| Title: |
64defining cancer initiating cells and their vulnerabilities in renal cell carcinoma |
| Authors: |
Mehrjoo, Zohreh; Kuasne, Hellen; Aguirre, Ariel Madrigal; Shahini, Ali; Annis, Matthew G; Fortier, Anne-Marie Norah; Lu, Tianyuan; Soto, Larisa Morales; Zhao, Hong; Zuo, Dongmei; Pilon, Virginie; Dankner, Matthew; Nishimura, Tamiko; Petrecca, Kevin; Spicer, Jonathan; Siegel, Peter; Tanguay, Simon; Najafabadi, Hamed Shateri; Park, Morag; Riazalhosseini, Yasser |
| Source: |
The Oncologist ; volume 30, issue Supplement_2 ; ISSN 1083-7159 1549-490X |
| Publisher Information: |
Oxford University Press (OUP) |
| Publication Year: |
2025 |
| Description: |
Background Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, leading to 179 000 cancer-related deaths annually. ccRCC initiating cells (CICs) are thought to drive tumor initiation, growth, therapy resistance, and metastasis, yet their molecular characteristics remain poorly defined. This study aims to identify putative CICs and their essential genes using a cell marker-agnostic strategy. Methods We performed a comprehensive analysis of ccRCC transcriptomes at single-cell resolution, developed patient-derived xenograft (PDX) and 3D patient-derived organoids (PDO) models of ccRCC, and conducted functional examinations in these models to investigate our findings. Results Computational modeling of tumor formation using single-cell RNA velocity analysis of five primary and metastatic ccRCC-PDXs revealed a minor cell population as the origin of other tumor cells, representing putative CICs. Pathway and network analyses suggested that a core network of proteins, conventionally known to regulate mitosis, are highly active in CICs and may be essential for their function. These proteins were expressed in PDOs and PDX-derived spheroids established following a CIC enrichment protocol. Spheroid cells exhibited higher tumorigenicity and colony formation ability than parental tumor cells, as confirmed by in-vivo injection in nude mice and in-vitro colony formation assays. Successive in vivo passaging confirmed the self-renewal capacity of spheroid-derived tumors. Pharmacological blockade of candidate proteins elicited dose-dependent inhibitory effect on spheroid and colony formation, with in-vivo validation showing that blocking these proteins significantly delayed tumor growth and more efficiently prevented tumor formation in mice. These results highlight the importance of these proteins in the cancer-initiating abilities of malignant cells. Interestingly, our results suggest that the identified target proteins may elicit their CIC-related function independently from their mitosis ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1093/oncolo/oyaf276.065 |
| Availability: |
https://doi.org/10.1093/oncolo/oyaf276.065; https://academic.oup.com/oncolo/article-pdf/30/Supplement_2/oyaf276.065/64572865/oyaf276.065.pdf |
| Rights: |
https://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.C9A996 |
| Database: |
BASE |