Cell Rep Med. 2026 Apr 10:102741. doi: 10.1016/j.xcrm.2026.102741. Online ahead of print.

ABSTRACT

Combined small-cell lung cancer (cSCLC) is an aggressive subtype of SCLC with mixed histologic components. Despite heterogeneity and poorer prognosis than de novo SCLC, cSCLC is managed as SCLC because molecular insight into biology, lineage plasticity, and tumor microenvironment (TME) is limited. We perform spatial whole-exome sequencing, spatial transcriptomics, and single-nucleus RNA sequencing across 19 treatment-naive cSCLC tumors. Different histologic components share a monoclonal origin, whereas divergence associates with distinct mutation and copy-number alteration patterns. Our results define spatially exclusive or interspersed tumor domains with distinct TME and immune landscapes; fibroblast-rich boundaries enriched for an aggressive fibroblast subtype may shape TME and treatment responses. We identify lineage plasticity, including adenocarcinoma-to-SCLC transdifferentiation and SCLC-subtype coexistence, and develop cSCLC Detector, a sensitive mutation-based assay improving cSCLC detection in tissue and liquid biopsies. These findings illuminate cSCLC evolution and heterogeneity, underscoring the need for tailored diagnostic and therapeutic strategies for this aggressive subtype.

PMID:41966692 | DOI:10.1016/j.xcrm.2026.102741

Cell Rep Med. 2026 Apr 10:102741. doi: 10.1016/j.xcrm.2026.102741. Online ahead of print.

ABSTRACT

Combined small-cell lung cancer (cSCLC) is an aggressive subtype of SCLC with mixed histologic components. Despite heterogeneity and poorer prognosis than de novo SCLC, cSCLC is managed as SCLC because molecular insight into biology, lineage plasticity, and tumor microenvironment (TME) is limited. We perform spatial whole-exome sequencing, spatial transcriptomics, and single-nucleus RNA sequencing across 19 treatment-naive cSCLC tumors. Different histologic components share a monoclonal origin, whereas divergence associates with distinct mutation and copy-number alteration patterns. Our results define spatially exclusive or interspersed tumor domains with distinct TME and immune landscapes; fibroblast-rich boundaries enriched for an aggressive fibroblast subtype may shape TME and treatment responses. We identify lineage plasticity, including adenocarcinoma-to-SCLC transdifferentiation and SCLC-subtype coexistence, and develop cSCLC Detector, a sensitive mutation-based assay improving cSCLC detection in tissue and liquid biopsies. These findings illuminate cSCLC evolution and heterogeneity, underscoring the need for tailored diagnostic and therapeutic strategies for this aggressive subtype.

PMID:41966692 | DOI:10.1016/j.xcrm.2026.102741

Mol Divers. 2026 Apr 12. doi: 10.1007/s11030-026-11545-y. Online ahead of print.

NO ABSTRACT

PMID:41966666 | DOI:10.1007/s11030-026-11545-y

Discov Oncol. 2026 Apr 11. doi: 10.1007/s12672-026-04951-z. Online ahead of print.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Chromosome 8 open reading frame 33 (C8orf33) has been noted as a potential oncogenic factor in several cancers, but its biological roles and regulatory mechanism in HCC microenvironment remain unknown.

METHODS: We integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) to characterize the expression landscape of C8orf33. We then performed C8orf33 loss-of-function studies in HCC cell lines, including in vitro phenotypic assays and subcutaneous xenografts.

RESULTS: C8orf33 was broadly overexpressed and associated with unfavorable prognosis across multiple Cancers. In HCC, higher C8orf33 aligned with advanced stage and shorter overall survival. C8orf33 knockdown reduced proliferation and migration, impaired tumorigenic capacity, and increased apoptosis. ScRNA-seq analyses identified a malignant population of Epi3 with high C8orf33 expression. Cell-cell communication analysis suggested that C8orf33-high Epi3 state was associated with an enriched MIF-CD74/CXCR4/CD44 signaling program toward macrophage populations with M2-like features. ST analyses further confirmed the colocalization of C8orf33 with malignant features in tumor cores. In Huh7 cells, C8orf33 knockdown was accompanied by reduced mRNA and protein levels of MIF and its receptor components. Consistently, xenografts derived from C8orf33-silenced cells showed lower expression of these MIF-axis components and reduced infiltration of CD163 and CD206-positive macrophages.

CONCLUSION: These results support a tumor-promoting association of C8orf33 in HCC and suggest a potential link to macrophage-associated immunomodulatory features, nominating C8orf33 as a candidate biomarker and therapeutic target.

PMID:41965457 | DOI:10.1007/s12672-026-04951-z

Discov Oncol. 2026 Apr 11. doi: 10.1007/s12672-026-04951-z. Online ahead of print.

ABSTRACT

BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality. Chromosome 8 open reading frame 33 (C8orf33) has been noted as a potential oncogenic factor in several cancers, but its biological roles and regulatory mechanism in HCC microenvironment remain unknown.

METHODS: We integrated bulk RNA sequencing, single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) to characterize the expression landscape of C8orf33. We then performed C8orf33 loss-of-function studies in HCC cell lines, including in vitro phenotypic assays and subcutaneous xenografts.

RESULTS: C8orf33 was broadly overexpressed and associated with unfavorable prognosis across multiple Cancers. In HCC, higher C8orf33 aligned with advanced stage and shorter overall survival. C8orf33 knockdown reduced proliferation and migration, impaired tumorigenic capacity, and increased apoptosis. ScRNA-seq analyses identified a malignant population of Epi3 with high C8orf33 expression. Cell-cell communication analysis suggested that C8orf33-high Epi3 state was associated with an enriched MIF-CD74/CXCR4/CD44 signaling program toward macrophage populations with M2-like features. ST analyses further confirmed the colocalization of C8orf33 with malignant features in tumor cores. In Huh7 cells, C8orf33 knockdown was accompanied by reduced mRNA and protein levels of MIF and its receptor components. Consistently, xenografts derived from C8orf33-silenced cells showed lower expression of these MIF-axis components and reduced infiltration of CD163 and CD206-positive macrophages.

