Genetic Deletion of Galectin-3 Inhibits Pancreatic Cancer Progression and Enhances the Efficacy of Immunotherapy.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) has a desmoplastic tumor stroma and immunosuppressive microenvironment. Galectin-3 (GAL3) is enriched in PDAC, highly expressed by cancer cells and myeloid cells. However, the functional roles of GAL3 in the PDAC microenvironment remain elusive. METHODS: We generated a novel transgenic mouse model (LSL-KrasG12D/+;Trp53loxP/loxP;Pdx1-Cre;Lgals3-/- [KPPC;Lgals3-/-]) that allows the genetic depletion of GAL3 from both cancer cells and myeloid cells in spontaneous PDAC formation. Single-cell RNA-sequencing analysis was used to identify the alterations in the tumor microenvironment upon GAL3 depletion. We investigated both the cancer cell-intrinsic function and immunosuppressive function of GAL3. We also evaluated the therapeutic efficacy of GAL3 inhibition in combination with immunotherapy. RESULTS: Genetic deletion of GAL3 significantly inhibited the spontaneous pancreatic tumor progression and prolonged the survival of KPPC;Lgals3-/- mice. Single-cell analysis revealed that genetic deletion of GAL3 altered the phenotypes of immune cells, cancer cells, and other cell populations. GAL3 deletion significantly enriched the antitumor myeloid cell subpopulation with high major histocompatibility complex class II expression. We also identified that GAL3 depletion resulted in CXCL12 upregulation, which could act as a potential compensating mechanism on GAL3 deficiency. Combined inhibition of the CXCL12-CXCR4 axis and GAL3 enhanced the efficacy of anti-PD-1 immunotherapy, leading to significantly inhibited PDAC progression. In addition, deletion of GAL3 also inhibited the basal/mesenchymal-like phenotype of pancreatic cancer cells. CONCLUSIONS: GAL3 promotes PDAC progression and immunosuppression via both cancer cell-intrinsic and immune-related mechanisms. Combined treatment targeting GAL3, CXCL12-CXCR4 axis, and PD-1 represents a novel therapeutic strategy for PDAC.

Genome-wide CRISPR screen reveals the synthetic lethality between BCL2L1 inhibition and radiotherapy.

Radiation therapy (RT) is one of the most commonly used anticancer therapies. However, the landscape of cellular response to irradiation, especially to a single high-dose irradiation, remains largely unknown. In this study, we performed a whole-genome CRISPR loss-of-function screen and revealed temporal inherent and acquired responses to RT. Specifically, we found that loss of the IL1R1 pathway led to cellular resistance to RT. This is in part because of the involvement of radiation-induced IL1R1-dependent transcriptional regulation, which relies on the NF-κB pathway. Moreover, the mitochondrial anti-apoptotic pathway, particularly the BCL2L1 gene, is crucially important for cell survival after radiation. BCL2L1 inhibition combined with RT dramatically impeded tumor growth in several breast cancer cell lines and syngeneic models. Taken together, our results suggest that the combination of an apoptosis inhibitor such as a BCL2L1 inhibitor with RT may represent a promising anticancer strategy for solid cancers including breast cancer.

Unraveling the intercellular communication disruption and key pathways in Alzheimer's disease: an integrative study of single-nucleus transcriptomes and genetic association.

BACKGROUND: Recently, single-nucleus RNA-seq (snRNA-seq) analyses have revealed important cellular and functional features of Alzheimer's disease (AD), a prevalent neurodegenerative disease. However, our knowledge regarding intercellular communication mediated by dysregulated ligand-receptor (LR) interactions remains very limited in AD brains. METHODS: We systematically assessed the intercellular communication networks by using a discovery snRNA-seq dataset comprising 69,499 nuclei from 48 human postmortem prefrontal cortex (PFC) samples. We replicated the findings using an independent snRNA-seq dataset of 56,440 nuclei from 18 PFC samples. By integrating genetic signals from AD genome-wide association studies (GWAS) summary statistics and whole genome sequencing (WGS) data, we prioritized AD-associated Gene Ontology (GO) terms containing dysregulated LR interactions. We further explored drug repurposing for the prioritized LR pairs using the Therapeutic Targets Database. RESULTS: We identified 190 dysregulated LR interactions across six major cell types in AD PFC, of which 107 pairs were replicated. Among the replicated LR signals, we found globally downregulated communications in the astrocytes-to-neurons signaling axis, characterized, for instance, by the downregulation of APOE-related and Calmodulin (CALM)-related LR interactions and their potential regulatory connections to target genes. Pathway analyses revealed 44 GO terms significantly linked to AD, highlighting Biological Processes such as 'amyloid precursor protein processing' and 'ion transmembrane transport,' among others. We prioritized several drug repurposing candidates, such as cromoglicate, targeting the identified dysregulated LR pairs. CONCLUSIONS: Our integrative analysis identified key dysregulated LR interactions in a cell type-specific manner and the associated GO terms in AD, offering novel insights into potential therapeutic targets involved in disrupted cell-cell communication in AD.

Unraveling the intercellular communication disruption and key pathways in Alzheimer's disease: An integrative study of single-nucleus transcriptomes and genetic association.

Background: Recently, single-nucleus RNA-seq (snRNA-seq) analyses have revealed important cellular and functional features of Alzheimer's disease (AD), a prevalent neurodegenerative disease. However, our knowledge regarding intercellular communication mediated by dysregulated ligand-receptor (LR) interactions remains very limited in AD brains. Methods: We systematically assessed the intercellular communication networks by using a discovery snRNA-seq dataset comprising 69,499 nuclei from 48 human postmortem prefrontal cortex (PFC) samples. We replicated the findings using an independent snRNA-seq dataset of 56,440 nuclei from 18 PFC samples. By integrating genetic signals from AD genome-wide association studies (GWAS) summary statistics and whole genome sequencing (WGS) data, we prioritized AD-associated Gene Ontology (GO) terms containing dysregulated LR interactions. We further explored drug repurposing for the prioritized LR pairs using the Therapeutic Targets Database. Results: We identified 316 dysregulated LR interactions across six major cell types in AD PFC, of which 210 pairs were replicated. Among the replicated LR signals, we found globally downregulated communications in astrocytes-to-neurons signaling axis, characterized, for instance, by the downregulation of APOE-related and Calmodulin (CALM)-related LR interactions and their potential regulatory connections to target genes. Pathway analyses revealed 60 GO terms significantly linked to AD, highlighting Biological Processes such as 'amyloid precursor protein processing' and 'ion transmembrane transport', among others. We prioritized several drug repurposing candidates, such as cromoglicate, targeting the identified dysregulated LR pairs. Conclusions: Our integrative analysis identified key dysregulated LR interactions in a cell type-specific manner and the associated GO terms in AD, offering novel insights into potential therapeutic targets involved in disrupted cell-cell communication in AD.