作者: O'Toole, Sandra A ; Chen, Yunn-Yi ; Varga, Zsuzsanna ; Harada, Oi ; Gobbi, Helenice ; Yang, Wentao ; Schmitt, Fernando ; Siziopikou, Kalliopi P ; Fox, Stephen B ; Djerroudi, Lounes ; Collins, Laura C ; Schnitt, Stuart J ; Vincent-Salomon, Anne ; Quinn, Cecily ; Badve, Sunil S ; Wen, Hannah ; Tse, Gary M ; Provenzano, Elena ; Kuroda, Hajime ; Chen, Chih Jung ; Pinder, Sarah E ; Jaffer, Shabnam ; Callagy, Grace ; Ellis, Ian O ; Li, Xiaoxian ; Shaaban, Abeer M ; Rakha, Emad A ; Brogi, Edi ; Sahin, Aysegul A ; Lakhani, Sunil R ; Allison, Kimberly H ; Foschini, Maria Pia ; Raymond, Wendy ; Cserni, Gábor ; Tan, Puay Hoon ; Yamaguchi, Rin ; Moriya, Takuya ; Gudi, Mihir ; Kulka, Janina ; Charafe-Jauffret, Emmanuelle ; Tang, Ping

Fibroepithelial lesions (FELs) of the breast represent a diverse group of biphasic tumors with varying morphologies and clinical behavior. The classification of FELs is mainly based on a constellation of diagnostic criteria, and intralesional heterogeneity is not uncommon. Therefore, reporting FELs in a core needle biopsy (CNB) with limited tissue material can be challenging as not all the features may be represented for assessment. Differentiating a classic fibroadenoma from a well-sampled phyllodes tumor (PT) is generally straightforward. However, cellular fibroadenoma, morphologically heterogeneous benign PT, and myoid hamartoma can overlap histologically. Accurate grading of PT is also challenging on CNB and carries significant management implications. In this article, we provide an overview and propose a pragmatic approach to reporting FELs on CNB, particularly for lesions with overlapping features. Guidance using the UK/European "B" classification of FELs alongside descriptive reporting of the various lesions, is also presented to aid in management decisions.

2025-04-21·Cancer Research

Abstract 2006: Exploring a novel crosstalk between PTK7 and EPHA2 tyrosine kinase receptors in metastatic colorectal cancer

作者: Daulat, Avais ; Camoin, Luc ; Borg, Jean-Paul ; Audebert, Stéphane ; Dessaux, Charlotte ; Baudelet, Emilie ; Semenchenko, Constantin ; Maina, Flavio

AbstractColorectal cancer (CRC) remains a significant public health challenge, with an urgent need of novel prognostic biomarkers and therapeutic targets. PTK7, a membrane tyrosine pseudokinase and Wnt receptor, is overexpressed in CRC and linked to poor prognosis. In CRC, PTK7 expression correlates with metastatic progression and decreased survival in non-metastatic patients, positioning PTK7 as both a potential biomarker and a promising drug target. Notably, a targeted antibody-drug conjugate (ADC) against PTK7 has recently shown efficacy in inducing tumor regression in patient-derived xenograft (PDX) models of solid tumors and has progressed to a Phase I clinical trial with promising results. Other PTK7-targeting ADCs and anti-PTK7 CAR-T cells recently entered into preclinical development.At the plasma membrane, PTK7 can interact with a range of membrane receptors, including VEGFR, EGFR, ROR2, and Plexins, enhancing their signaling capabilities. Using biotin proximity labeling in HCT116 CRC cells, we identified a novel network of PTK7-associated membrane proteins. Among these, we focused on EPHA2, an active tyrosine kinase receptor also implicated in cancer. Our findings indicate that PTK7 and EPHA2 interact via their extracellular domains (ECDs), and that PTK7 depletion significantly upregulates EPHA2 expression and signaling in response to its ligand EFNA-1 in HCT116 cells. Additionally, PTK7 regulates EPHA2’s endosomal sorting through a Rab11-dependent mechanism, as well as its K63-linked ubiquitination and subsequent lysosomal degradation. Mechanistically, PTK7 does not appear to participate directly in EFNA-1 binding but instead promotes multimerization of active EPHA2, a crucial step in amplifying EPHA2 signaling.This study aims to elucidate the functional role of the interaction between PTK7 and EPHA2 in colorectal cancer progression. By mapping the PTK7:EPHA2 interface using AlphaFold3 predictions and introducing targeted deletions and mutations within the ECDs of both receptors, we seek to understand how disrupting this interaction influences tumorigenic and metastatic processes. Our findings indicate that PTK7 depletion triggers cell rounding and detachment, with a marked increase in total and activated EPHA2 levels, which may drive pro-metastatic activity in vivo. Outcomes may significantly impact the use of anti-PTK7-ADCs or CAR-T cells and orient new therapeutic strategies to design agents interfering with PTK7 and EPHA2 interaction and function.Citation Format:Charlotte Dessaux, Constantin Semenchenko, Luc Camoin, Stéphane Audebert, Emilie Baudelet, Avais Daulat, Flavio Maina, Jean-Paul Borg. Exploring a novel crosstalk between PTK7 and EPHA2 tyrosine kinase receptors in metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2006.

