Abstract A019: Investigating of the impact of <i>COL1A1::PDGFB</i> fusion in mouse <i>Col1a2+</i> dermal embryonic fibroblasts as a potential cell of origin of dermatofibrosarcoma protuberans

Abstract Dermatofibrosarcoma protuberans (DFSP) is the most common cutaneous sarcoma and is characterized by chromosomal translocations, most frequently t(17;22) encoding the fusion protein COL1A1::PDGFB. This malignancy arises in the dermis of the skin and exhibits spindle cell morphology and deep invasion to the subcutis. DFSP is presumed to arise as a result of COL1A1::PDGFB fusion-driven uncontrolled PDGFB expression by the COL1A1 promoter, which is highly active in dermal fibroblasts. However, the cell of origin of DFSP remains unclear, as this tumor exhibits expression of neural markers and CD34 positivity, leading to longstanding speculation regarding a non-fibroblastic cell of origin. Interestingly, several pediatric cases of DFSP are noted at the time of birth, raising the possibility of an embryonic cell-of-origin in some patients. In addition, emerging evidence suggests that early stem cell populations can be reprogrammed by oncogenic fusion proteins and impact cellular phenotypes. We sought to test the hypothesis that embryonic dermal fibroblasts expressing a modified fusion protein could develop DFSP-like tumors in mouse skin. To test this, a 747 base pair fusion protein cDNA was designed to include the regions of the COL1A1::PDGFB conserved across human DFSP tumors, particularly the COL1A1 signal peptide and exons 2-7 of PDGFB in a DNA construct that contains fibroblast-specific promoter and enhancer elements of Col1a2. An internal ribosome entry site (IRES) followed by the mCherry red fluorescent protein (RFP) sequence allowed identification of transgene expression by RFP fluorescence. This construct was introduced into fertilized mouse oocytes via pronuclear injection and embryos were collected for analysis. Effective transgene expression was detected by RFP and genotypes were confirmed by PCR with transgene-specific primers. A total of 15 out of 99 (15.2%) of embryos harbored the transgene and revealed a spectrum of phenotypes. Strong transgene expression caused severe embryonic malformations, whereas weaker expression was associated with abnormal development of the dermis, epidermis, and hair follicles. No tumors or obvious proliferations were present in any embryos evaluated. Taken together, this work shows that fusion oncogene and/or high-level PDGFB signaling in developing dermal fibroblasts causes embryonic toxicity, whereas lower degrees of signaling demonstrate impaired development of normal cutaneous structures. Further studies to investigate other putative cells of origin, as well as strategies to mitigate embryonic toxicity (such as using an inducible system which allows for postnatal transgene expression) are warranted. These studies suggest a degree of oncogene toxicity due to COL1A1::PDGFB expression in some cells. Future studies to investigate how cells tolerate this oncogene may lead to new insights regarding the growth and survival of DFSP cells that could be exploited for therapy. Citation Format: Elisabeth A. Pedersen, Li-Jyun Syu, Andrzej A. Dlugosz, Monique E. Verhaegen. Investigating of the impact of COL1A1::PDGFB fusion in mouse Col1a2+ dermal embryonic fibroblasts as a potential cell of origin of dermatofibrosarcoma protuberans [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Fusion-Positive Cancer: From Discovery to Therapy; 2026 Jan 13-15; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(1_Suppl):Abstract nr A019.