Selected Articles from This Issue

Conventional therapies have demonstrated limited therapeutic efficacy in most ovarian cancer patients, highlighting the need to identify alternative therapeutic targets. In their study, Lesage and colleagues investigated how the ferroptosis pathway may be manipulated to improve the response of ovarian tumor cells to PARP inhibitors (PARPi). DDR2 knockdown CAF cell lines treated with ferroptosis inducers showed an accumulation of lipid peroxides that was reversable upon treatment with an iron chelator or treatment with a lipid peroxidation inhibitor. The authors also found that expression of the antioxidant xCT-GSH-GPX4 axis was depleted upon DDR2 knockdown in CAF cell lines. Intracellular ROS levels measured using superoxide indicator dye DHE after treatment with hydrogen peroxide also exhibited enhanced levels of ROS in DDR2 depleted cells. DDR2 proficient and deficient cells treated with an NRF2 inhibitor or activator, respectively, revealed that DDR2 modulates ferroptosis through a p62-KEAP1-NRF2-dependent pathway. Interestingly, immunohistochemical analyses of ovarian tumor tissues and single cell RNA-sequencing showed an association between DDR2 expression and clinical PARPi resistance. Cell death assays performed with DDR2 proficient and deficient cells treated with olaparib validated these findings, with enhanced olaparib sensitivity observed in DDR2 deficient cells compared to proficient cells. Taken together, this study demonstrates the role of DDR2 in CAF-mediated ferroptosis sensitivity and highlights the utility of DDR2 targeting to improve PARPi response in ovarian cancer.The tumor microenvironment (TME) plays an important role in cancer progression and treatment response, but there are limited modalities to study the TME at the genomic level in established clinically annotated cancer multi-omics cohorts. To address this, Bayati and colleagues developed the PACIFIC method, which allowed them to evaluate how genomic alterations in cancer cells interact with transcriptome-derived immune signatures in TCGA datasets corresponding to 26 different cancer types. Utilizing PACIFIC, the authors found that immunogenomic interactions were associated with survival, and that driver mutations including those in PIK3CA and KMT2D were similarly associated with immunogenomic interactions in specific cancer types. In addition, the authors observed an association between genomic deletions and decreased expression of tumor suppressors, and genomic gains with increased expression of oncogenes. Immunogenomic interactions also demonstrated an association with prognosis, specific immune cell populations, and ICI targets. The utility of immunogenomic interactions as biomarkers and potential therapeutic targets was also indicated using the loss of MEN1 in luminal-A breast cancer as a model. Altogether, this study proposes a computational methodology to evaluate immunogenomic interactions in the context of tumor progression and therapeutics and emphasizes the value of understanding the interactions of the TME and genomic alterations in tumors.FOXA1 is a key transcriptional regulator and promising therapeutic target in hormone-dependent cancers. However, our understanding of its regulatory mechanism and protein interactions is limited. To address this, Plagens and colleagues mapped the FOXA1 interactome in ER-positive breast cancer. Proximity-dependent biotinylation using miniTurbo labeling and LC-MS/MS analysis of FOXA1 in MCF-7 cells revealed a high-confidence FOXA1-interactome comprised of 185 proteins, including known FOXA1 interactors. Comparison against the known BioGRID database for FOXA1 interactors showed that miniTurbo labeling identified 157 novel interactions. One candidate protein, NR2C2, also demonstrated strong interaction with FOXA1 in coimmunoprecipitation assays of ER-positive breast cancer cells. Further ChIP-seq and motif analysis of FOXA1 proficient and deficient MCF-7 cells found altered NR2C2 binding in FOXA1 deficient cells, specifically noting enhanced binding of NR2C2 to the NFIL3 motif. The authors also observed patterns of FOXA1-independent and -dependent NR2C2 binding, where NR2C2 binding at the ESR1 promoter was found to be FOXA1-dependent. FOXA1/NR2C2 codependent genes, including EXO1, CCNA2, and RUVBL2, were also identified using transcriptome analysis and ChIP-sequencing. Overall, this study defines the FOXA1/NR2C2 interaction and provides a resource for future mechanistic studies that interrogate the FOXA1 interactome.