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Perturb-map coupled with spatial transcriptomics identifies mutation associated gene signatures in a mouse model of lung adenocarcinoma

ABSTRACT: The cellular architecture of a tumor has a major impact on cancer outcome, and thus there is interest in identifying genes controlling the tumor microenvironment (TME). While CRISPR screens are helping uncover genes regulating many cell-intrinsic processes, existing approaches are suboptimal for identifying gene functions operating extracellularly or within a tissue context. To address this, we developed an approach for spatial functional genomics called Perturb-map, which utilizes protein barcodes (Pro-Code) to enable spatial detection of barcoded cells within tissue. We applied Perturb-map to knockout dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each knockout influenced tumor growth, histopathology, and immune composition. Additionally, we paired Perturb-map and spatial transcriptomics for unbiased molecular analysis of Pro-Code/CRISPR lesions. Our studies found in Tgfbr2 knockout lesions, the TME was converted to a fibro-mucinous state and T-cells excluded, concomitant with upregulated TGFb and TGFb-mediated stroma activation, suggesting Tgfbr2 loss on lung cancer cells increased TGFb bioavailability and enhanced its suppressive effects on the TME. These studies establish Perturb-map for functional genomics within a tissue at single cell-resolution with spatial architecture preserved.

ORGANISM(S): Mus musculus

PROVIDER: GSE193460 | GEO | 2022/01/15

REPOSITORIES: GEO

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Defining the immunophenotype within the clear cell renal cell carcinoma tumour microenvironment to guide immune checkpoint blockade

Project description:We performed spatial transcriptome profiling (ST-seq) on nine fresh frozen tissue sections to understand the immunophenotypes; immune cell types, states and their spatial location within the clear cell renal cell carcinoma (ccRCC) tumour microenvironment (TME).

2023-08-16 | E-MTAB-12767 | biostudies-arrayexpress

Uncovering the spatial landscape of molecular interactions within the tumor microenvironment through latent spaces

Project description:Recent advances in spatial transcriptomics (ST) enable gene expression measurements from a tissue sample while retaining its spatial context. This technology enables unprecedented in situ resolution of the regulatory pathways that underlie the heterogeneity in the tumor and its microenvironment (TME). The direct characterization of cellular co-localization with spatial technologies facilities quantification of the molecular changes resulting from direct cell-cell interaction, as occurs in tumor-immune interactions. We present SpaceMarkers, a novel bioinformatics algorithm to infer molecular changes from cell-cell interaction from latent space analysis of ST data. We apply this approach to infer molecular changes from tumor-immune interactions in Visium spatial transcriptomics data of metastasis, invasive and precursor lesions, and immunotherapy treatment. Further transfer learning in matched scRNA-seq data enabled further quantification of the specific cell types in which SpaceMarkers are enriched. Altogether, SpaceMarkers can identify the location and context-specific molecular interactions within the TME from ST data.

2023-04-19 | GSE224411 | GEO

A Spatiomolecular Map of the Striatum

Project description:The striatum is organized into two major outputs formed by striatal projection neuron (SPN) subtypes with distinct molecular identities. In addition, the histochemical division into patch and matrix compartments represents an additional spatial organization, proposed to mirror a functional specialization in a motor-motivation dimension. To map the molecular diversity of SPNs in the context of the patch and matrix division, we genetically labeled mu-opioid receptor (Oprm1) expressing striatal neurons and performed single-nucleus RNA sequencing (snRNA-seq). This allowed us to establish new molecular definitions of the patch-matrix compartments, resulting in a molecular code for mapping patch SPNs at the cellular level. In addition, Oprm1 expression labeled exopatch SPNs, which we found to be molecularly distinct from both patch as well as neighboring matrix SPNs, thereby forming a separate molecular entity. At the cell-type level, we found an unexpected SPN diversity, leading to the identification of a new Col11a1+ striatonigral SPN type. At the tissue level, we found that mapping the spatial expression of a number of markers revealed new definitions of spatial domains in the striatum, which were conserved in the non-human primate brain. Interestingly, the spatial markers were cell-type independent and instead represented a spatial code that was found across all SPNs within a spatially restricted domain. This spatiomolecular map establishes a formal system for targeting and studying the striatal subregions and SPNs subtypes, beyond the classical striatonigral and striatopallidal division.

