1. Kumar Das, Dibash PhD

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Renal cell carcinoma (RCC) has been noted as the seventh most common type of neoplasm in the developed world. The clear cell subtype of RCC (ccRCC) makes up 75-85 percent of all cases. When ccRCC is confined to the kidneys, the prognosis is often positive and surgical resection or thermal ablation of the tumor is frequently curative.

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However, approximately 25 percent of patients present with metastatic disease. In the metastatic setting, ccRCC continues to be a lethal disease having a 5-year survival rate of under 10 percent. To improve the avenues of therapeutic intervention for metastatic RCC, a careful dissection of the complex relationship between stromal cells and tumor cells within the ecosystem of the tumor microenvironment (TME) is required.


Now, novel research reveals that, among patients with ccRCC, the activity of four specific genes seems to reveal a distinct transcriptional signature that is predictive of metastatic potential and the patient's chances of survival. The preclinical study was published in Nature Communications (2022;


Study Details

The current study consists of researchers at Karolinska Institutet in Sweden; clinicians at Massachusetts General Hospital, where the patients were recruited; and computational scientists from Harvard Medical School in Boston. The coordinated surgical and research teams profiled fresh patient samples from nine patients, which included human ccRCC tumors and their matched normal control kidney tissue from treatment-naive patients. In two patients, the investigators also compared primary tumor tissue from the kidney with tissue from skeletal metastases.


A single-cell transcriptomic analysis of treatment-naive ccRCC primary tumors and adjacent normal kidney tissue with a focus on the TME was performed. The analysis revealed the following observations:


* Tumor cells are transcriptionally similar to a proximal tubule cell population subset, which potentially represents ccRCC cell of origin.


* The synchronous assessment of primary tumor and bone-metastatic tumor tissues from two patients presenting with de novo metastases uncovered a specific metastatic signature linked with poor prognosis.


* Stromal cells found in RCC tumors revealed the highest transcriptional variation of analyzed cell types compared to adjacent normal kidney.


* Additional components of the TME were identified. They included a cellular map of the stromal cell compartment and of cell-to-cell interactions in the tumor that are perhaps vulnerable to therapeutic targeting.



Importantly, the study revealed that a genetic signature of four specific genes is predictive of tumor metastasis to the skeleton and whether it can predict survival. Simultaneous upregulation of SAA1, SAA2, and APOL1 in high-grade ccRCC, and MET as a tyrosine kinase receptor involved in tumor cell proliferation, survival, and migration as a therapeutic target of cabozantinib, indicate the patient has a greater risk of developing a tumor that spreads and a poorer survival outcome.


"This could potentially become a tool to gain a better understanding of the course of the disease at an early stage. Patients with a cancer profile with a high probability of spreading could then be monitored more closely to quickly detect and treat any growth of the tumor," noted senior study author, Ninib Baryawno, PhD, a researcher and team leader at the Department of Women's and Children's Health, Karolinska Institutet.


Additionally, within the complex immune microenvironment, TREM2 was discovered to be elevated in the TME myeloid cells. This finding elevated the receptor's prospect as a prognostic marker in ccRCC and as a biomarker for detecting patients who could benefit from checkpoint blockade immunotherapy.


Researchers identified the CD70-CD27 relationship as potentially important with regard to cell-cell interactions. An in silico cell-to-cell interaction analysis showed that the CXCL9/CXCL10-CXCR3 axis and CD70-CD27 axis were possible therapeutic targets that could provide further promise in preclinical models. Researchers noted CD70-CD27 interactions could cause immune evasion by the tumor. Overall, these findings reveal biological insights on interactions between tumor cells and the ccRCC microenvironment.


"We hope that our results will contribute to further investigations of factors that affect the tumor microenvironment, which can ultimately provide new ways to treat relapse and the spread of cancer. For us, the next step is to study how metastases in the bone marrow and the skeleton differ from the local tumor in the kidney, but also how the bone marrow in patients with kidney cancer metastases in the skeleton differs from healthy bone marrow. We hope that it can help us answer the question as to why immunotherapy does not work in some kidney cancer patients," concluded study author, Adele Alchahin, PhD, student at the Department of Women's and Children's Health at the Karolinska Institutet.


Dibash Kumar Das is a contributing writer.