Anniina Färkkilä

A first-in-class polymerase theta inhibitor selectively targets homologous-recombination-deficient tumors

DNA polymerase theta (POLθ) is synthetic lethal with Homologous Recombination (HR) deficiency and thus a candidate target for HR-deficient cancers. Through high-throughput small molecule screens we identified the antibiotic Novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells

Tumor-Derived Lysophosphatidic Acid Blunts Protective Type I Interferon Responses in Ovarian Cancer

Abstract Lysophosphatidic acid (LPA) is a bioactive lipid enriched in the tumor microenvironment of immunosuppressive malignancies such as ovarian cancer. Although LPA enhances the tumorigenic attributes of cancer cells, the immunomodulatory activity of this phospholipid messenger remains largely unexplored. Here, we report that LPA operates as a negative regulator of type I interferon (IFN) responses in ovarian cancer. Ablation of the LPA-generating enzyme autotaxin (ATX) in ovarian cancer cells reprogrammed the tumor immune microenvironment, extended host survival, and improved the effects of therapies that elicit protective responses driven by type I IFN. Mechanistically, LPA sensing by dendritic cells triggered PGE2 biosynthesis that suppressed type I IFN signaling via autocrine EP4 engagement. Moreover, we identified an LPA-controlled, immune-derived gene signature associated with poor responses to combined PARP inhibition and PD-1 blockade in patients with ovarian cancer. Controlling LPA production or sensing in tumors may therefore be useful to improve cancer immunotherapies that rely on robust induction of type I IFN. Significance: This study uncovers that ATX–LPA is a central immunosuppressive pathway in the ovarian tumor microenvironment. Ablating this axis sensitizes ovarian cancer hosts to various immunotherapies by unleashing protective type I IFN responses. Understanding the immunoregulatory programs induced by LPA could lead to new biomarkers predicting resistance to immunotherapy in patients with cancer. See related commentary by Conejo-Garcia and Curiel, p. 1841. This article is highlighted in the In This Issue feature, p. 1825

Decoding the epigenetics of persister states in ovarian cancer

Dumbrava et al. map a unified epigenetically primed persister state in high-grade serous ovarian carcinoma using single-nucleus multi-omics. Their work uncovers a chromatin-encoded tolerance program that precedes transcriptional change, revealing therapeutic options and motivating deeper spatiotemporal mapping of persister cells.

Tracing back primed resistance in cancer via sister cells

Abstract Exploring non-genetic evolution of cell states during cancer treatments has become attainable by recent advances in lineage-tracing methods. However, transcriptional changes that drive cells into resistant fates may be subtle, necessitating high resolution analysis. Here, we present ReSisTrace that uses shared transcriptomic features of sister cells to predict the states priming treatment resistance. Applying ReSisTrace in ovarian cancer cells perturbed with olaparib, carboplatin or natural killer (NK) cells reveals pre-resistant phenotypes defined by proteostatic and mRNA surveillance features, reflecting traits enriched in the upcoming subclonal selection. Furthermore, we show that DNA repair deficiency renders cells susceptible to both DNA damaging agents and NK killing in a context-dependent manner. Finally, we leverage the obtained pre-resistance profiles to predict and validate small molecules driving cells to sensitive states prior to treatment. In summary, ReSisTrace resolves pre-existing transcriptional features of treatment vulnerability, facilitating both molecular patient stratification and discovery of synergistic pre-sensitizing therapies.

Ex Vivo Immuno-Oncology Platform Reveals Spatial T-cell Infiltration Patterns Linked to ATR Inhibition Responses in High-Grade Serous Ovarian Cancer

Abstract Identifying new therapeutic approaches in high-grade serous ovarian cancer (HGSC) requires the development of more accurate preclinical models that replicate the patient-specific tumor and its microenvironment. To address this, we established immunocompetent patient-derived cultures (iPDC) for HGSC, cultured on a physiologically relevant human omentum gel matrix. We developed a high-throughput platform that combines drug testing, histologic analysis, genomic profiling, single-cell studies, and spatial biomarker discovery. Our results from 47 tumors showed that iPDCs recapitulated the tumor genomic and histologic characteristics while also retaining the intratumoral immune cells. The iPDC treatment responses correlated significantly with the patients’ clinical treatment responses. Using iPDCs and single-cell RNA sequencing, we identified potentially effective therapeutic options for patients with recurrent HGSC linked to distinct tumor cell states and mechanisms of resistance. High-throughput drug response profiling with single-cell imaging identified ataxia telangiectasia and Rad3-related inhibitor (ATRi) combined with an immunotherapy targeting autotaxin as a promising new combination treatment for HGSC. Using hyperplexed imaging and spatial analysis, we discovered that ATRi responses were associated with significant increases in both intra- and peritumoral T-cell infiltration, particularly in PD-1+ CD8+ T cells. Additionally, the ATRi-induced reactivation of CD8+ T cells was linked to spatial interactions with replication stress–positive tumor cells. Thus, our iPDC platform presents a representative high-throughput ex vivo model to advance precision oncology in HGSC, uncovering the ATRi-immunotherapy combination as a potentially effective therapeutic option for clinical translation.