Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer

Lee, Hae Ock; Hong, Yourae; Etlioglu, Hakki Emre; Cho, Yong Beom; Pomella, Valentina; Bosch, Ben Van den; Vanhecke, Jasper; Verbandt, Sara; Hong, Hye-Kyung; Min, Jae; Kim, Nayoung; Eum, Hye Hyeon; Qian, Junbin; Boeckx, Bram; Lambrechts, Diether; Tsantoulis, Petros; Hertogh, Gert De; Chung, Wingyan; Lee, Taeseob; An, Minae; Shin, Hyun Tae; Joung, Je Gun; Jung, Min; Ko, Gunhwan; Wirapati, Pratyaksha; Kim, Seok Hyung; Kim, Hee Cheol; Yun, Seong Hyeon; Tan, Iain Bee Huat; Ranjan, Bobby; Lee, Woo Yong; Kim, Tae You; Choi, Jung Kyoon; Kim, Young-Joon; Prabhakar, Shyam; Tejpar, Sabine; Park, Woong-Yang

doi:10.1038/s41588-020-0636-z

Cited by 482 publications

(743 citation statements)

References 73 publications

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“…In contrast, we observed a decrease in total B and plasma cell numbers in the tumor microenvironment compared to the adjacent normal tissue counterparts (Fig. 2B), which is in line with a recent study 17 . Three immune cell clusters were larger in tumors compared to normal tissue across all patients analyzed: these were the plasma cell clusters L2 and K2, which were expanded in the tumor in contrast to the overall trend for less plasma cells in tumor tissue, as well as the CD8+ T4 T cell cluster.…”

Section: Cell Type Census In Crc Versus Normal Colonsupporting

confidence: 93%

“…Three immune cell clusters were larger in tumors compared to normal tissue across all patients analyzed: these were the plasma cell clusters L2 and K2, which were expanded in the tumor in contrast to the overall trend for less plasma cells in tumor tissue, as well as the CD8+ T4 T cell cluster. Plasma cell clusters L2 and K2 contain more IgG producing cells, which confirms the previously observed loss of IgA + but gain of IgG + plasma cells 17 . CD8 + T4 is characterized by proliferating cells with reduced effector gene expression potentially indicating reduced anti-tumor activity.…”

Section: Cell Type Census In Crc Versus Normal Colonsupporting

confidence: 90%

“…7C). In line with the previous analyses, P007T showed the highest MAPK activity, and the highest proportion of Recent single cell studies defined features of the CRC immune microenvironment 16,17 ; however, no consensus exists on how to subtype CRC on the single cell level. Here, we subgroup the epithelial tumor component of CRC into tumor-specific TC1-4, stem/TA-like, and goblet-like cells (Fig.…”

Section: Mapk Target Gene Expression Defines Crc Differentiation Statessupporting

confidence: 69%

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Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Uhlitz

Bischoff

Peidli³

et al. 2020

Preprint

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In colorectal cancer, oncogenic mutations transform a hierarchically organized and homeostatic epithelium into invasive cancer tissue. To define differences in cellular composition between the normal colon and colorectal cancer, and to map potential cellular interactions between tumor cells and their microenvironment, we profiled transcriptomes of >50,000 single cells from tumors and matched normal tissues of eight colorectal cancer patients. We find that tumor formation is accompanied by changes in epithelial, immune and stromal cell compartments in all patients. In the epithelium, we identify a continuum of five tumor-specific stem cell and progenitor-like populations, and persistent multilineage differentiation. We find multiple stromal and immune cell types to be consistently expanded in tumor compared to the normal colon, including cancer-associated fibroblasts, pericytes, monocytes, macrophages and a subset of T cells. We identify epithelial tumor cells and cancer-associated fibroblasts as relevant for assigning colorectal cancer consensus molecular subtypes. Our survey of growth factors in the tumor microenvironment identifies cell types responsible for increased paracrine EGFR, MET and TGF-β signaling in tumor tissue compared to the normal colon.We show that matched colorectal cancer organoids retain cell type heterogeneity, allowing to define a distinct differentiation trajectory encompassing stem and progenitor-like tumor cells. In summary, our single-cell analyses provide insights into cell types and signals shaping colorectal cancer cell plasticity.

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Section: Cell Type Census In Crc Versus Normal Colonsupporting

confidence: 93%

Section: Cell Type Census In Crc Versus Normal Colonsupporting

confidence: 90%

Section: Mapk Target Gene Expression Defines Crc Differentiation Statessupporting

confidence: 69%

See 1 more Smart Citation

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Uhlitz

Bischoff

Peidli³

et al. 2020

Preprint

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“…• Segerstolpe2016 (https://doi.org/10.5281/zenodo.3928276) includes pancreatic islet cells from healthy donors and type 2 diabetic patients [28].…”

Section: Four Datasets Reveal the Intestinal Cell Compositionmentioning

confidence: 99%

“…The second set of GEPs can be used as input basis matrix for a multitude of cell deconvolution tools such as EPIC[52] and CIBERSORT[50]. The resulting GEPs derived from the Segerstolpe2016 and Kotliarov2020 datasets(Table 1,[23,28]) utilizing both strategies are shown for comparison inSupplementary Figures S15-S18.Here, we focus on the first strategy, applied to both datasets, utilizing SCDC by example, as it shows how to leverage scRNA-seq data to demonstrate Bescape's functionality best. Bulk RNAseq was simulated from the pancreatic islets[28] and hematopoietic CITE-seq[23] datasets using the GEPs across all genes from the raw count.…”

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confidence: 99%

Besca, a single-cell transcriptomics analysis toolkit to accelerate translational research

Mädler

Julien-Laferrière

Wyss

et al. 2020

Preprint

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Single-cell RNA sequencing (scRNA-seq) revolutionised our understanding of disease biology and presented the promise of transforming translational research. We developed Besca, a toolkit that streamlines scRNA-seq analyses according to current best practices. A standard workflow covers quality control, filtering, and clustering. Two complementary Besca modules, utilizing hierarchical cell signatures or supervised machine learning, automate cell annotation and provide harmonised nomenclatures across studies. Subsequently, Besca enables estimation of cell type proportions in bulk transcriptomics studies. Using multiple heterogeneous scRNA-seq datasets we show how Besca aids acceleration, interoperability, reusability, and interpretability of scRNA-seq data analysis, crucial aspects in translational research and beyond.

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KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix

et al. 2021

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Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS mutant (KRAS‐mt) and KRAS ‐wild‐type (KRAS‐wt) patients. We found that KRAS‐mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix. We validated our findings using samples from The Cancer Genome Atlas (TCGA) and also by performing immunohistochemistry (IHC) and immunofluorescence (IF) in orthogonal cohorts. Using in vitro and in vivo models, we show that oncogenic KRAS signaling within the epithelial cancer cells modulates the activity of the surrounding fibroblasts in the tumor microenvironment.

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Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer

Cited by 482 publications

References 73 publications

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Mitogen-activated protein kinase activity drives cell trajectories in colorectal cancer

Besca, a single-cell transcriptomics analysis toolkit to accelerate translational research

KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix

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