Cancer‐associated fibroblasts (CAFs) are key regulators of tumorigenesis and promising targets for next‐generation therapies. We discovered that cancer cell‐derived activin A reprograms fibroblasts into pro‐tumorigenic CAFs. Mechanistically, this occurs via Smad2‐mediated transcriptional regulation of the formin mDia2, which directly promotes filopodia formation and cell migration. mDia2 also induces expression of CAF marker genes through prevention of p53 nuclear accumulation, resulting in the production of a pro‐tumorigenic matrisome and secretome. The translational relevance of this finding is reflected by activin A overexpression in tumor cells and of mDia2 in the stroma of skin cancer and other malignancies and the correlation of high activin A/mDia2 levels with poor patient survival. Blockade of this signaling axis using inhibitors of activin, activin receptors, or mDia2 suppressed cancer cell malignancy and squamous carcinogenesis in 3D organotypic cultures, ex vivo, and in vivo, providing a rationale for pharmacological inhibition of activin A‐mDia2 signaling in stratified cancer patients.

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Thermal deformation is one of the contributors of critical errors of machine tools. ISO 10791-10 describes standardized tests to evaluate a machine tool’s thermal deformation; however, they do not include cutting operations. By repeatedly performing the same machining feature, one can observe the change in geometric accuracy, which is typically caused by the thermal influence of the environment or the heat generated by the machine tool. This paper proposes a simple machining test to evaluate a machine tool’s thermal displacement in the tool’s axial direction (Z-direction). Together with a technical committee of the Japan Machine Tool Builders’ Association, the authors proposed the revision of ISO 10791-10 in ISO/TC39/SC2 to add the present machining tests. This paper presents the test procedures and case studies as well as a comparison with an alternative machining test.

Background: There is a critical necessity to reveal novel and tractable targets for anti-cancer treatments in indications with high unmet medical need, such as high grade serous ovarian cancer (HGSOC). However, standard process for target discovery using models such as outgrown cell lines and well-averaged readouts has yielded a less than 5% approval rate for drugs entering trials (Thomas et al. 2016 Bio.org). Here, we describe patient-centric target discovery through the use of disease relevant primary OC samples and single cell functional characterization using a platform with proven hemonc translatability (Kornauth et al. 2021, Snijder et al. 2017). We integrate data from our functional drug testing platform under multiple drug perturbations with matching genomic and transcriptomic data to reveal associations with novel downstream regulators of sensitivity. Methods: Sensitivity of the cancer cell compartment in primary malignant ascites samples (n = 20; 75% HGSOC) to 85 small molecule drugs, was evaluated using a proprietary and translatable deep learning-driven single cell imaging platform (Vladimer et al. 2017). Cancer cell sensitivity from the drugs was combined with WES, bulk-RNAseq and drug induced changes in phosphoproteome, and single cell RNAseq transcriptome to identify perturbed targets and pathways. Results: Here we describe a family of TKIs including ALKi that induce cytotoxicity of cancer cells in primary samples, not previously captured in publicly available cell line drug sensitivity screening data (Iorio et al. 2016). We report novel sensitivity of OC driven by non-canonical targets of ceritinib such as FAK1 or IGF1R, mediated by the downstream signaling hub YBX1 (Kuenzi et al. 2017), involved in NFB pathway regulation (Motolani et al. 2021). Indeed, transcriptomic scRNA analysis upon ceritinib treatment of primary OC cells revealed rapid perturbation of numerous NFB pathway members, alongside YBX1 inactivation. Conclusions: Combining functional endpoints and single cell-based differential expression analysis of primary OC samples, we have identified the NFB pathway and the regulator YBX1 as a promising novel sensitivity for HGSOC treatment development. These and several other important targetable nodes identified, sit outside the recently suggested JAK/STAT pathway (Izar et al. 2020), thereby demonstrating a pipeline towards novel drug target and pathway discovery driven by patient-centric, disease relevant models of high-need indications. Citation Format: Irene Gutierrez-Perez, Bekir Ergüner, Pisanu Buphamalai, Joost Van Ham, Paul Heinz, Valentin Aranha, Rin Okumura, Elisabeth Waltenberger, Isabella Alt, Claudia Baumgaertler, Maja Stulic, Edgar Petru, Christoph Minichsdorfer, Judith Lafleur, Lukas Hefler, Laudia Hadjari, Lucia Dzurillova, Jozef Sufliarsky, Nikolaus Krall, Thorsten Füreder, Gregory Ian Vladimer, Bojan Vilagos, Robert Sehlke. Discovering novel targetable pathways by combining functional and multi-omic data from primary ovarian cancer samples. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4956.

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