During the last ten years, many research results have been referring to a particular type of cancer-associated fibroblasts associated with poor prognosis, invasiveness, metastasis and resistance to therapy in multiple cancer types, characterized by a gene expression signature with prominent presence of genes COL11A1, THBS2 and INHBA. Identifying the underlying biological mechanisms responsible for their creation may facilitate the discovery of targets for potential pan-cancer therapeutics. Using a novel computational approach for single-cell gene expression data analysis identifying the dominant cell populations in a sequence of samples from patients at various stages, we conclude that these fibroblasts are produced by a pan-cancer cellular transition originating from a particular type of adipose-derived stromal cells naturally present in the stromal vascular fraction of normal adipose tissue, having a characteristic gene expression signature. Focusing on a rich pancreatic cancer dataset, we provide a detailed description of the continuous modification of the gene expression profiles of cells as they transition from APOD-expressing adipose-derived stromal cells to COL11A1-expressing cancer-associated fibroblasts, identifying the key genes that participate in this transition. These results also provide an explanation to the well-known fact that the adipose microenvironment contributes to cancer progression.

Bulk samples of the same patient are heterogeneous in nature, comprising of different subpopulations (subclones) of cancer cells. Cells in a tumor subclone are characterized by unique mutational genotype profile. Resolving tumor heterogeneity by estimating the genotypes, cellular proportions and the number of subclones present in the tumor can help in understanding cancer progression and treatment. We present a novel method, ChaClone2, to efficiently deconvolve the observed variant allele fractions (VAFs), with consideration for possible effects from copy number aberrations at the mutation loci. Our method describes a state-space formulation of the feature allocation model, deconvolving the observed VAFs from samples of the same patient into three matrices: subclonal total and variant copy numbers for mutated genes, and proportions of subclones in each sample. We describe an efficient sequential Monte Carlo (SMC) algorithm to estimate these matrices. Extensive simulation shows that the ChaClone2 yields better accuracy when compared with other state-of-the-art methods for addressing similar problem and it offers scalability to large datasets. Also, ChaClone2 features that the model parameter estimates can be refined whenever new mutation data of freshly sequenced genomic locations are available. MATLAB code and datasets are available to download at: https://github.com/moyanre/method2.

SUMMARY: We developed 2DImpute, an imputation method for correcting false zeros (known as dropouts) in single-cell RNA-sequencing (scRNA-seq) data. It features preventing excessive correction by predicting the false zeros and imputing their values by making use of the interrelationships between both genes and cells in the expression matrix. We showed that 2DImpute outperforms several leading imputation methods by applying it on datasets from various scRNA-seq protocols. AVAILABILITY AND IMPLEMENTATION: The R package of 2DImpute is freely available at GitHub (https://github.com/zky0708/2DImpute). CONTACT: [email protected]. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.