Biology subjects

Collier, C. D.

Publications and source records attributed to Collier, C. D..

2 recordsLinked to original sources

bioRxiv2026

ZNF423 depletion induces the integrated stress response and represents a potential vulnerability in NF1-associated MPNST

Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited systemic therapies and represent the leading cause of mortality for individuals with neurofibromatosis type 1 (NF1). Malignant progression can reactivate developmental precursor programs that are largely absent from normal nerve and benign tumors, creating tumor-selective vulnerabilities. Zinc finger protein 423 (ZNF423; also known as OAZ/ROAZ) is a developmentally regulated transcription factor that delays olfactory precursor differentiation and has been implicated in B-cell malignancy. Here, we asked whether ZNF423 is reactivated and functionally required in NF1-associated MPNST. In genetically defined models, Nf1 loss reduced Zfp423 in a benign tumor cell-of-origin context, whereas combined Nf1 and Cdkn2a loss induced marked Zfp423 upregulation during transformation. ZNF423 depletion impaired DNA synthesis and proliferation, induced DNA damage signaling, and activated the integrated stress response (ISR), increasing sensitivity to cytotoxic agents. In an orthotopic MPNST model, shRNA-mediated suppression of ZNF423 reduced tumor initiation in vivo; however, tumors that eventually emerged showed restoration of ZNF423 expression. ZNF423 is developmentally restricted in the peripheral nerve lineage yet elevated in MPNST, with single-cell analyses of patient nerve sheath tumors revealing localized expression restricted to malignant cells rather than SOX10-positive benign tumor cells. These data identify ZNF423 as a putative malignant biomarker, a potential dependency in NF1-MPNST, and nominate downstream stress and genome maintenance pathways as cooperative therapeutic vulnerabilities. STATEMENT OF SIGNIFICANCEZNF423 is a developmentally restricted transcription factor selectively reactivated in NF1-associated malignant peripheral nerve sheath tumors. Targeted ablation triggers the integrated stress response, impairs DNA synthesis, sensitizes cells to chemotherapy and PARP inhibition, and restricts in vivo growth. ZNF423 represents a candidate biomarker and therapeutic vulnerability in this aggressive sarcoma.

cancer biology↗

bioRxiv2025

Repurposing Romidepsin for Osteosarcoma: Screening FDA-Approved Oncology Drugs with Three-Dimensional Osteosarcoma Spheroids

Osteosarcoma is the most common primary malignant bone tumor and predominantly affects children, adolescents, and young adults. It is the third most common cause of cancer-related deaths among 9-24-year-olds. Despite aggressive chemotherapeutic and surgical therapies, the survival rate is only 25% for patients with detectable lung metastases at diagnosis and only 70% in patients that present without detectable lung metastases. The poor prognosis is due to growth of metastases irrespective of whether they are initially large enough to detect clinically. It is therefore necessary to develop new methods to target the growth of lung micrometastases. An NCI panel of FDA-approved oncology drugs was therefore screened using three highly metastatic human osteosarcoma cell lines. To more closely approximate in vivo micro-metastases, the screen used a 3D multicellular in vitro osteosarcoma spheroid (sarcosphere) model. Among 13 hits from the initial screen, we identified the histone deacetylase inhibitor (HDI) romidepsin as the most promising inhibitor in secondary screens based on sarcosphere viability. Romidepsin potency was evident with and without standard-of-care chemotherapeutics (MAP: Methotrexate, Adriamycin, Cisplatin) at drug concentrations that are clinically achievable and did not affect non-transformed cells. By those criteria, romidepsin also substantially outperformed the other three FDA-approved HDIs and eight HDIs in clinical trials. Importantly, sarcospheres derived from 30-50% of human and canine patient samples were also sensitive to romidepsin with ED50s 10- to 700-fold less than the Cmax in human patients. Based on these 3-D screening approaches, romidepsin is a promising drug to repurpose for osteosarcoma. Significance StatementOur unbiased sarcosphere-based drug screen identified romidepsin as a promising candidate to repurpose for canine and human patients with metastatic osteosarcoma. This screening strategy allowed us to identify romidepsin-sensitive and -resistant patients. Sarcosphere-based screening may therefore be useful to stratify patients most likely to respond clinically to romidepsin or other drugs.

cancer biology↗