Single-cell and spatial transcriptomics identify COL6A3 as a prognostic biomarker in undifferentiated pleomorphic sarcoma

Sep 21, 2026

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Undifferentiated pleomorphic sarcoma (UPS) and related pleomorphic sarcomas show heterogeneous causes, metastasis rates, and survival. Distinguishing the dermal subtypes atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) is difficult at initial biopsy, yet their prognoses differ markedly. Using single-cell and spatial transcriptomics across AFX, PDS, and a PDS excision specimen, top differential genes stratified overall survival in external cancers. In UPS cohorts, COL6A3 predicted overall survival and improved metastasis prediction beyond an established sarcoma prognostic gene panel.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages6

Reading Time15 min

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Abstract

Tumor heterogeneity and diagnostic challenge

Transcriptomic strategy and gene discovery

COL6A3 performance as a prognostic biomarker

Limitations of existing prognostic markers

Context of sarcoma prognostic panels

Klein etal. Molecular Cancer (2024) 23:257 [https://doi.org/10.1186/s12943-024-02168-8](https://doi.org/10.1186/s12943-024-02168-8) Molecular Cancer CORRESPONDENCE Open Access Single-cell and spatial transcriptomics identify COL6A3 as a prognostic biomarker in undifferentiated pleomorphic sarcoma Jason C. Klein 1,2*, Lei Wang3, Douglas Strand4, Chewlan Lastufka5, Gregory A. Hosler2,5 and Gary C. Hon3* Abstract Undifferentiated pleomorphic sarcoma (UPS) and related tumors are the most common type of soft tissue sarcoma. However, this spectrum of tumors has different etiologies with varying rates of metastasis and survival. Two dermal-based neoplasms in this class of pleomorphic sarcomas, atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS), are challenging to differentiate at initial biopsy but vary significantly in prognosis. We performed single-cell transcriptomics on five AFX and PDS biopsy specimens as well as both single-cell and spatial transcriptomics on one PDS excision specimen to better characterize these tumors. The top differential genes between AFX and PDS were predictive of overall survival in 17 other cancers included in the Human Protein Atlas. Of these genes, COL6A3 and BGN predicted overall survival and metastasis-free survival in independent cohorts of 46 and 38 UPS tumors, respectively. COL6A3 was most predictive of overall survival in UPS patients and outperformed an established sarcoma prognostic gene panel at predicting metastasis in UPS. Keywords Sarcoma, Prognosis, Biomarker, Single-cell transcriptomics, Spatial transcriptomics, Collagen, Undifferentiated pleomorphic sarcoma, Atypical fibroxanthoma, Pleomorphic dermal sarcoma *Correspondence: Jason C. Klein [jason.klein@cuanschutz.edu](jason.klein@cuanschutz.edu)[ ](jason.klein@cuanschutz.edu)Gary C. Hon [gary.hon@utsouthwestern.edu](gary.hon@utsouthwestern.edu) 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA 2Department of Dermatology, University of Texas Southwestern Medical Center, Dallas TX75390, USA 3Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA 4Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA 5ProPath/Sonic Healthcare, Dallas, TX 75390, USA To the editor According to the American Cancer Society, over 13,000 soft tissue sarcomas are diagnosed annually in the United States and result in approximately 5,000 deaths. Of these, undifferentiated pleomorphic sarcoma (UPS), previously named malignant fibrous histiocytoma, is most common. UPS, which includes neoplasms of internal organs, retroperitoneum, and bone, falls in a broader family of pleomorphic sarcomas including two dermal-based neoplasms, atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS). Therefore, prognosis varies greatly within this spectrum of tumors, from a very rare metastasis rate of AFX to > 50% metastasis rate of deep UPS [1]. Currently, prognosis for AFX and PDS is based on histopathologic evidence of invasion into the subcutis. Invasive tumors (PDS) have a higher 5-year risk of local © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Comm

FAQs

Why are AFX and PDS challenging to differentiate at diagnosis, and why does it matter?

AFX and PDS are difficult to distinguish at initial biopsy, although they show significantly different prognoses and metastasis risks within the pleomorphic sarcoma spectrum.

What transcriptomic approaches were used in this study?

The study used single-cell transcriptomics on AFX and PDS biopsy specimens and combined single-cell and spatial transcriptomics on a PDS excision specimen to characterize tumor biology.

How does COL6A3 relate to prognosis in UPS?

COL6A3 predicted overall survival in UPS patients and outperformed an established sarcoma prognostic gene panel for predicting metastasis in UPS.

Sep 21, 2026

Uploaded by Eden