2025-04-01·The Journal of Pathology

Redefining phenotypic intratumor heterogeneity of pancreatic ductal adenocarcinoma: a bottom‐up approach

Article

作者: Cros, Jérôme ; Blum, Yuna ; Raffenne, Jérôme ; Neuzillet, Cindy ; Nicolle, Rémy ; Delecourt, Flore ; Hilmi, Marc ; Richard, Magali ; Rebours, Vinciane ; Iovanna, Juan ; Dusetti, Nelson ; Bourega, Taib ; de Mestier, Louis ; Tihy, Matthieu ; Couvelard, Anne

AbstractPancreatic ductal adenocarcinoma (PDAC) tumor interpatient heterogeneity has been well described with two major prognostic subtypes (classical and basal‐like). An important intrapatient heterogeneity has been reported but has not yet been studied extensively due to the lack of standardized, reproducible, and easily accessible high‐throughput methods. We built an immunohistochemical (IHC) tool capable of differentiating RNA‐defined classical and basal‐like tumors by selecting relevant antibodies using a multistep process. The successive stages of (i) an in silico selection from a literature review and a bulk transcriptome analysis of 309 PDACs, (ii) a tumor‐specific selection from 30 patient‐derived xenografts and single‐cell data, followed by (iii) the validation on tissue microarrays in 50 PDAC were conducted. We used our final IHC panel on two independent cohorts of resected PDAC (n = 95, whole‐slide, n = 148, tissue microarrays) for external validation. After digitization and registration of pathology slides, we performed a tile‐based analysis in tumor areas to identify relevant marker combinations. Sequential marker selection led to the following panel: GATA6, CLDN18, TFF1, MUC16, S100A2, KRT17, PanBasal. Four different phenotypes were identified: one classical, one intermediate (KRT17+), and two basal‐like (MUC16+ versus S100A2+) with specific biological properties. The presence of a minor basal contingent drastically reduced overall survival [hazard ratio (HR) = 1.90, p = 0.03], even in classical predominant PDACs. Analysis of preneoplastic lesions suggested that pancreatic carcinogenesis might follow a progressive evolution from classical toward a basal through an early intermediate phenotype. In conclusion, our IHC panel redefined and easily assessed the high degree of intra‐ and intertumoral heterogeneity of PDAC. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

项与 Centre de Recherche en Cancérologie de Marseille 相关的新闻（医药）

2024-10-21

·PRNewswire

Okomera Gets €1.5 Million Grant to Develop Microfluidics & AI Powered CRISPR Editing Platform for Target Validation

PARIS, Oct. 21, 2024 /PRNewswire/ -- Okomera announces Bpifrance funding to develop and standardize novel CRISPR screening assay to accelerate drug discovery in oncology with leading cancer research center of Marseille, CRCM. Okomera is developing desktop platform for automated organoid screening using droplet-microfluidics and AI to accelerate drug discovery. Their patented tech developed after 10 years of research at Pasteur Institute and Ecole Polytechnique, provides Multiplexing, Co-culture and High-throughput screening of drug candidates on miniaturized Patient Derived Organoids (PDOs). Continue Reading Raphael Tomasi, CTO & Co-Founder of Okomera "We are honored to receive this grant from Bpifrance," said Sidarth Radjou, CEO of Okomera. Dr. Thomas Miller, Principal Investigator at IPC and CRCM, emphasized the significance of this collaboration: "This partnership is an extraordinary opportunity to advance our understanding of cancer biology. By developing and standardizing a CRISPR screening assay that can be directly applied to PDOs, we can create more accurate disease models. This will not only improve our ability to study cancer mechanisms but also enhance our capability to identify new therapeutic targets and develop more effective treatments." "We are thrilled to embark on this collaboration, as it offers an unprecedented opportunity to leverage cutting-edge technologies in cancer research," said Dr. Geraldine Guasch, Research Director Inserm at CRCM and Scientific Director of the 3D-HUB-O organoid platform. "By integrating CRISPR technology with Okomera's advanced organoid screening platform, we are setting the stage for more precise and effective therapeutic strategies. This project represents a significant step forward in translating scientific discoveries into tangible clinical applications, ultimately bringing us closer to improving outcomes for cancer patients." Corentin Molson, representing Bpifrance, commented: "Bpifrance is proud to support Okomera in this pioneering effort. Their innovative approach to developing and standardizing CRISPR screening on PDOs reflects our commitment to fostering innovation in healthcare. This project has the potential to make significant contributions to the field of precision medicine and improve outcomes for cancer patients." We would also like to recognize the contribution and assistance provided by AstraZeneca to support the successful grant application. About Okomera, visit our website: Paoli-Calmettes Institute: Based in Marseilles, Paoli-Calmettes Institute (IPC) is the first cancer comprehensive centre in region providing global care for cancer. It is a member of the national federation Unicancer. Further information: Photo - Logo - Contact: Sidarth Radjou, CEO [email protected] SOURCE Okomera WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

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