The stromal compartment of the tumor microenvironment consists of a heterogeneous set of tissue-resident and tumor-infiltrating cells, which are profoundly moulded by cancer cells. An outstanding question is to what extent this heterogeneity is similar between cancers affecting different organs. Here, we profile 233,591 single cells from patients with lung, colorectal, ovary and breast cancer ( n = 36) and construct a pan-cancer blueprint of stromal cell heterogeneity using different single-cell RNA and protein-based technologies. We identify 68 stromal cell populations, of which 46 are shared between cancer types and 22 are unique. We also characterise each population phenotypically by highlighting its marker genes, transcription factors, metabolic activities and tissue-specific expression differences. Resident cell types are characterised by substantial tissue specificity, while tumor-infiltrating cell types are largely shared across cancer types. Finally, by applying the blueprint to melanoma tumors treated with checkpoint immunotherapy and identifying a naïve CD4 + T-cell phenotype predictive of response to checkpoint immunotherapy, we illustrate how it can serve as a guide to interpret scRNA-seq data. In conclusion, by providing a comprehensive blueprint through an interactive web server, we generate the first panoramic view on the shared complexity of stromal cells in different cancers.
3538 Background: Addition of (ziv)-aflibercept (A) to FOLFIRI in second-line therapy for metastatic colorectal cancer (CRC) has been shown to be beneficial in phase III VELOUR trial (NCT00561470). A follow-up study (NCT01754272) was undertaken to acquire tumor samples for biomarker analyses and identify subgroups of patients with differential treatment effects. The primary results assessing efficacy according to well-established CRC subgroups defined by RAS, BRAF status and sidedness are reported here. Methods: Tissue specimens were collected for 666 patients from 1226 ITT pts. Suitable specimens were assayed for somatic mutation using NGS targeting extended RAS and BRAF genes. NGS assays with no missing values were obtained for 482 pts. Affymetrix gene chip technology was used for whole-transcriptome profiling; sidedness was extracted from available pathological reports. Differences between subgroups were assessed by interaction analysis. Results: The treatment effects on overall survival (OS) for the 482 pts is still significant HR=0.80 (CI 0.65-0.99), and similar to the ITT (n=1226) results (HR=0.82, CI 0.71-0.93). Two established ways of defining mutations (traditional KRAS exon 2 and extended RAS using NGS) show a trend for a differential effect across mutation groups.(see table for OS). Interestingly, BRAF mutants (which are all RAS wild type) show a trend for better outcome Same is seen for PFS and RR. Sidedness did not affect efficacy (HR: 0.83 (0.63- 1.1) for left and HR: 0.83 (0.54-1.3) for right. Conclusions: None of the mutations subgroup results shows significant interaction, although the ratios of treatment HR favor RAS wild types. Similar trends were observed in published trials with bevacizumab or ramucirumab. Sanofi supported this ISS. Clinical trial information: NCT01754272. [Table: see text]
The EGFR inhibitor cetuximab is approved for the treatment of colorectal cancer. However, both innate and acquired resistance mechanisms, including compensatory feedback loops, limit its efficacy. Nevertheless, the emergence of these feedback loops has remained largely unexplored to date. Here, we showed feedback upregulation of HER3 and induction of HER3 phosphorylation after cetuximab treatment in colon cancer cells. We also showed that this upregulation occurs, at least partly, through AKT inhibition. Together with this, we observed increased HER2:HER3 dimerization upon cetuximab treatment. Interestingly, lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, blocked the increase of cetuximab-induced HER3 phosphorylation. Additionally, we showed that upon HER3 knockdown, cetuximab combined with lapatinib was able to decrease cell viability compared to HER3 expressing cells. These results suggest the existence of a cetuximab-induced feedback HER3 activation that could potentially result in reduced cetuximab efficacy in colorectal cancer patients. Taken together, we provide evidence of the limited effectiveness of cetuximab monotherapy compared to rational combinations.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.