2019-11-01 | GSE139265 | GEO

Cancer-associated Fibroblast Spatial Heterogeneity and EMILIN1 Expression in Cancer Stroma Modulate TGF-b Activity and CD8+ T-Cell Infiltration in Breast Cancer

Project description:The tumor microenvironment (TME) and its multifaceted interactions with cancer cells are major targets for cancer treatment. Single-cell technologies have brought major insights into the TME, but the resulting complexity frequently precludes conclusions on function. Therefore, we combined single-cell RNA sequencing and spatial transcriptomic data to explore the relationship between different cancer-associated fibroblast (CAF) populations and immune cell exclusion in breast tumors. Our data show for the first time the degree of spatial organization of different CAF populations in breast cancer. We found that IL-iCAFs, Detox-iCAFs, and IFNγ-iCAFs tended to cluster together, while Wound-myCAFs, TGFb-myCAFs, and ECM-myCAFs formed another group that overlapped with elevated TGF-b signaling. Differential gene expression analysis of areas with CD8+ T-cell infiltration/exclusion within the TGF-b signaling-rich zones identified elastin microfibrillar interface protein 1 (EMILIN1) as a top modulated gene. EMILIN1, a TGF-b inhibitor, was upregulated in IFNγ-iCAFs directly modulating TGFb immunosuppressive function. Histological analysis of 74 breast cancer samples confirmed that high EMILIN-1 expression in the tumor margins was related to high CD8+ T-cell infiltration, consistent with our spatial gene expression analysis. High EMILIN-1 expression was also associated with better prognosis of patients with breast cancer, underscoring its functional significance for the recruitment of cytotoxic T cells into the tumor area. In conclusion, our data show that correlating TGF-b signaling to a CAF subpopulation is not enough because proteins with TGF-b-modulating activity originating from other CAF subpopulations can alter its activity. Therefore, therapeutic targeting should remain focused on biological processes rather than on specific CAF subtypes.

2024-04-16 | GSE243022 | GEO

Combined PD-L1/TGFb blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors

Project description:TGFb signaling is a major pathway associated with poor clinical outcome in patients with advanced metastatic cancers and non-response to immune checkpoint blockade, particularly in the immune-excluded tumor phenotype. While previous pre-clinical studies demonstrated that converting tumors from an excluded to an inflamed phenotype and curative anti-tumor immunity require attenuation of both PD-L1 and TGFb signaling, the underlying cellular mechanisms remain unclear. Recent studies suggest that stem cell-like CD8 T cells (TSCL) can differentiate into non-exhausted CD8 T effector cells that drive durable anti-tumor immunity. Here, we show that TGFb and PD-L1 restrain TSCL expansion as well as replacement of progenitor exhausted and dysfunctional CD8 T cells with non-exhausted IFNghi CD8 T effector cells in the tumor microenvironment (TME). Blockade of TGFb and PD-L1 generated IFNghi CD8 T effector cells with enhanced motility, enabling both their accumulation in the TME and increased interaction with other cell types. Ensuing IFNg signaling markedly transformed myeloid, stromal, and tumor niches to yield a broadly immune-supportive ecosystem. Blocking IFNg completely abolished the effect of anti-PD-L1/ TGFb combination therapy. Our data suggest that TGFb works in concert with PD-L1 to prevent TSCL expansion and replacement of exhausted CD8 T cells with fresh CD8 T effector cells, thereby maintaining the CD8 T cell compartment in a dysfunctional state.

2023-06-16 | MSV000092193 | MassIVE

Response of unmodified and TGFBR2 knockout tumor infiltrating lymphocytes (TIL) to TGF-B stimulation

Project description:TGFBR2 was deleted in ovarian cancer TIL via CRISPR/Cas9 gene editing. Response of unmodified and TGFBR2 knockout TIL to TGF-B stimulation was evaluated via RNA sequencing.

