Demetri, G. D. | Search bioRxiv

bioRxiv2025

Epigenetic dysregulation of metabolic programs mediates liposarcoma cell plasticity

Sarcomas are rare connective tissue cancers thought to arise from aberrant mesenchymal stem cell (MSC) differentiation. Liposarcoma (LPS) holds valuable insights into dysfunctional differentiation given its well- and dedifferentiated histologic subtypes (WDLPS, DDLPS). Despite well-established differences in histology and clinical behavior, the molecular pathways underlying each subtype are poorly understood. Here, we performed single-nucleus multiome sequencing and spatial profiling on carefully curated human LPS samples and found defects in adipocyte-specific differentiation within LPS. Loss of insulin-like growth factor 1 (IGF1) and gain of cellular programs related to early mesenchymal development and glucagon-like peptide-1 (GLP-1)-induced insulin secretion are primary features of DDLPS. IGF1 loss was associated with worse overall survival in LPS patients. Through in vitro stimulation of the IGF1 pathway, we identified that DDLPS cells are deficient in the adipose-specific PPARG isoform 2 (PPARG2). Defects in IGF1/PPARG2 signaling in DDLPS led to a block in differentiation that could not be fully overcome with the addition of exogenous IGF1 or the pro-adipogenic agonists to PPARG and GLP-1. However, we noted upregulation of the IGF1 receptor (IGF1R) in the setting of IGF1 deficiency, which promoted sensitivity to an IGF1R-targeted antibody-drug conjugate that may serve as a novel therapeutic strategy in LPS. In summary, lineage-specific defects in adipogenesis drive dedifferentiation in LPS and may translate into selective therapeutic targeting in this disease.

cancer biology↗

bioRxiv2019

The Angiosarcoma Project: enabling genomic and clinical discoveries in a rare cancer through patient-partnered research

Despite collectively accounting for 25% of tumors in U.S. adults, rare cancers have significant unmet clinical needs as they are difficult to study due to low incidence and geographically dispersed patient populations. We sought to assess whether a patient-partnered research approach using online engagement can overcome these challenges and accelerate scientific discovery in rare cancers, focusing on angiosarcoma (AS), an exceedingly rare sarcoma with a dismal prognosis and an annual U.S. incidence of 300 cases. Here, we describe the development of the Angiosarcoma Project (ASCproject), an initiative enabling patients across the U.S. and Canada to remotely share their clinical information and biospecimens for research. The project generates and publicly releases clinically annotated genomic data on tumor and germline specimens on an ongoing basis. Over 18 months, 338 AS patients registered for the ASCproject, comprising a significant fraction of all patients. Whole exome sequencing of 47 AS tumors revealed several recurrently mutated genes, including KDR, TP53, and PIK3CA. Activating mutations in PIK3CA were observed nearly exclusively in primary breast AS, suggesting a therapeutic rationale in these patients. AS of the head, neck, face, and scalp (HNFS) was associated with high tumor mutation burden and a dominant mutational signature of UV light exposure, suggesting that UV damage may be a causative factor in HNFS AS and that this AS subset might be amenable to immune checkpoint inhibitor therapy. Medical record review revealed two patients with HNFS AS received off-label treatment with anti-PD-1 therapy and experienced exceptional responses, highlighting immune checkpoint inhibition as a therapeutic avenue for HNFS AS. This patient-partnered approach has catalyzed an opportunity to discover the etiology and potential therapies for AS patients. Collectively, this proof of concept study demonstrates that empowering patients to directly participate in research can overcome barriers in rare diseases and enable biological and clinical discoveries.

cancer biology↗