Cancer Discov. 2026 Apr 15. doi: 10.1158/2159-8290.CD-25-1663. Online ahead of print.

ABSTRACT

Brain metastases (BM) remain a devastating disease with dismal prognosis. How circulating tumor cells (CTCs) penetrate the blood brain barrier (BBB) and reprogram the brain microenvironment remain unclear. Using spatially resolved multi-omic profiling of CTCs and brain metastases, integrated with experimental and clinical analyses, we identified Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) as a CTC-secreted driver of vascular disruption and brain colonization. CBX3 upregulation induced GPNMB expression, which bound endothelial EGFR, triggering CBL-mediated ubiquitination and degradation. Attenuated EGFR signaling suppressed FTO and disrupted endothelial junctions via YTHDF2-dependent TJP1 m6A methylation. Remarkably, GPNMB-induced BBB remodeling promoted immune infiltration via CXCL12-CXCR4 axis, and induced time course-dependent T cell exhaustion within the brain microenvironment. Clinically, elevated CBX3⁺GPNMB⁺ CTCs and plasma CXCL12 were significantly associated with BM progression in lung cancer and melanoma. Therapeutically, dual blockade of GPNMB and PD1 enhanced anti-BM efficacy in mice, unveiling GPNMB as a promising target for precision immunotherapy.

PMID:41973996 | DOI:10.1158/2159-8290.CD-25-1663

Am J Surg Pathol. 2026 Jun 1;50(6):695-704. doi: 10.1097/PAS.0000000000002533. Epub 2026 Mar 13.

ABSTRACT

With the application of molecular techniques in pathologic diagnosis, several novel primary pulmonary epithelial tumors have been continuously discovered and classified under the WHO classification of thoracic tumors. Recently, a pulmonary tumor with NFATC2 :: NUTM2B fusion was first documented, but the spectrum of NFATC2::NUTM2 fusion variants and their associated pathologic features remains incompletely characterized. Coincidentally, we also found and described 6 primary pulmonary tumors harboring recurrent NFATC2::NUTM2A/E fusions through integrated genomic analysis. These patients, including 4 females and 2 males, with a median age of 53 years, presented with incidentally detected peripheral lung nodules composed of monotonous epithelioid cells arranged in cords, nests, and trabeculae within a prominent desmoplastic stroma. All tumors exhibited a consistent immunophenotype: CK5/6+/GATA3+/calponin+/EMA+/DOG1 (perinuclear dot-like staining)/p63-. High-throughput chromosome conformation capture (Hi-C) analysis showed the structural variation of NFATC2::NUTM2E in all 6 cases, whereas RNA sequencing detected the fusion transcripts in 5 cases ( NFATC2::NUTM2A , n=2; NFATC2::NUTM2E , n=3). Ultrastructural examination of 1 case suggested epithelial differentiation. All patients remained disease-free after complete resection (median follow-up: 24 mo; range: 9 to 41 mo). These findings define a novel primary pulmonary tumor entity driven by NFATC2::NUTM2 fusions, and characterized by a distinctive immunophenotype, expanding the spectrum of NUTM2 -associated neoplasms. Our study underscores the utility of multiomics approaches for characterizing rare neoplasms and provides a diagnostic framework for this entity.

PMID:41821426 | DOI:10.1097/PAS.0000000000002533

Am J Surg Pathol. 2026 Mar 13. doi: 10.1097/PAS.0000000000002533. Online ahead of print.

ABSTRACT

With the application of molecular techniques in pathologic diagnosis, several novel primary pulmonary epithelial tumors have been continuously discovered and classified under the WHO classification of thoracic tumors. Recently, a pulmonary tumor with NFATC2::NUTM2B fusion was first documented, but the spectrum of NFATC2::NUTM2 fusion variants and their associated pathologic features remains incompletely characterized. Coincidentally, we also found and described 6 primary pulmonary tumors harboring recurrent NFATC2::NUTM2A/E fusions through integrated genomic analysis. These patients, including 4 females and 2 males, with a median age of 53 years, presented with incidentally detected peripheral lung nodules composed of monotonous epithelioid cells arranged in cords, nests, and trabeculae within a prominent desmoplastic stroma. All tumors exhibited a consistent immunophenotype: CK5/6+/GATA3+/calponin+/EMA+/DOG1 (perinuclear dot-like staining)/p63-. High-throughput chromosome conformation capture (Hi-C) analysis showed the structural variation of NFATC2::NUTM2E in all 6 cases, whereas RNA sequencing detected the fusion transcripts in 5 cases (NFATC2::NUTM2A, n=2; NFATC2::NUTM2E, n=3). Ultrastructural examination of 1 case suggested epithelial differentiation. All patients remained disease-free after complete resection (median follow-up: 24 mo; range: 9 to 41 mo). These findings define a novel primary pulmonary tumor entity driven by NFATC2::NUTM2 fusions, and characterized by a distinctive immunophenotype, expanding the spectrum of NUTM2-associated neoplasms. Our study underscores the utility of multiomics approaches for characterizing rare neoplasms and provides a diagnostic framework for this entity.

PMID:41821426 | DOI:10.1097/PAS.0000000000002533