Lin, X., Xiao, Z., Chen, T., Liang, S. H. & Guo, H. Glucose metabolism on tumor plasticity, diagnosis, and treatment. Front. Oncol. 10, 317 (2020).
Hay, N. Reprogramming glucose metabolism in cancer: Can it be exploited for cancer therapy? Nat. Rev. Cancer 16, 635–649 (2016).
Liberti, M. V. & Locasale, J. W. The Warburg effect: How does it benefit cancer cells? Trends Biochem. Sci. 41, 211–218 (2016).
Nagarajan, S. R., Butler, L. M. & Hoy, A. J. The diversity and breadth of cancer cell fatty acid metabolism. Cancer Metab. 9, 2 (2021).
Palm, W. & Thompson, C. B. Nutrient acquisition strategies of mammalian cells. Nature 546, 234–242 (2017).
DeWaal, D. et al. Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat. Commun. 9, 446 (2018).
Chan, D. A. et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci. Transl. Med. 3, 94ra70 (2011).
Liu, Y. et al. A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol. Cancer Ther. 11, 1672–1682 (2012).
Fernandez, L. P., Gomez de Cedron, M. & Ramirez de Molina, A. Alterations of lipid metabolism in cancer: implications in prognosis and treatment. Front. Oncol. 10, 577420 (2020).
Khan, W. et al. Lipid metabolism in cancer: a systematic review. J. Carcinog. 20, 4 (2021).
Wang, W., Bai, L., Li, W. & Cui, J. The lipid metabolic landscape of cancers and new therapeutic perspectives. Front. Oncol. 10, 605154 (2020).
Snaebjornsson, M. T., Janaki-Raman, S. & Schulze, A. Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer. Cell Metab. 31, 62–76 (2020).
Mason, P. et al. SCD1 inhibition causes cancer cell death by depleting mono-unsaturated fatty acids. PLoS ONE 7, e33823 (2012).
Guseva, N. V., Rokhlin, O. W., Glover, R. A. & Cohen, M. B. TOFA (5-tetradecyl-oxy-2-furoic acid) reduces fatty acid synthesis, inhibits expression of AR, neuropilin-1 and Mcl-1 and kills prostate cancer cells independent of p53 status. Cancer Biol. Ther. 12, 80–85 (2011).
Seki, T. et al. Brown-fat-mediated tumour suppression by cold-altered global metabolism. Nature 608, 421–428 (2022).
Symonds, M. E., Aldiss, P., Pope, M. & Budge, H. Recent advances in our understanding of brown and beige adipose tissue: the good fat that keeps you healthy. F1000Res 7, F1000 (2018).
Virtanen, K. A. et al. Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360, 1518–1525 (2009).
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004).
Klingenberg, M. Uncoupling protein—a useful energy dissipator. J. Bioenerg. Biomembr. 31, 419–430 (1999).
Suzuki, D., Murata, Y. & Oda, S. Changes in Ucp1, D2 (Dio2) and Glut4 (Slc2a4) mRNA expression in response to short-term cold exposure in the house musk shrew (Suncus murinus). Exp. Anim. 56, 279–288 (2007).
Vimaleswaran, K. S., Radha, V., Deepa, R. & Mohan, V. Absence of association of metabolic syndrome with PPARGC1A, PPARG and UCP1 gene polymorphisms in Asian Indians. Metab. Syndr. Relat. Disord. 5, 153–162 (2007).
Feldmann, H. M., Golozoubova, V., Cannon, B. & Nedergaard, J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab. 9, 203–209 (2009).
Tabuchi, C. & Sul, H. S. Corrigendum: signaling pathways regulating thermogenesis. Front. Endocrinol. (Lausanne) 12, 698619 (2021).
Yi, D. et al. Zc3h10 acts as a transcription factor and is phosphorylated to activate the thermogenic program. Cell Rep. 29, 2621–2633.e4 (2019).
Puigserver, P. & Spiegelman, B. M. Peroxisome proliferator–activated receptor-γ coactivator 1α (PGC-1α): transcriptional coactivator and metabolic regulator. Endocr. Rev. 24, 78–90 (2003).
Lin, J. et al. Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice. Cell 119, 121–135 (2004).
Kajimura, S. Promoting brown and beige adipocyte biogenesis through the PRDM16 pathway. Int. J. Obes. Suppl. 5, S11–S14 (2015).
Harms, M. J. et al. PRDM16 binds MED1 and controls chromatin architecture to determine a brown fat transcriptional program. Genes Dev. 29, 298–307 (2015).
Ohno, H., Shinoda, K., Spiegelman, B. M. & Kajimura, S. PPARgamma agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein. Cell Metab. 15, 395–404 (2012).
Kajimura, S. et al. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-β transcriptional complex. Nature 460, 1154–1158 (2009).
Seale, P. et al. PRDM16 controls a brown fat/skeletal muscle switch. Nature 454, 961–967 (2008).
Kajimura, S. et al. Regulation of the brown and white fat gene programs through a PRDM16/CtBP transcriptional complex. Genes Dev. 22, 1397–1409 (2008).
