Implantation of engineered adipocytes suppresses tumor progression in cancer models
Tumors exhibit an increased ability to obtain and metabolize nutrients. Here, we implant engineered adipocytes that outcompete tumors for nutrients and show that they can substantially reduce cancer progression, a technology termed adipose manipulation transplantation (AMT). Adipocytes engineered to use increased amounts of glucose and fatty acids by upregulating UCP1 were placed alongside cancer cells or xenografts, leading to significant cancer suppression. Transplanting modulated adipose organoids in pancreatic or breast cancer genetic mouse models suppressed their growth and decreased angiogenesis and hypoxia. Co-culturing patient-derived engineered adipocytes with tumor organoids from dissected human breast cancers significantly suppressed cancer progression and proliferation. In addition, cancer growth was impaired by inducing engineered adipose organoids to outcompete tumors using tetracycline or placing them in an integrated cell-scaffold delivery platform and implanting them next to the tumor. Finally, we show that upregulating UPP1 in adipose organoids can outcompete a uridine-dependent pancreatic ductal adenocarcinoma for uridine and suppress its growth, demonstrating the potential customization of AMT.
Authors
- Filipa C. Lynce (ORCID: https://orcid.org/0000-0001-6615-7076)
- Luis Valdiviez
- Laura A. Huppert (ORCID: https://orcid.org/0000-0002-8512-5608)
- Sook Wah Yee (ORCID: https://orcid.org/0000-0001-8121-8746)
- Xujia Zhou (ORCID: https://orcid.org/0009-0001-5796-7357)
- Bhushan N. Kharbikar (ORCID: https://orcid.org/0000-0003-0394-0308)
- Elizabeth Murray (ORCID: https://orcid.org/0009-0000-6973-8829)
- J Klein
- Jennifer M. Rosenbluth (ORCID: https://orcid.org/0000-0003-1314-6976)
- Mai Nobuhara
- Heinz Hammerlindl (ORCID: https://orcid.org/0000-0001-5119-9791)
- Aki Ushiki (ORCID: https://orcid.org/0000-0002-0889-4577)
- Tejal A. Desai (ORCID: https://orcid.org/0000-0003-3409-9208)
- Sarah Fong (ORCID: https://orcid.org/0000-0003-0900-5505)
- Kelly An
- Rory R Sheng (ORCID: https://orcid.org/0000-0002-9254-8836)
- Michael Brück (ORCID: https://orcid.org/0009-0009-7695-8016)
- Deborah Dillon (ORCID: https://orcid.org/0000-0002-4977-6673)
- Mark Jesus M. Magbanua (ORCID: https://orcid.org/0000-0003-2113-3593)
- Laura J. Esserman (ORCID: https://orcid.org/0000-0001-9202-4568)
- Beatriz Paredes
- Daniel A. Bernards (ORCID: https://orcid.org/0000-0002-8176-1690)
- Yusuke Ito (ORCID: https://orcid.org/0000-0002-1521-5931)
- Nadav Ahituv (ORCID: https://orcid.org/0000-0002-7434-8144)
- Oliver Fiehn (ORCID: https://orcid.org/0000-0002-6261-8928)
- Hai P. Nguyen (ORCID: https://orcid.org/0000-0001-8071-0886)
- Kimberly Pham
- Cassandra Biellak
Institutions
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of California, San Francisco (US)
- Brown University (US)
- Dana-Farber Cancer Institute (US)
- Chan Zuckerberg Initiative (United States) (US)
- University of California, Davis (US)
- The University of Texas at Austin (US)
Publication Details
- Journal
- Nature Biotechnology
- Published
- 2025-02-04
- DOI
- https://doi.org/10.1038/s41587-024-02551-2
- Citations
- 34
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 31.83
Funders
- Susan G. Komen for the Cure
- California Institute for Regenerative Medicine
- California Breast Cancer Research Program
- San Francisco State University
- Sandler Foundation
- Susan G. Komen
- METAvivor
- National Institutes of Health
- University of California, Davis
- University of California, San Francisco
- Office of the President, University of California
- National Human Genome Research Institute
- National Cancer Institute
- National Institute of Diabetes and Digestive and Kidney Diseases