TY - JOUR
T1 - Spatially resolved ex vivo drug response profiling in SMARCB1-deficient sinonasal carcinoma
AU - Jurmeister, Philipp
AU - Flach, Susanne
AU - Bergmayr, Linda
AU - Schleich, Konstanze
AU - Chimal Calderon, Edgar
AU - H Mochmann, Liliana
AU - Zhdanovich, Yauheniya
AU - Klingler, Doreen
AU - Pusztai, Ada
AU - Kübler, Anna
AU - Walz, Christoph
AU - Westphalen, Christoph Benedikt
AU - Beck, Alexander
AU - Leitheiser, Maximilian
AU - Breimer, Gerben E
AU - Rijken, Johannes A
AU - Devriese, Lot
AU - Baumeister, Philipp
AU - Skálová, Alena
AU - Schallenberg, Simon
AU - Klauschen, Frederick
AU - Mock, Andreas
N1 - Publisher Copyright:
© The Author(s) 2026.
PY - 2026/6/15
Y1 - 2026/6/15
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105037715362
U2 - 10.1038/s44321-026-00437-1
DO - 10.1038/s44321-026-00437-1
M3 - Article
C2 - 42070010
SN - 1757-4676
VL - 18
SP - 2360
EP - 2378
JO - Embo Molecular Medicine
JF - Embo Molecular Medicine
IS - 6
ER -