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Spatially resolved ex vivo drug response profiling in SMARCB1-deficient sinonasal carcinoma
Philipp Jurmeister1,2, Susanne Flach3,4, Linda Bergmayr5
1Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany. philipp.jurmeister@med.uni-muenchen.de.
Abstract:
SMARCB1-deficient sinonasal carcinoma (SDSC) is a rare, highly aggressive malignancy with limited therapeutic options and no established preclinical models. Here, single-nucleus RNA sequencing (snRNAseq), spatial transcriptomics, and ex vivo patient-derived tissue slice culture (TSC) were combined to resolve intratumoral heterogeneity, niche organization, and treatment vulnerabilities in an index SDSC. snRNAseq identified three malignant subpopulations, including two specialized states marked by ALDH1A1 and NTN4. Spatial profiling mapped these states to distinct niches. The ALDH1A1+ compartment localized to a basal-associated niche with intermingled p63-positive basal cells adjacent to stroma, showed reduced proliferative activity, and displayed stem-like transcriptional features. Ex vivo drug testing revealed a striking response: the mTOR inhibitor Sapanisertib induced extensive tumor necrosis and was associated with near-complete depletion of ALDH1A1+ and NTN4+ states, accompanied by strong stress/apoptosis signatures and reduced endothelial cells. In an additional retrospective cohort of 12 SDSC, ALDH1A1 was present in all cases with heterogeneous spatial patterns and higher levels in recurrences. Mesothelin was expressed in the index case and a subset of tumors, supporting mesothelin-directed therapeutic strategies.
Insights
SMARCB1-deficient sinonasal carcinoma (SDSC) is aggressive. Targeting mTOR with Sapanisertib depleted key tumor cells and reduced tumor size, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Genomics
- Cancer Biology
Background:
- SMARCB1-deficient sinonasal carcinoma (SDSC) is a rare, aggressive cancer with few treatments.
- Lack of preclinical models hinders research into SDSC.
Purpose of the Study:
- Investigate intratumoral heterogeneity and treatment vulnerabilities in SDSC.
- Establish preclinical models for SDSC research.
Main Methods:
- Single-nucleus RNA sequencing (snRNAseq) to identify tumor cell states.
- Spatial transcriptomics to map cell locations.
- Ex vivo patient-derived tissue slice culture (TSC) for drug testing.
Main Results:
- Identified three malignant subpopulations, including ALDH1A1+ and NTN4+ states in distinct niches.
- Sapanisertib (mTOR inhibitor) induced tumor necrosis and depleted ALDH1A1+ and NTN4+ cells.
- ALDH1A1 was elevated in recurrences; mesothelin expression suggests therapeutic potential.
Conclusions:
- SDSC exhibits significant intratumoral heterogeneity.
- Targeting mTOR with Sapanisertib shows promise for SDSC treatment.
- ALDH1A1 and mesothelin are potential biomarkers and therapeutic targets for SDSC.
