Northwestern Medicine scientists have discovered how a specific transcription factor promotes genetic reprogramming and chemotherapy resistance in ovarian cancer cells, findings that may inform new targeted treatment approaches that inhibit this process and improve patient outcomes, according to a recent study published in The Journal of Clinical Investigation.
Mazhar Adli, PhD, the Thomas J. Watkins Memorial Professor of Tumor Genomics, was senior author of the study.
More than 20,000 individuals are diagnosed with ovarian cancer each year, and of those, nearly half will die from the disease, according to the American Cancer Society.
Chemotherapy resistance remains an urgent challenge in treating high-grade serous ovarian cancer, the most common type of ovarian cancer. Therefore, identifying the molecular mechanisms utilized by ovarian cancer cells in the early stages of chemoresistance could help significantly improve patient outcomes, according to Adli.
“Understanding what makes these cancer cells resistant to therapy is one of the key biological questions that we want to understand, and we want to develop therapies to potentially interfere with this chemoresistance reprogramming,” said Adli, who is also a professor of Obstetrics and Gynecology in the Division of Reproductive Science in Medicine and of Cell and Developmental Biology.
Previous work led by Adli established that the SOX9 protein is a super-enhancer regulated transcription factor whose expression is significantly upregulated in chemoresistant ovarian cancer cells.
In the current study, Adli’s team used a combination of multiomics, tumor microarrays and epigenetic modulation to study the role of SOX9 in driving and maintaining chemoresistance ovarian cancer.
They discovered that SOX9 is epigenetically upregulated in response to chemotherapy treatment in ovarian cancer cell lines. The investigators also used this multi-pronged approach to study ovarian cancer patient samples collected before and after chemotherapy treatment and found that SOX9 was upregulated in these samples, as well.
Next, the investigators used CRISPR/Cas9 gene-editing to turn on the SOX9 gene in the cancer cell lines and, through subsequent transcriptome analysis, found that increasing SOX9 expression reprogrammed the ovarian cancer cells into stem-like cancer cells. These cells, which are often referred to as tumor-initiating cells, continuously self-renew and proliferate and contribute to chemotherapy resistance.
“We saw that cells were becoming resistant very rapidly, and they didn’t die as quickly as other cells,” Adli said.
Using single-cell RNA sequencing in primary patient ovarian cancer tumors, the scientists discovered a rare cluster of cells in the tumors with high SOX9 expression and stem-like features.
“We think SOX9 is the master regulator of these stem cells,” Adli said. “We detected these stem cells in the primary patient samples, and we established this causal relationship between SOX9 expression and chemoresistance in high-grade serious ovarian cancer.”
The findings, Adli said, also underscore the potential of using SOX9 as a biomarker that can be therapeutically targeted to block this cancer cell reprogramming.
“We still want to know where exactly in the genome SOX9 binds and can we use small molecule drugs or target other genes downstream of SOX9 so that we prevent this reprogramming. I think this is a fundamental first step toward targeting acquired chemoresistance in cancer,” Adli said.
Alexander Duval, a student in the Driskill Graduate Program in Life Sciences (DGP), was the lead author of the study.
Co-authors include DGP students Ozlem Neyisci and Yaqi Zhang; and Daniela Matei, MD, the Diana, Princess of Wales Professor of Cancer Research and chief of Reproductive Science in Medicine in the Department of Obstetrics and Gynecology.
Adli and Matei are members of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
This work was supported by National Cancer Institute grants R01CA267544 and U54CA268084, and in part from the U.S. Department of Veterans Affairs Merit Awards VA-ORDI01 BX006020 and I01 BX006012.
