bims-gerecp 2024-07-28 papers

Int J Cancer. 2024 Jul 19.

High-confidence calling of normal epithelial cells allows identification of a novel stem-like cell state in the colorectal cancer microenvironment.

Tzu-Ting Wei, Eric Blanc, Stefan Peidli, Philip Bischoff, Alexandra Trinks, David Horst, Christine Sers, Nils Blüthgen, Dieter Beule, Markus Morkel, Benedikt Obermayer.

Single-cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identification using Somatic Mutations) to exploit genomic single nucleotide variants for the disambiguation of cancer cells from genomically normal non-cancer cells in single-cell data. We find that our method and others based on gene expression or allelic imbalances identify overlapping sets of colorectal cancer versus normal colon epithelial cells, depending on molecular characteristics of individual cancers. Further, we define consensus cell identities of normal and cancer epithelial cells with higher transcriptome cluster homogeneity than those derived using existing tools. Using the consensus identities, we identify significant shifts of cell state distributions in genomically normal epithelial cells developing in the cancer microenvironment, with immature states increased at the expense of terminal differentiation throughout the colon, and a novel stem-like cell state arising in the left colon. Trajectory analyses show that the new cell state extends the pseudo-time range of normal colon stem-like cells in a cancer context. We identify cancer-associated fibroblasts as sources of WNT and BMP ligands potentially contributing to increased plasticity of stem cells in the cancer microenvironment. Our analyses advocate careful interpretation of cell heterogeneity and plasticity in the cancer context and the consideration of genomic information in addition to gene expression data when possible.

Keywords: cellular heterogeneity; single‐cell genomics; somatic variants

DOI: https://doi.org/10.1002/ijc.35079

Nat Rev Cancer. 2024 Jul 24.

Pre-empting drug resistance.

Anna Dart.

DOI: https://doi.org/10.1038/s41568-024-00729-z

Methods Mol Biol. 2024 ;2811 165-175

Characterizing Rare Dormant and Cycling Lineages Using the Watermelon System.

Abram Handly-Santana, Yaara Oren.

Barcode-based lineage tracing approaches enable molecular characterization of clonal cell families. Barcodes that are expressed as mRNA can be used to deconvolve lineage identity from single-cell RNA sequencing transcriptional data. Here we describe the Watermelon system, which facilitates the simultaneous tracing of lineage, transcriptional, and proliferative state at a single cell level.

Keywords: Expressed barcodes; Lineage tracing; Proliferation tracking; Single-cell RNA sequencing (scRNA-seq)

DOI: https://doi.org/10.1007/978-1-0716-3882-8_12

Cell Stem Cell. 2024 Jul 18. pii: S1934-5909(24)00250-9. [Epub ahead of print]

Analyzing embryo dormancy at single-cell resolution reveals dynamic transcriptional responses and activation of integrin-Yap/Taz prosurvival signaling.

Rui Chen, Rui Fan, Fei Chen, Niraimathi Govindasamy, Heike Brinkmann, Martin Stehling, Ralf H Adams, Hyun-Woo Jeong, Ivan Bedzhov.

Embryonic diapause is a reproductive adaptation that enables some mammalian species to halt the otherwise continuous pace of embryonic development. In this dormant state, the embryo exploits poorly understood regulatory mechanisms to preserve its developmental potential for prolonged periods of time. Here, using mouse embryos and single-cell RNA sequencing, we molecularly defined embryonic diapause at single-cell resolution, revealing transcriptional dynamics while the embryo seemingly resides in a state of suspended animation. Additionally, we found that the dormant pluripotent cells rely on integrin receptors to sense their microenvironment and preserve their viability via Yap/Taz-mediated prosurvival signaling.

Keywords: Taz; Yap; embryo dormancy; embryonic diapause; embryonic stem cells; epiblast; extracellular matrix; integrin; pluripotency; single-cell RNA sequencing

DOI: https://doi.org/10.1016/j.stem.2024.06.015

Nature. 2024 Jul 24.

