Precision Sarcoma Research

Sarcomas are mainly divided into two types, bone sarcoma and soft-tissue sarcoma. Sarcomas display remarkable genetic and histologic diversity, as reflected by more than 150 subtypes according to the World Health Organization Classification, which in turn poses significant diagnostic and therapeutic difficulties. “Actionable” lesions that allow prediction of response to conventional or targeted anti-cancer drugs and/or represent direct targets for therapeutic intervention are lacking in the majority of cases due to incomplete understanding of the events that drive sarcoma development.

The Precision Sarcoma Research group funded by the Emmy Noether Program of the German Research Foundation (DFG) has been established to improve the understanding of sarcomagenesis and identify targets for biological stratification and molecular mechanism-guided therapeutic intervention.

We have established an integrated pipeline connecting foundational science to translation, beginning with clinical discovery and moving through robust experimental validation to deliver clinically relevant therapeutic targets and biomarkers for evaluation in sarcoma patients. Our approach is to map sarcoma subtype-specific disease programs in order to understand how they can be targeted most efficiently.

Our team brings expertise across a diverse set of topics, matched to the heterogeneity of sarcoma biology: structural genomics, genomic instability and DNA damage biology; immune cell types and interactions within the tumor microenvironment; energy metabolism and metabolomics; and more broadly applicable analytical approaches including machine learning and multi-omics factor analysis. This breadth allows us to investigate the biology of a diverse set of sarcoma subtypes across the full spectrum of genetic aberrations, from fusion-driven sarcomas to those displaying high levels of genomic instability, from soft-tissue to bone sarcomas, and from common to ultra-rare entities.

In a project-specific manner, we apply the latest technology platforms, including long-read sequencing, single-nucleus sequencing (scATAC, scRNA-seq, scWGS) and spatial transcriptomics, to gain deeper insight into the biology of these tumors. Mechanistic investigation of selected aberrations is enabled by our expanding panel of model systems and a comprehensive functional genomics toolkit (e.g. CRISPR/Cas9 libraries). Strongly grounded biology and robust validation ensure that the sparse translational opportunities in these rare cancers are pursued with the best possible odds of success.

Our goal is evidence-based path forward and improved clinical care for each sarcoma patient. 

Sarcomas with high chomorosmal instability (CIN) are challenging subset of sarcomas as they display substantial intratumor heterogeneity, and lack a recurrent driver that could be targeted directly or via secondary dependencies. High-CIN sarcomas sub-entities include, among others,  leiomyosarcoma, myxofibrosarcoma, and osteosarcoma. A frequent but therapeutically unexploited feature of high-CIN sarcomas is loss of the chromatin remodelling factor ATRX, which is associated with activation of alternative lengthening of telomeres (ALT) pathway. ALT consistently tracks with aggressive disease and inferior survival relative to canonical TERT-mediated telomere maintenance. Building on our initial observation of frequent ALT in leiomyosarcoma (Chudasama et al., 2018), within the Precision Sarcoma Research Group, we developed a comparative genomics framework to define ALT prevalence, biology and vulnerabilities across sarcoma to assess its potential as a common denominator.  

Thus far, we have screened >800 human sarcoma tumor samples to identify frequency of ALT in various sarcoma sub-entities. Following this stratification, we have employed integrative multi-omics analysis to identify genetic alterations that separate ALT-positive tumors from the ALT-negative tumors to identify ALT-associated aberrations that may be targetable directly or via secondary dependencies. Using a large panel of rare sarcoma cell lines and patient-derived xenografts, we are validating the “druggability” of candidate alterations and mechanistically characterizing those using phospho-proteomics to lay the groundwork for nominating ALT-specific targets for evaluation in the clinical setting. Moreover, we are developing methods to address the impact of heterogeneity in telomere maintenance mechanisms using machine learning tools (Belova et al. 2023 biorXiv) and spatially resolved technologies (Frank et al. Nucleic Acids Res 2022).

