13: Spatially resolved single cell transcriptomic analysis of matched primary and metastatic lesions in sarcomatoid renal cell carcinoma reveals insights to tumor biology

Background: Sarcomatoid renal cell carcinoma (sRCC) is a de-differentiated form of RCC, most commonly derived from clear cell RCC (ccRCC). sRCC is highly aggressive and associated with metastasis. Limited data exists to understand whether it is the ccRCC or sRCC tumor cell features that promote metastasis in these tumors. Here, we use single cell spatial technology to understand the transcriptomic features present in ccRCC vs sRCC in primary tumors and matched metastases.

Methods: A total of 6 specimens (4 primary lesions and 2 metastatic lesions) from 2 patients with ccRCC/sRCC were analyzed for spatially resolved single cell transcriptomics using the NanoString CosMx platform. Cell types were analyzed by semi supervised clustering and nearest neighbor methodology was utilized to perform neighborhood or niche analysis. Cell types, niches, and transcriptomic patterns were assessed between tumor regions.

Results: sRCC regions displayed high intra-region and inter-region heterogeneity of cell type, niches, and transcriptomic patterns while ccRCC and metastatic lesions were fairly homogenous and more transcriptionally similar to each other than to sRCC regions. ccRCC and metastatic lesions consisted of a higher percentage of dendritic cells relative to sRCC whereas sRCC regions had increased macrophage infiltrate. Several genes, notably POU5F1 which is a known contributor to pluripotency and associated with dendritic cell infiltrate, were overexpressed in ccRCC and metastatic lesions of both patients compared to sRCC regions.

Conclusions: This data supports a hypothesis that ccRCC cell types with stem-like features may be more apt to metastasis than sRCC cells. We identify POU5F1 as an important gene for further study in ccRCC/sRCC metastasis. Unique microenvironmental niches are associated with ccRCC, sRCC, and metastatic lesions and ongoing work explores the role of these niches in shaping the aggressive biology of sRCC.