In vivo interaction screening reveals liver-derived constraints to metastasis.

It is estimated that only 0.02% of disseminated tumour cells are able to seed overt metastases1. While this suggests the presence of environmental constraints to metastatic seeding, the landscape of host factors controlling this process remains largely unclear. Here, combining transposon technology2 and fluorescence niche labelling3, we developed an in vivo CRISPR activation screen to systematically investigate the interactions between hepatocytes and metastatic cells. We identify plexin B2 as a critical host-derived regulator of liver colonization in colorectal and pancreatic cancer and melanoma syngeneic mouse models. We dissect a mechanism through which plexin B2 interacts with class IV semaphorins on tumour cells, leading to KLF4 upregulation and thereby promoting the acquisition of epithelial traits. Our results highlight the essential role of signals from the liver parenchyma for the seeding of disseminated tumour cells before the establishment of a growth-promoting niche. Our findings further suggest that epithelialization is required for the adaptation of CRC metastases to their new tissue environment. Blocking the plexin-B2-semaphorin axis abolishes metastatic colonization of the liver and therefore represents a therapeutic strategy for the prevention of hepatic metastases. Finally, our screening approach, which evaluates host-derived extrinsic signals rather than tumour-intrinsic factors for their ability to promote metastatic seeding, is broadly applicable and lays a framework for the screening of environmental constraints to metastasis in other organs and cancer types.

DOI: https://doi.org/10.1038/s41586-024-07715-3

Nat Biotechnol. 2024 Jul 25.

A mini-colon models colon cancer and its microenvironment.

Colin Hutton, Vivian S W Li.

DOI: https://doi.org/10.1038/s41587-024-02343-8

Cancer Med. 2024 Jul;13(14): e70041

Molecular subtypes of colorectal cancer in the era of precision oncotherapy: Current inspirations and future challenges.

Qin Dang, Lulu Zuo, Xinru Hu, Zhaokai Zhou, Shuang Chen, Shutong Liu, Yuhao Ba, Anning Zuo, Hui Xu, Siyuan Weng, Yuyuan Zhang, Peng Luo, Quan Cheng, Zaoqu Liu, Xinwei Han.

BACKGROUND: Colorectal cancer (CRC) is among the most hackneyed malignancies. Even patients with identical clinical symptoms and the same TNM stage still exhibit radically different clinical outcomes after receiving equivalent treatment regimens, indicating extensive heterogeneity of CRC. Myriad molecular subtypes of CRC have been exploited for decades, including the most compelling consensus molecular subtype (CMS) classification that has been broadly applied for patient stratification and biomarker-drug combination formulation. Encountering barriers to clinical translation, however, CMS classification fails to fully reflect inter- or intra-tumor heterogeneity of CRC. As a consequence, addressing heterogeneity and precisely managing CRC patients with unique characteristics remain arduous tasks for clinicians.
REVIEW: In this review, we systematically summarize molecular subtypes of CRC and further elaborate on their clinical applications, limitations, and future orientations.
CONCLUSION: In recent years, exploration of subtypes through cell lines, animal models, patient-derived xenografts (PDXs), organoids, and clinical trials contributes to refining biological insights and unraveling subtype-specific therapies in CRC. Therapeutic interventions including nanotechnology, clustered regulatory interspaced short palindromic repeat/CRISPR-associated nuclease 9 (CRISPR/Cas9), gut microbiome, and liquid biopsy are powerful tools with the possibility to shift the immunologic landscape and outlook for CRC precise medicine.

Keywords: CMS classification; colorectal cancer; heterogeneity; molecular subtype; precision oncotherapy

DOI: https://doi.org/10.1002/cam4.70041

Nat Methods. 2024 Jul 22.

Contextual AI models for context-specific prediction in biology.

DOI: https://doi.org/10.1038/s41592-024-02342-2

Nat Cancer. 2024 Jul 23.

Using machine learning to translate tumor dependencies.

DOI: https://doi.org/10.1038/s43018-024-00790-5