ANO6-mediated trogocytosis of cancer-associated fibroblasts promotes pancreatic cancer cell growth and immune suppression
In pancreatic ductal adenocarcinoma (PDAC), the fibroblastic stroma constitutes most of the tumor mass and is remarkably devoid of functional blood vessels, leaving unresolved how PDAC cells obtain essential metabolites and water-insoluble lipids. We find that cancer-associated fibroblasts (CAFs) acquire and transfer lipids from blood-borne particles to PDAC cells through trogocytosis of CAF plasma membranes, a process requiring the CAF-expressed phospholipid scramblase anoctamin 6 (ANO6) to promote PDAC cell survival. Cancer cells and CAFs form synapse-like contacts that induce cytosolic calcium influx in CAFs through Orai channels, activating ANO6 and driving phosphatidylserine exposure on CAF membranes, which initiates trogocytosis and transfer of membrane lipids, including cholesterol, to PDAC cells. This ANO6-dependent phosphatidylserine externalization also supports CAF-mediated immunosuppression of cytotoxic T cells through trogocytosis. Blockade of ANO6 antagonizes tumor growth, partly by disrupting cholesterol delivery to cancer cells, and attenuates immune suppression, identifying ANO6 as a candidate therapeutic target in PDAC.
Authors
- Alexander A. Dolskiy (ORCID: https://orcid.org/0000-0001-9956-1163)
- Alexander Y. Deneka (ORCID: https://orcid.org/0000-0003-2448-5156)
- Erica A. Golemis (ORCID: https://orcid.org/0000-0003-3618-3673)
- Sven A. Miller (ORCID: https://orcid.org/0000-0001-7295-5592)
- Debora Barbosa Vendramini Costa (ORCID: https://orcid.org/0000-0001-7617-4945)
- Jaye C. Gardiner (ORCID: https://orcid.org/0000-0002-5455-0572)
- Serge Yu. Fuchs (ORCID: https://orcid.org/0000-0002-0136-5103)
- Charline Ogier (ORCID: https://orcid.org/0000-0002-4129-0433)
- Bojana Gligorijevic (ORCID: https://orcid.org/0000-0001-9071-7467)
- Alena Klochkova (ORCID: https://orcid.org/0000-0001-6138-7497)
- Margret B. Einarson (ORCID: https://orcid.org/0000-0003-2324-9717)
- Ludmila Recoules (ORCID: https://orcid.org/0000-0002-4818-2988)
- Mayura R. Dhamdhere (ORCID: https://orcid.org/0000-0002-6062-7943)
- Diana Restifo (ORCID: https://orcid.org/0000-0002-8271-2831)
- Edna Cukierman (ORCID: https://orcid.org/0000-0002-1452-9576)
- Mark Andrake (ORCID: https://orcid.org/0000-0003-2957-4350)
- Aizhan Surumbayeva (ORCID: https://orcid.org/0000-0002-5372-7313)
- Émmanuelle Nicolas (ORCID: https://orcid.org/0000-0002-0368-3519)
- Jerome F. Cros (ORCID: https://orcid.org/0000-0002-4935-3865)
- Linara Gabitova-Cornell (ORCID: https://orcid.org/0000-0002-6603-3214)
- Janusz Franco‐Barraza (ORCID: https://orcid.org/0000-0003-3652-5311)
- Quoc Thang Bui (ORCID: https://orcid.org/0009-0008-8169-0248)
- Nathaniel W. Snyder (ORCID: https://orcid.org/0000-0001-5643-8747)
- Mariia Dmitrieva (ORCID: https://orcid.org/0009-0006-6887-6852)
- Battuya Bayarmagnai
- Jonathan Soboloff (ORCID: https://orcid.org/0000-0001-5192-1297)
- Anna C. Lilly (ORCID: https://orcid.org/0000-0002-0385-6088)
- Emily Megill (ORCID: https://orcid.org/0000-0002-0244-8779)
- Corinne Bousquet (ORCID: https://orcid.org/0000-0002-2501-0593)
- Kathy Q. Cai (ORCID: https://orcid.org/0000-0002-6034-3377)
- Natalie Z. Phinney (ORCID: https://orcid.org/0000-0001-5366-0510)
- Igor A. Astsaturov (ORCID: https://orcid.org/0000-0002-8613-1890)
- Rolf A. Brekken (ORCID: https://orcid.org/0000-0003-2704-2377)
- Ralph A. Francescone III (ORCID: https://orcid.org/0000-0002-3149-6825)
- Alyssa Sipman (ORCID: https://orcid.org/0009-0004-9597-6985)
- Zhen Lu (ORCID: https://orcid.org/0009-0003-5074-4171)
- Tiffany Luong (ORCID: https://orcid.org/0000-0001-9702-7362)
- Elena Bondarenko
- Yingying Tang
- Yunyun Zhou
- Akino Mercy Charles Solomon
- Andrei Efimov
- Zhijing Wu (ORCID: https://orcid.org/0009-0002-6363-0520)
Institutions
- Fox Chase Cancer Center (US)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Hôpital Beaujon (FR)
- Henry Ford Hospital (US)
- Centre de Recherches en Cancérologie de Toulouse (FR)
- Université de Toulouse (FR)
- Drexel University (US)
- University of Pennsylvania (US)
- Temple University (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Cancer
- Published
- 2026-10-30
- DOI
- https://doi.org/10.1038/s43018-026-01265-5
- Primary Topic
- Cancer, Lipids, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense
- American Cancer Society
- Pancreatic Cancer Action Network
- University of Pennsylvania
- Emerald Foundation
- Ligue Contre le Cancer
- Institut National Du Cancer
- National Institutes of Health
- Fox Chase Cancer Center
- National Cancer Institute