2022-08-03 | GSE169659 | GEO

Liver gene expression profiling of transforming growth factor beta receptor 2 heterozygous knockout (Tgfbr2+/-) mice

Project description:Transforming growth factor beta receptor 2 (Tgfbr2) was predicted as a causal gene for abdominal using a novel statistical method named LCMS (Schadt et al., 2005, Nature Genetics). In order to validate this prediction, we profiled the liver tissues of Tgfbr2 heterozygous knockout mice (Tgfbr2+/-) and their littermate wild-type (wt) controls to examine the gene expression signature as well as pathways/networks resulting from the single gene perturbation. 6 Tgfbr2+/- mice and 4 wt controls were profiled. Reference pool included RNA extracted from the liver of 6 wt control mice. Dye-swap was involved in the profiling.

2009-03-07 | E-GEOD-11994 | biostudies-arrayexpress

Next-generation RNA Sequencing and Transcriptome Comparison of Mouse Wild Type and Mesenchymal Tgfbr2 conditional knockout lungs of E15.5

Project description:Lung mesenchymal knockout of transforming growth factor, beta receptor II (Tgfbr2) will lead to lung malformation, including impaired lung branching and cystic lesion. In order to understand the underlying mechanisms, total RNA of wild type and mesenchymal Tgfbr2 knockout lungs were isolated and sequenced using the next-generation RNA sequencing technique.

2021-04-20 | GSE98138 | GEO

Hepatocyte-specific knockout of Pten and of Pten and Tgfbr2 in mice

Project description:Gene expression of hepatocyt-specific knockout of Pten and of Pten and Tgfbr2 in mice as a model for human cholangiocarcinoma was determined Affymetrix Mouse 1.0ST chips were used to measure gene expression Gene expression of the following mouse livers were characterized A. WT (n=3). B. Pten-/- (n=4). C. Pten-/- Tgfbr2-/- (n=4).

2016-02-26 | E-GEOD-66717 | biostudies-arrayexpress

Homeoprotein SIX1 compromises anti-tumor immunity through TGF-β-mediated regulation of collagens

Project description:Purpose: The tumor microenvironment (TME), such as non-immune-infiltrated “cold” tumors, has been associated with immune suppression. However, the complex mechanisms regulating tumor immunogenicity have not been clearly elucidated. In this study, we investigated whether Transcription factor sine oculis homeobox 1 (SIX1) expression in the cancer cells regulated anti-tumor immunity by reshaping TME. Methods: The expression of SIX1 in human tumor tissues was analyzed based on TCGA data. Six1 knockout murine cell lines were generated to analyze the SIX1-associated tumor progression and anti-tumor immune response in tumor xenograft models. Immune cells and cytokines in TME were quantified by immunofluorescence, flow cytometry, quantitative reverse transcription-PCR, and ELISPOT assay. SIX1-associated differentially expressed genes were investigated in cancer cells and tissues with RNA-Seq. At the end, Correlation of SIX1 with TGFBR2 expression was assessed by Western blot and Dual-luciferase reporter assay. Results:SIX1 was highly upregulated in human tumor tissues, while rarely expressed in matched normal tissues. Deletion of the Six1 in cancer cells inhibited tumor growth, depending on adaptive immunity. Moreover, Six1 deficiency significantly enhanced CD8+ T cells infiltration, leading to eradication of poorly immunogenic tumors and maintaining a long-term protection from tumor re-challenge. Mechanistically, SIX1 as a transcription factor upregulated TGFBR2 expression, which induced collagen genes expression via the Smad2/3 phosphorylation, increased collagens deposition in TME and hampered CD8+ T cells infiltration. Conclusions: Six1 deletion in cancer cells improved tumor immunogenicity, leading to tumor destruction by enhancing anti-tumor immune responses. Our observations uncovered a crucial role of SIX1 on remodulating tumor immunogenicity and demonstrated a proof of concept for targeting SIX1 in cancer immunotherapy.

2021-09-09 | GSE183580 | GEO

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