Single-cell RNA sequencing reveals the tumor microenvironment and facilitates strategic choices to circumvent treatment failure in a chemorefractory bladder cancer patient

Abstract

Background: Tumor cell-intrinsic mechanisms and complex interactions with the tumor microenvironment contribute to therapeutic failure via tumor evolution. It may be possible to overcome treatment resistance by developing a personalized approach against relapsing cancers based on a comprehensive analysis of cell typespecific transcriptomic changes over the clinical course of the disease using single-cell RNA sequencing (scRNA-seq). Methods: Here, we used scRNA-seq to depict the tumor landscape of a single case of chemo-resistant metastatic, muscle-invasive urothelial bladder cancer (MIUBC) addicted to an activating Harvey rat sarcoma viral oncogene homolog (HRAS) mutation. In order to analyze tumor evolution and microenvironmental changes upon treatment, we also applied scRNA-seq to the corresponding patient-derived xenograft (PDX) before and after treatment with tipifarnib, a HRAS-targeting agent under clinical evaluation.

Weighted gene co‐expression network analysis can sort cancer‐associated fibroblast‐specific markers promoting bladder cancer progression

“…For a better comparison, we selected images containing both urothelial carcinoma cells and stroma with the help of pathologists. In addition to the confirmation by pathologists, we also used the marker fibroblast activation protein (FAP) of CAFs and the marker desmin (DES) of the smooth muscle cell to confirm the position and approximate shape of the stromal part and exclude muscle tissue (Lee et al, 2020; Z. Yu et al, 2019). Including the previously identified CAF markers MMP2, PDGFRB, and SPARC, we found 14 immunohistochemical images of the 15 markers.…”

Epitranscriptomics and epiproteomics in cancer drug resistance: therapeutic implications

“…An era of single-cell omics has arrived, and the future clinical applications based on epitranscriptomics and epiproteomics are very promising: (i) single-cell multiple omics sequencing technique can be used widely to analyze the transcriptome, proteome, epitranscriptome, and epiproteome simultaneously at the single-cell level in drug resistance cancer cells, which allows us to reveal the unknown mechanisms and targets; 220 , 221 (ii) personalized single-cell sequencing provides comprehensive clues to optimize the therapeutic strategy against relapsing cancers; 222 and (iii) application of single-cell sequencing on tumor liquid biopsy can surveil and prevent the drug-resistant events during therapeutic treatment. 223 …”

New Insights into Therapy-Induced Progression of Cancer

“…Analysis of the transcriptional profiles of muscle-invasive urothelial bladder cancer samples before and after tipifarnib treatment made it possible to demonstrate that tumor cells that survived through therapy are in a state of dormancy, also characterized by increased expression levels of the IGFBP7, MDK, and B2M genes [24]. Such a slow-cycling, persistent quiescent state promotes tumor cell survival during therapy, and such cells can potentially give rise to actively proliferating resistant cells.…”

“…Modern techniques for the genome sequencing of small populations of cells located in different tumor zones [ 15 , 16 , 17 , 18 , 19 ], as well as single-cell sequencing, have enabled tracing tumor heterogeneity in vivo before and after therapy [ 20 , 21 , 22 , 23 , 24 ]. Moreover, the molecular barcoding approach made it possible to study the dynamics of how the ratio and abundance of the descendants of individual cancer cells change both in the case of normal tumor growth and under the influence of various methods of therapy [ 25 , 26 ].…”