Biology subjects

Apfelbaum, A.

Publications and source records attributed to Apfelbaum, A..

2 recordsLinked to original sources

bioRxiv2025

O-mannosylation and protein maturation check-points represent therapeutic opportunities in BRAF fusion protein oncogenesis

Fusions between protein-coding genes are common oncogenic drivers across cancers, typically pairing a proto-oncogene with partner that does not independently drive cancer. In all therapeutically actionable fusions, the proto-oncogene is the drug target, the contributions to oncogenicity of the fusion partner have largely been ignored. We studied the role of BRAF fusion partners and found that they are necessary for transformation. In the setting of KIAA1549::BRAF, the most common fusion protein across brain tumors, we found that KIAA1549 is necessary for the oncogenicity of KIAA1549::BRAF and engenders a striking and specific dependency on the protein O-mannosyltransferase complex (POMT1/2). Specifically, we show that genetic silencing or pharmacologic inhibition of the protein O-mannosyltransferase complex (POMT1/2) reverses fusion-induced transformation, thereby representing a novel and MAPK independent therapeutic target. Furthermore, POMT1/2 is required to glycosylate and enable maturation of the K::B fusion protein. These findings represent a proof-of-concept for targeting the partners in oncogenic fusions as a potential cancer therapeutic strategy.

cancer biology↗

bioRxiv2025

Autocrine TGFβ2 enforces a transcriptionally hybrid cell state in Ewing sarcoma

Sub-populations of cancer-associated fibroblast (CAF)-like tumor cells deposit extracellular matrix (ECM) proteins that support Ewing sarcoma (EwS) progression and metastasis. We previously showed a hallmark of CAF-like EwS cells is their hybrid transcriptional state wherein the driver fusion oncogene, EWS::FLI1, maintains activation of proliferative programs but loses capacity to repress mesenchymal genes. Here, we studied primary patient tumors and cell line models to identify molecular drivers of this hybrid state. Our data reveal that hybrid EwS cells are induced and maintained by a TGF{beta} signaling positive feedback loop. Hybrid cells de-repress TGFBR2 and upregulate expression and secretion of TGF{beta}2 to sustain pathway activation and ECM deposition. While TGF{beta} ligands can potently induce growth arrest in cells of epithelial origin, we show that TGF{beta}1 and TGF{beta}2 promote cell invasion of EwS cells without affecting proliferation. Thus, stroma and tumor-derived TGF{beta} ligands induce and maintain hybrid EwS cells to promote pro-metastatic cell phenotypes.

cancer biology↗