SSO 2022 Press Release – Single-cell RNA Sequencing Reveals Differential Tumor Cell Response to Imatinib in Gastrointestinal Stromal Tumor
(Dallas, March 11, 2022; 1:11 p.m.) — Gastrointestinal stromal tumor is the most common human sarcoma and is typically driven by a single mutation in the KIT receptor. Targeted therapy with tyrosine kinase inhibitors is effective in gastrointestinal stromal tumor, but usually not curative.
Andrew Tieniber, MD, from the University of Pennsylvania in Philadelphia sought to define the molecular subsets of tumor cells in GIST to identify potential mechanisms of tumor cell persistence during imatinib therapy. He presented his research at the at the Society of Surgical Oncology 2022 International Conference on Surgical Care
Dr. Tieniber used KitV558Δ/+ mice, which spontaneously develop gastrointestinal stromal tumors. The mice were treated with imatinib or with a control for one week. Tumors were sorted for non-immune (CD45-) cells and submitted for single-cell RNA sequencing (ScRNAseq, n=3/group). An existing bulk RNA sequencing human gastrointestinal stromal tumors dataset was used to correlate gene expression with pathologic features.
Unsupervised clustering revealed four molecularly defined subsets of tumor cells which expressed the canonical markers of including Kit and Ano1 (Dog1), and the transcription factor Etv1. Clusters 2 and 3 were enriched for genes associated with epithelial-mesenchymal transition and metastasis (NES >2.0, FDR< 0.01), suggesting increased malignant potential.
After imatinib therapy, clusters one and four decreased by 30% and 41%, while clusters two and three increased by 44% and 29%, respectively. Subsets of cells that increased in proportion following imatinib had greater expression of the transcription factor Hand1, the growth factor Mdk (midkine), and the proliferation marker Pcna (p< 0.0001), all of which increased following imatinib.
In human GIST, Hand1 expression was associated with metastatic and imatinib-resistant tumors as well as higher mitotic rate (p< 0.05, n=75), suggesting downstream Hand1 targets are important in tumor progression. Human GIST Mdk expression was associated with metastatic tumors and higher mitotic rate (p< 0.05, n=75), which may provide independent growth signaling in the presence of imatinib.
“Our analysis of gastrointestinal stromal tumors revealed molecularly defined subsets of tumor cells at baseline. Imatinib increased specific tumor subsets expressing genes associated with GIST progression, highlighting the need for novel therapeutic strategies to target these persisting clusters,” Dr. Tieniber reported.
About the Society of Surgical Oncology
The Society of Surgical Oncology is a dynamic global community of cancer surgeons shaping advancements in the profession to deliver the highest quality surgical care for cancer patients. SSO promotes leading-edge research, quality standards and knowledge exchange, connecting cancer surgeons worldwide to continuously improve cancer outcomes. Our highly regarded educational resources, the Society’s clinical journal, Annals of Surgical Oncology and events, including SSO 2022 – International Conference on Surgical Cancer Care, inspire members and spur each cancer surgeon to grow, improve and thrive.