & Mosialou, I. Regulation of Energy Metabolism by Bone-Derived Hormones. Cold Spring Harb Perspect Med, doi:10.1101 (2017).

[5] Uluckan, O. & Wagner, E. F. Chronic systemic inflammation originating from epithelial tissues. FEBS J 284, 505-516 (2017).