Implantation of engineered adipocytes suppresses tumor progression in cancer models

Hai P Nguyen; Kelly An; Yusuke Ito; Bhushan N Kharbikar; Rory Sheng; Breanna Paredes; Elizabeth Murray; Kimberly Pham; Michael Bruck; Xujia Zhou; Cassandra Biellak; Aki Ushiki; Mai Nobuhara; Sarah L Fong; Daniel A Bernards; Filipa Lynce; Deborah A Dillon; Mark Jesus M Magbanua; Laura A Huppert; Heinz Hammerlindl; Jace Anton Klein; Luis Valdiviez; Oliver Fiehn; Laura Esserman; Tejal A Desai; Sook Wah Yee; Jennifer M Rosenbluth; Nadav Ahituv

doi:10.1038/s41587-024-02551-2

Implantation of engineered adipocytes suppresses tumor progression in cancer models

Nat Biotechnol. 2025 Feb 4. doi: 10.1038/s41587-024-02551-2. Online ahead of print.

Authors

Hai P Nguyen^{1

2

3}, Kelly An^{1

2}, Yusuke Ito^{1

2}, Bhushan N Kharbikar¹, Rory Sheng^{1

2}, Breanna Paredes^{1

2}, Elizabeth Murray^{1

2}, Kimberly Pham^{1

2}, Michael Bruck⁴, Xujia Zhou^{1

2}, Cassandra Biellak^{1

2}, Aki Ushiki^{1

2}, Mai Nobuhara^{1

2}, Sarah L Fong^{1

2}, Daniel A Bernards¹, Filipa Lynce^{5

6}, Deborah A Dillon⁷, Mark Jesus M Magbanua⁸, Laura A Huppert⁴, Heinz Hammerlindl⁹, Jace Anton Klein³, Luis Valdiviez¹⁰, Oliver Fiehn¹⁰, Laura Esserman¹¹, Tejal A Desai^{1

12}, Sook Wah Yee¹, Jennifer M Rosenbluth^{4

13}, Nadav Ahituv^{14

15}

Affiliations

¹ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
² Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
³ Department of Nutritional Sciences, University of Texas at Austin, Austin, TX, USA.
⁴ Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁶ Harvard Medical School, Boston, MA, USA.
⁷ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁸ Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA.
⁹ Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
¹⁰ University of California Davis West Coast Metabolomics Center, Davis, CA, USA.
¹¹ Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
¹² School of Engineering, Brown University, Providence, RI, USA.
¹³ Chan Zuckerberg Biohub, San Francisco, CA, USA.
¹⁴ Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA. nadav.ahituv@ucsf.edu.
¹⁵ Institute for Human Genetics, University of California San Francisco, San Francisco, CA, USA. nadav.ahituv@ucsf.edu.

PMID: 39905264
DOI: 10.1038/s41587-024-02551-2

Abstract

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.

Abstract

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