Researchers at The University of Texas MD Anderson Cancer have engineered a new model of aggressive renal cell carcinoma (RCC), highlighting molecular targets and genomic events that trigger chromosomal instability and drive metastatic progression.
The study, published in Nature Cancer, demonstrates that the loss of a cluster of interferon receptor (IFNR) genes plays a pivotal role in allowing cancer cells to become tolerant of chromosomal instability. This genomic feature may be used to help clinicians predict a tumor’s potential to become metastatic and treatment resistant.
Researchers led by Luigi Perelli, M.D., Ph.D., postdoctoral fellow of Genitourinary Medical Oncology, and Giannicola Genovese, MD, PhD, professor of Genitourinary Medical Oncology, used CRISPR/Cas9 gene editing to create a model that faithfully represents RCC in humans, using cross-species analyses to provide further insights into the mechanisms involved in aggressive kidney cancer evolution.
The researchers used CRISPR/Cas 9-based genome editing to generate RCC models lacking common tumor suppressor genes. They then targeted cell cycle regulator genes to mimic common chromosomal abnormality associated with metastatic RCC in humans, leading to a phenotype consistent with the human disease. This is the first immunocompetent somatic mosaic model for metastatic RCC, meaning the model has an accumulation of different mutations that result in uncontrolled cell growth but still maintains a functional immune system.
Using genome sequencing and single-cell RNA sequencing to further examine these models, the researchers uncovered molecular drivers of RCC and gained a new understanding of the evolution of chromosomal instability.
Their single cell analyses revealed that a cluster of highly conserved IFNR genes were suppressed in the model, and that this cluster normally functions as a critical gatekeeper, or tumor suppressor, of renal cancer progression.
IFNR gene clusters normally are involved in the immune response. After analyzing various data sets from both mice and humans, the researchers discovered an inverse correlation between the loss of these IFNR genes and aneuploidy, a condition marked by having an abnormal number of chromosomes.
This study suggests that the tumors adapt to high levels of chromosomal instability through the disruption of the IFNR pathway and that this is likely a major biomarker of metastatic potential. It also highlights how renal cancers in different species have followed similar evolutionary patterns that converge around chromosomal instability, which in turn may explain the heterogeneity of these tumors.