CONCLUSION: These results support a tumor-promoting association of C8orf33 in HCC and suggest a potential link to macrophage-associated immunomodulatory features, nominating C8orf33 as a candidate biomarker and therapeutic target.

PMID:41965457 | DOI:10.1007/s12672-026-04951-z

Front Immunol. 2026 Mar 24;17:1796926. doi: 10.3389/fimmu.2026.1796926. eCollection 2026.

ABSTRACT

BACKGROUND: Pulmonary immune homeostasis requires tight control of adaptive responses. Integrin β3 is a well-known mediator of cell adhesion and platelet function. However, its role in adaptive immunity, especially in B cell responses, remains unclear.

METHODS: We defined the pulmonary phenotype of constitutive β3-deficient (β3^-/-) mice by histopathology. We performed integrated transcriptomic and proteomic profiling of lung tissue to map the molecular signature of spontaneous pulmonary inflammation. We further probed the underlying mechanisms with additional histology and functional assays and tested for biological significance using transcriptomics data from auto-immune disease patients.

RESULTS: β3^-/- mice developed spontaneous pulmonary inflammation marked by B cell activation and in situ immune-complex deposition within alveoli. Multi-omics integration implicated the CD40-CD40 Ligand (CD40L) axis as a central driver of this pathology. Mechanistically, loss of β3 enhanced CD40L-CD40 engagement on B cells, resulting in NF-κB pathway hyperactivation. Consistent with our murine data, reduced ITGB3 expression in patients with autoimmune disease correlated with transcriptional signatures of B cell activation and inflammation.

CONCLUSIONS: These results reframe integrin β3 as a threshold regulator of B cell activation. The β3-CD40L-CD40 axis therefore represents a potential therapeutic target for B cell-mediated autoimmune diseases.

PMID:41953039 | PMC:PMC13055533 | DOI:10.3389/fimmu.2026.1796926

Front Immunol. 2026 Mar 24;17:1796926. doi: 10.3389/fimmu.2026.1796926. eCollection 2026.

ABSTRACT

BACKGROUND: Pulmonary immune homeostasis requires tight control of adaptive responses. Integrin β3 is a well-known mediator of cell adhesion and platelet function. However, its role in adaptive immunity, especially in B cell responses, remains unclear.

METHODS: We defined the pulmonary phenotype of constitutive β3-deficient (β3^-/-) mice by histopathology. We performed integrated transcriptomic and proteomic profiling of lung tissue to map the molecular signature of spontaneous pulmonary inflammation. We further probed the underlying mechanisms with additional histology and functional assays and tested for biological significance using transcriptomics data from auto-immune disease patients.

RESULTS: β3^-/- mice developed spontaneous pulmonary inflammation marked by B cell activation and in situ immune-complex deposition within alveoli. Multi-omics integration implicated the CD40-CD40 Ligand (CD40L) axis as a central driver of this pathology. Mechanistically, loss of β3 enhanced CD40L-CD40 engagement on B cells, resulting in NF-κB pathway hyperactivation. Consistent with our murine data, reduced ITGB3 expression in patients with autoimmune disease correlated with transcriptional signatures of B cell activation and inflammation.

CONCLUSIONS: These results reframe integrin β3 as a threshold regulator of B cell activation. The β3-CD40L-CD40 axis therefore represents a potential therapeutic target for B cell-mediated autoimmune diseases.

PMID:41953039 | PMC:PMC13055533 | DOI:10.3389/fimmu.2026.1796926

Acta Biochim Biophys Sin (Shanghai). 2026 Mar 25. doi: 10.3724/abbs.2025238. Online ahead of print.

ABSTRACT

The environmental pollutant benzo(a)pyrene (B(a)P), a representative polycyclic aromatic hydrocarbon (PAH), is a recognized carcinogen, and chronic pulmonary inflammation is closely associated with lung carcinogenesis. Although alveolar type 2 (AT2) cells are the origin of lung adenocarcinoma, the genetic and functional changes in AT2 cells and the mechanisms involved in inflammation-related lung tumorigenesis have not been elucidated. Here, C57BL/6J mice are exposed to B(a)P and the inflammatory irritant lipopolysaccharide (LPS) to establish a model of inflammation-related lung tumorigenesis. Single-cell RNA sequencing is performed on lung tissues. DNA mutations in AT2 cells are analyzed via whole-exome sequencing. The protein expression of AT2 cells in lung cancer tissue is determined by immunofluorescence staining. The results reveal that LPS promotes B(a)P-induced lung tumorigenesis; in the whole lungs of B(a)P/LPS, a decreased proportion, altered differentiation trajectory, and increased gene mutation number in AT2 cells are observed. Additionally, in B(a)P/LPS-treated lung cancer tissue, the levels of γ-H2AX DNA damage and the proliferation marker Ki67 in AT2 cells are increased, whereas the levels of differentiation markers are decreased. Single-cell RNA transcriptomics reveals that the autophagy-related genes Foxo3 and Ppp2r5, which are enriched in the PI3K-Akt pathway, and the autophagy-related genes in AT2 cells in lung cancer are decreased in the B(a)P/LPS group. Thus, chronic inflammation promotes DNA damage, gene mutation and dysfunction in AT2 cells, and decreased autophagy in AT2 cells may be an important mechanism for inflammation-related lung tumorigenesis.

PMID:41952558 | DOI:10.3724/abbs.2025238