Research Hölzel Lab

Tumor cell plasticity, inflammation and therapy resistance 

We have a holistic view on the tumor tissue, as it is composed of different cellular compartments including tumor, immune, endothelial and stromal cells. All these different cell types are in constant exchange with each other, which provides a mechanistic basis for the dynamic adaptive changes that drive disease progression and therapy resistance.

Within this scenario, a phenomenon called tumor cell plasticity plays a central role and it describes how tumor cells can switch their phenotypes in order to resist microenvironmental or therapeutic stress conditions. Initially focusing on malignant melanoma, an aggressive skin cancer originating from the pigment producing melanocytes, we explored how inflammatory signals from the tumor microenvironment act as key drivers of melanoma cell plasticity.

Currently, we are also studying the dynamic interplay between lipid metabolism, immune signaling and melanoma phenotype switching. Also, we have extended our view on other cancer types inspired by our many clinical collaborations, most notably urologic oncology, neuro-oncology and gynecology.

In our projects we aim to understand the molecular mechanisms that orchestrate tumor cell plasticity and identify drug targets to promote favorable rewiring of tumor cell phenotypes to overcome therapy resistance. For this, we are using a broad range of experimental approaches such as cultures of tumor cell lines and patient-derived organoids, preclinical in vivo models, various flavors of in vitro genetic engineering as well as multiparametric and high-dimensional analytical methods like flow cytometry, multiplex-IF (CODEX(R)) and genomics (scRNA-seq, RNA-seq, WES, WGS).

Deep spatial phenotyping of the human tumor microenvironment

In the recent years, several technologies have advanced rapidly that allow for a comprehensive analysis of tumor tissues on the single cell level, in particular single-cell RNA-sequencing (scRNA-seq) and multiparametric flow cytometry.

High-plex immunofluorescence (high-plex IF) is another very recent method that allows to detect many different markers (>50) on a single tumor tissue section. By this, different cell types and their phenotypes can be analyzed while preserving the information about the spatial context of each cell, which is in contrast to scRNA-seq or flow cytometry.

High-plex IF therefore provides entirely novel insights into the complex architecture of tumor tissues and how different cell populations influence each other in spatial vicinity.

Hence, scRNA-seq, flow cytometry and high-plex IF are three complementary technologies and in conjunction allow us to analyze the human tumor microenvironment at so far unprecedented depth.
Having established the technical and analytical expertise, we aim to integrate the findings obtained from spatial deep phenotyping of human tumors with different types of clinical information, most importantly treatment responses to immune checkpoint inhibitors or latest antibody drug conjugates. By this, we expect to learn more about the heterogeneity of treatment responses seen in patients and delineate novel counterstrategies to overcome resistance.

Our deep phenotyping approaches are complemented by a concerted effort with our clinical collaborators from University Hospital Bonn (UKB) employing patient-derived organoids and short-term cultures of tumor fragments to investigate drug responses.