Associated projects

Crosstalk of adipocyte inflammation and adrenal function in obesity

Obesity is a chronic inflammatory metabolic disorder, in which aberrant metabolism is linked to the activation of the immune system and inflammation of the tissue. An important aspect of disease progression is the recruitment of professional immune cells into adipose tissue, which contributes to endocrine imbalance and metabolic dysfunction. However, the impact of adipose inflammation on steroid hormone and catecholamine production in the adrenal gland is not well characterized. A detailed mechanistic understanding of this endocrine crosstalk might help to find better solutions for controlling metabolic rate and cardiovascular function in obesity. This project investigates the mechanisms linking adipose tissue dysfunction to energy metabolism, blood pressure, and cardiovascular function. This project will provide a novel understanding of the mechanisms linking adipose inflammation to adrenal function. We will study the crosstalk of adipose-derived inflammatory mediators, exemplified here using the Nfe2l1-trangenic mouse model and adrenal hormones using in vitro, in vivo, and imaging models. Our project will advance the molecular understanding of obesity-linked endocrine tissue communication, a critical step forward towards developing new therapeutics for the treatment of diabetic and cardiovascular complications.

Aims

(I) Characterize cardiometabolism in adipose Nfe2l1 KO mice

(II) Investigate molecular regulation of Nfe2l1 by adrenal hormones

(III) Clinical outcomes associated with adipose-adrenal crosstalk

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CRISPR/Cas9-mediated genome editing for genetic transformation of the adrenal cortex and adrenocortical tumorigenesis

Advancements regarding novel treatment strategies for adrenocortical carcinoma as well as fostered understanding of potential drivers of adrenocortical tumorigenesis have been limited by the lack of tumor models reflecting genetic disease heterogeneity. To gather new insights into disease onset and identify new therapeutically relevant targets, it is obvious that new tools are desperately required to advance the field of ACC research. In this regard, we established a novel workflow for culturing and longitudinal propagation of non-transformed adrenocortical cells. This unique ex vivo setup holds the potential to study adrenal cell homeostasis and biology, and allows us to replicate oncogenic transformation of adrenocortical cells using CRISPR/Cas9-mediated genome editing. It furthermore presents a starting point for the development of versatile and clinically relevant isogenic mouse models for adrenocortical tumors and enables members of the consortium to validate putative translational findings in clinically relevant model systems, genetically tailored to suit the question.

Aims

(I) Establish primary adrenocortical cultures derived from different mouse strains, sexes and human adrenal glands

(II) Immortalization and cell-specific oncogenic transformation of generated cell lines using CRISPR/Cas9 reflecting common mutations identified in ACC

(III) Generation and characterization of corresponding mouse models

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This project aims at developing novel cell therapy approaches for the treatment of adrenocortical cancer (ACC) using chimeric antigen receptor (CAR)-transduced T cells. Within this project, we will identify novel antigens and explore their potential for the treatment of ACC. Furthermore, we will dissect ACC-specific mechanisms of tumour immune evasion and resistance to identify novel approaches for the development of cell products tailored to elicit potent anti-tumour efficacy. For this purpose, we will focus on advanced genome and cell engineering techniques and explore the therapeutic potential of synergistic treatment approaches.

Aims

(I) Identification and assessment of novel targets for the treatment of ACC using CAR-T cells.

(II) Identification and characterization of novel approaches to circumvent ACC-specific tumour immune evasion mechanisms.

(III) Development and functional characterization of advanced CAR-T cell products for the treatment of ACC in vitro and in vivo.

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Scientific staff

Defining the cellular origins of adrenal tumors

The adrenal gland and the sympathetic nervous system (SNS) gives rise to different malignant tumors in childhood and adulthood, including neuroblastomas (NBs), pheochromocytomas and paragangliomas (PPGLs). The cellular origins and the evolutionary histories are largely unknown. In addition, lineage-specific features that may predispose distinct cell types of the adrenal gland/SNS to malignant transformation are still elusive. Our specific goal is to define the cellular origin(s) of PPGLs and, if possible, also adrenocortical tumors. Based on this approach, which has been successfully applied already to childhood neuroblastomas, we will define the exact onset of PPGLs and mutations involved in disease progression and therapy resistance. With collaboration partners from the CRC/TRR205, we will expand our approach to malignant adrenocortical tumors.

Aims

(I) Define genetic programs that are involve in the development and aging of the adrenal gland and sympathetic nervous system by using single-cell analysis

(II) Define the cellular origin and evolution of PPGLs and if possible also of adrenocortical tumors

(III) Define the role of telomere maintenance mechanisms in tumor initiation and malignant progression

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