New understanding of why kidney tumors become metastatic uncovered by MD Anderson researchers

Giannicola Genovese, MD, Ph.D.

image: Giannicola Genovese, MD, Ph.D.
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Credit: University of Texas MD Anderson Cancer Center

HOUSTON University of Texas MD Anderson Cancer researchers have designed 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 today in Cancer of nature, demonstrates that the loss of a group of interferon receptor (IFNR) genes plays a critical role in allowing cancer cells to become tolerant to chromosomal instability. This genomic trait can be used to help doctors predict a cancer’s potential to become metastatic and resistant to treatment.

Researchers led by Luigi Perelli, MD, Ph.D., postdoctoral fellow in Genitourinary Medical Oncology, and Giannicola Genovese, MD, Ph.D., professor of Genitourinary Medical Oncology, used CRISPR/Cas9 gene editing to create a model that faithfully represents RCC in humans, using cross-species analyzes to provide further insights into the mechanisms involved in the aggressive evolution of kidney cancer.

“Until now, there have been no effective experimental models for the progression of metastatic renal cancer, but we have introduced specific mutations that closely mimic the early stages of human cancers to see how tumors evolve and metastasize,” Genovese said. “These tumors become extremely genomically unstable and, in order to tolerate this instability, they tend to lose genetic material at a specific site where the interferon genes are located. These insights may help clinicians identify tumors that have the genomic potential to become aggressive.”

Renal cell carcinoma is the most common type of kidney cancer, and often patients are treated effectively with surgery, targeted therapy, immunotherapy, or a combination of these treatments. However, up to a third of these patients will have aggressive disease progression, highlighting the need to understand the specific mechanisms that drive metastasis in order to identify more effective therapeutic strategies and predict treatment responses.

A hallmark of cancer is chromosomal instability, which is associated with resistance to many types of therapy and a poor prognosis. However, it is unclear whether specific types of chromosomal abnormalities are involved in driving metastasis and how tumors are able to tolerate them.

Researchers used CRISPR/Cas 9-based genome editing to generate RCC models that lack common tumor suppressor genes. They then targeted cell cycle regulatory genes to mimic the common chromosomal abnormality associated with metastatic RCC in humans, leading to a phenotype consistent with human disease. This is the first immunocompetent somatic mosaic model for metastatic RCC, meaning that the model has an accumulation of several mutations that result in uncontrolled cell growth but still maintain a functioning immune system.

Using genome sequencing and single cell RNA sequencing to further examine these patterns, researchers have uncovered the molecular drivers of RCC and gained new understanding of the evolution of chromosomal instability.

Their single-cell analyzes revealed that a group of highly conserved IFNR genes was suppressed in the model and that this group normally functions as a critical custodian, or tumor suppressor, of renal cancer progression.

IFNR gene clusters are normally involved in the immune response. After analyzing various datasets from both mice and humans, the researchers discovered an inverse correlation between the loss of these IFNR genes and aneuploidy, a condition characterized by an abnormal number of chromosomes.

This study suggests that tumors adapt to high levels of chromosomal instability through disruption of the IFNR pathway and that this is likely an important biomarker of metastatic potential. It also highlights how kidney tumors in different species have followed similar evolutionary patterns converging around chromosomal instability, which in turn may explain the heterogeneity of these tumors.

In the future, the researchers plan to test drug combinations in these newly generated models to determine how tumors adapt to various therapies, with the aim of rapidly translating these studies into clinical trials that can help predict response. to treatment in patients with RCC.

This work was supported by the AIRC Foundation for Research on Cancer (AIRC), the Conquer Cancer Foundation of the American Society of Clinical Oncology, the Kidney Cancer Association, Horizon Europe, the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer, the Pancreatic Cancer Action Network, Inc., Ransom Horne Jr. Chair in Cancer Research, Barbara Massie Memorial Fund, MD Anderson Moon Shots Program®Bruce Krier Prostate Cancer Research Endowment Fund, Lyda Hill Foundation, UK Medical Research Council, National Institutes of Health (NIH) (R01 CA258226-03) and US Department of Defense (W81XWH-21-1-0950 ) . A complete list of collaborating authors and their disclosures is available with the full paper here.

Read the full press release in MD Anderson’s newsroom.

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