Cancer cells can respond very differently to the same chemotherapy treatment, even within the same type of cancer. Because of this, it is difficult to predict which tumors will respond to treatment and which will become resistant. Researchers at the University of Illinois Urbana-Champaign are taking a new approach that focuses on how gene activity inside cancer cells influences these outcomes.
In the publication “Comparative Analysis of the Transcriptomic Response to Cisplatin in Drug-Sensitive and Drug-Resistant Testicular Germ Cell Tumors,” Cancer Center at Illinois (CCIL) member Ratnakar Singh, CCIL member Michael Spinella, and visiting scientist and the paper’s first author, Mehwish Khan, studied how changes in gene expression affect how cancer cells respond to cisplatin, a commonly used chemotherapy drug. Their research also includes lab members Doha Shokry and Raya Boyd.
“Our research focuses on understanding why some cancers respond to chemotherapy, while others become resistant,” Singh said. “Using testicular cancer models, we study how changes in gene activity, rather than changes in the DNA sequence itself, affect treatment outcomes.”
“Our research focuses on understanding why some cancers respond to chemotherapy, while others become resistant. Using testicular cancer models, we study how changes in gene activity, rather than changes in the DNA sequence itself, affect treatment outcomes.”
RATNAKAR SINGH
The study focuses on how these changes act like switches that control whether cancer cells shut down or keep growing after treatment.
“In chemotherapy-sensitive tumors, protective pathways, such as p53, are activated, promoting cancer cell death, while growth signals like MYC are suppressed,” Singh said. “In resistant tumors, these responses are altered, allowing cancer cells to survive treatment.”
One of the clearest differences between sensitive and resistant tumors is how strongly they respond to chemotherapy damage.
“One of the interesting findings of the study is that sensitive tumors pull the emergency brake by activating protective pathways, such as p53,” Singh said. “At the same time, they switch off growth signals like MYC, which normally drive cell division.”
In resistant tumors, this response is weaker, allowing cancer cells to continue growing despite damage.
“The p53 pathway is not fully activated, so damaged cells don’t get a strong signal to stop or die,” Singh said. “Meanwhile, MYC-driven growth signals are not properly shut down, allowing the cells to keep growing despite the damage.”
This muted response plays a key role in how resistance develops. “It’s almost like they’re ignoring the warning signals,” Singh said.
The researchers also found that these patterns are not limited to the lab. The same gene activity linked to sensitive tumors was associated with better outcomes in patients.
“This is an exciting aspect of the study,” Singh said. “The same gene patterns that identify sensitive cells in our experiments are associated with improved survival in patients. These genes could potentially serve as biomarkers to predict which patients will respond well to treatment.”
The study also points to a possible connection between chemotherapy response and iron metabolism. Resistant cancer cells did not properly activate genes involved in iron regulation, including those linked to TFRC and MYC.
“One of the most intriguing findings is that cisplatin-resistant cancer cells don’t properly activate a group of genes linked to iron metabolism,” Singh said. “This suggests that disruptions in this iron-related network may help tumors survive treatment.”
Because iron metabolism has recently been recognized as an important factor in how well chemotherapy works, this finding could open new directions for treatment.
“These findings indicate that iron metabolism could be an important yet underexplored factor in chemotherapy response,” Singh said. “This highlights the potential of combining traditional chemotherapy with treatments targeting iron metabolism.”
The team is now working to translate these findings into new treatment strategies.
“We aim to understand how pathways involving p53, MYC, and TFRC1 contribute to chemotherapy resistance,” Singh said. “We also plan to explore treatments targeting these pathways to determine whether we can restore sensitivity in resistant tumors.”
Looking ahead, Singh said the focus is on turning these findings into real treatments. “The goal is to translate these findings into combination therapies that can overcome resistance and improve outcomes for patients.”
Ratnakar Singh
Research Assistant Professor, Comparative Biosciences
CCIL Research Program and Theme
- Program: Cancer Engineering and Biological Systems
- Theme: Comparative and Engineered Oncology Models
Research Focus
Singh studies testicular germ cell tumors to find the epigenetic mechanisms that regulate the chemoresponse in TGCTs. He seeks to understand the role of H3K27 methylation in chemo-resistance or chemo-sensitivity in germ cell lines, and the role of microRNAs in chemo-resistance or chemo-sensitivity in germ cell lines.
Michael Spinella
Professor, Comparative Biosciences
CCIL Research Program and Theme
- Program: Cancer Engineering and Biological Systems
- Theme: Anticancer Chemistry
Research Focus
Michael Spinella’s laboratory explores the molecular genetics of cancer, particularly mechanisms of tumorigenesis, cancer therapy, and drug resistance. One research focus is on uncovering mechanisms that account for the curability of metastatic testicular germ cell tumors in order to inform novel therapeutic strategies for advanced somatic solid tumors, including glioblastoma and breast cancer. Other interests include the concept of differentiation therapy and the identification of mechanistic links between stem cell pluripotency, cancer, and response to chemotherapy. Spinella has a strong background in anticancer target identification and in molecular mechanisms of carcinogenesis, cancer therapeutics, and chemoresistance. Learn more about Michael Spinella’s lab.
Editor’s notes:
Ratnakar Singh is a Research Assistant Professor in Comparative Biosciences at the University of Illinois Urbana-Champaign. His research focuses on cancer biology, drug resistance, and epigenetic mechanisms that influence chemotherapy response. He can be reached at rsingh02@illinois.edu.
The paper, Comparative Analysis of the Transcriptomic Response to Cisplatin in Drug-Sensitive and Drug-Resistant Testicular Germ Cell Tumors, published in MDPI is available here.
DOI: doi.org/10.3390/cancers18040575
This story was written by Hailee Munno, CCIL Communications Intern.