See our latest work on comparative genomics on ALT+ and ALT- complex sarcomas, and discovery of ALT-associated “telomere healing” mechanism, bioRxiv, under revision in Nature Communications here https://www.biorxiv.org/content/10.64898/2026.05.17.725728v2

Limited availability of tumor samples, absence of model systems, lower number of patients for understanding of disease biology and drug development are critical hurdles in advancing basic, translational, and clinical research in rare cancers (<6 cases per 100,000/year) such as sarcoma. A subset of sarcoma, termed as ultra-rare sarcoma (≤1 case per 1,000,000, Stacchiotti S et al, 2021, Cancer, 27:2934) are exceedingly rare, with significant augmentation of above challenges. Our team aims to push forward ultra-rare sarcoma research by performing in-depth molecular characterization of tumor samples to inform diagnosis, classification, identification of pathognomonic alterations, model development, and entry points for biology-guided treatment. 

Below are our currently on-going projects on ultra-rare sarcoma

Clear cell sarcoma (CCS), originating from neural crest cells and driven by EWSR1-ATF1 fusion protein, is particularly devastating, as quite often it is frequently diagnosed late, with disseminated metastasis, associated with an accelerated clinical course, and displays complete resistance to chemotherapy and radiotherapy. Targeted protein degradation approaches that exploit the cellular protein degradation system by induced proximity with ubiquitinylating E3 ligases, have expanded the “druggable” proteome, and we asked if this could be applied to EWSR1-ATF1.

Our recent work has identified E3 ligase regulating the stability of EWSR1-ATF1 fusion protein. By leveraging functional genomics tools, we have uncovered perturbation of homeostasis as an entry point for metabolic vulnerabilities in clear cell sarcoma, which our team is currently investigating as a therapeutic target in CCS.

One example of ultra-rare sarcoma is follicular dendritic sarcoma (FDCS) that originates from follicular dendritic cells (FDCs). Diagnosis of FDCS is difficult due to histological similarities with many epithelial, mesenchymal, meningeal, or lymphoid malignancies. FDCS patients have poor prognosis and are still commonly treated with a lymphoma chemotherapy regimen (CHOP) despite evidence of mesenchymal origin of FDCs. We have assembled a cohort of >30 FDCS samples and have characterized the genomic and transcriptomic landscape of alterations, which led to identification of previously not described targetable lesions and oncogenic mechanisms, such as BRAFV600E mutations and telomerase overexpression by enhancer hijacking. Results of our analysis have led to clinical benefit to FDCS patient and we have identified a rare histological subtype of this ultra-rare sarcoma, and identification of distinct spatial ecotypes. We continue to characterize this intriguing disease using DNA methylation landscape and spatial technologies.

Alveolar-soft part sarcoma (ASPS) is yet another ultra-rare sarcoma with poor prognosis in the metastatic setting. ASPS is driven by (X;17) (p11;q25) translocation to form the ASPSCR1-TFE3 fusion oncoprotein, with low number of additional genomic alterations, such as mutations or structural variants. We were intrigued by the finding of high level of immune cell infiltration in ASPS tumors, which according to the current dogma, is not a frequent feature of tumors of “silent” genomes. Furthermore, certain patients with ASPS tumors show exceptional response to checkpoint inhibition, which, however, does not correlate with expression levels of immune checkpoint molecules. We are employing transcriptome-based immune profiling approaches and spatial proteomics to 1) uncover the secrets of immune cell chemotaxis, 2) identification of a biomarker for response to checkpoint blockade treatment and 3) identify new mechanisms and vulnerabilities of fusion-driven modulation of immune microenvironment. To this end, in collaboration with group of Ana Banito (Soft-tissue Sarcoma, DKFZ and KiTZ) we have developed an immunocompetent ASPS mouse model that will allow pre-clinical validation of targets and biomarkers.

The Precision Sarcoma Research Group received a financial boost and solid encouragement from two very strong women – a loving mother and aunt of an ultra-rare sarcoma patient.
Mrs. Schwarz and Mrs. Fiebig-Frik are extremely talented in knitting, and love making Teddy bears and other decorative articles. In the cold but jolly Christmas market in Munich, they sold their latest creations, and, as a very touching gesture, donated all their proceedings to our research group. With the bottom of our hearts, we thank Mrs. Schwarz and Mrs. Fiebig-Frik for their generous contribution and recognition of our research.