Seale, P. et al. Transcriptional control of brown fat determination by PRDM16. Cell Metab. 6, 38–54 (2007).
Wang, C. H. et al. CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice. Sci. Transl. Med. 12, eaaz8664 (2020).
Nwosu, Z. C. et al. Uridine-derived ribose fuels glucose-restricted pancreatic cancer. Nature 618, 151–158 (2023).
Kim, H. K. et al. Deep learning improves prediction of CRISPR-Cpf1 guide RNA activity. Nat. Biotechnol. 36, 239–241 (2018).
Flint, J. & Shenk, T. Viral transactivating proteins. Annu. Rev. Genet. 31, 177–212 (1997).
Wu, Z., Yang, H. & Colosi, P. Effect of genome size on AAV vector packaging. Mol. Ther. 18, 80–86 (2010).
Bates, R., Huang, W. & Cao, L. Adipose tissue: an emerging target for adeno-associated viral vectors. Mol. Ther. Methods Clin. Dev. 19, 236–249 (2020).
Kaushik, N., Kaushik, N. K., Choi, E. H. & Kim, J. H. Blockade of cellular energy metabolism through 6-aminonicotinamide reduces proliferation of non-small lung cancer cells by inducing endoplasmic reticulum stress. Biology (Basel) 10, 1088 (2021).
Li, Y. et al. Targeting glucose-6-phosphate dehydrogenase by 6-AN induces ROS-mediated autophagic cell death in breast cancer. FEBS J. 290, 763–779 (2023).
Varshney, R., Dwarakanath, B. & Jain, V. Radiosensitization by 6-aminonicotinamide and 2-deoxy-d-glucose in human cancer cells. Int. J. Radiat. Biol. 81, 397–408 (2005).
O’Connor, R. S. et al. The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations. Sci. Rep. 8, 6289 (2018).
Shim, J.-K. et al. Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres. Cancer Cell Int. 22, 309 (2022).
Lee, C.-K. et al. Tumor metastasis to lymph nodes requires YAP-dependent metabolic adaptation. Science 363, 644–649 (2019).
Loo, S. Y. et al. Fatty acid oxidation is a druggable gateway regulating cellular plasticity for driving metastasis in breast cancer. Sci. Adv. 7, eabh2443 (2021).
Manerba, M. et al. Metabolic activation triggered by cAMP in MCF-7 cells generates lethal vulnerability to combined oxamate/etomoxir. Biochim. Biophys. Acta Gen. Subj. 1863, 1177–1186 (2019).
Strobel, H. A., Gerton, G. & Hoying, J. B. Vascularized adipocyte organoid model using isolated human microvessel fragments. Biofabrication 13, 035022 (2021).
Taylor, J. et al. Generation of immune cell containing adipose organoids for in vitro analysis of immune metabolism. Sci. Rep. 10, 21104 (2020).
Kir, S. & Spiegelman, B. M. Cachexia and brown fat: a burning issue in cancer. Trends Cancer 2, 461–463 (2016).
Bierie, B. et al. Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells. Proc. Natl Acad. Sci. USA 114, E2337–E2346 (2017).
Saito, Y. et al. LLGL2 rescues nutrient stress by promoting leucine uptake in ER+ breast cancer. Nature 569, 275–279 (2019).
Takaku, M., Grimm, S. A. & Wade, P. A. GATA3 in breast cancer: Tumor suppressor or oncogene? Gene Expr. 16, 163–168 (2015).
Jia, L. et al. EEF1A2 interacts with HSP90AB1 to promote lung adenocarcinoma metastasis via enhancing TGF-β/SMAD signalling. Br. J. Cancer 124, 1301–1311 (2021).
Giudici, F. et al. Elevated levels of eEF1A2 protein expression in triple negative breast cancer relate with poor prognosis. PLoS ONE 14, e0218030 (2019).
Abrahams, A., Parker, M. I. & Prince, S. The T-box transcription factor Tbx2: its role in development and possible implication in cancer. IUBMB Life 62, 92–102 (2010).
Yang, H. et al. HOXD10 acts as a tumor-suppressive factor via inhibition of the RHOC/AKT/MAPK pathway in human cholangiocellular carcinoma. Oncol. Rep. 34, 1681–1691 (2015).
Chang, J. W. et al. Wild-type p53 upregulates an early onset breast cancer-associated gene GAS7 to suppress metastasis via GAS7–CYFIP1-mediated signaling pathway. Oncogene 37, 4137–4150 (2018).
Liu, S. et al. MAP2K4 interacts with Vimentin to activate the PI3K/AKT pathway and promotes breast cancer pathogenesis. Aging (Albany NY) 11, 10697–10710 (2019).
Aizawa, T. et al. Cancer-associated fibroblasts secrete Wnt2 to promote cancer progression in colorectal cancer. Cancer Med. 8, 6370–6382 (2019).
Joshi, S. et al. Rac2 controls tumor growth, metastasis and M1–M2 macrophage differentiation in vivo. PLoS ONE 9, e95893 (2014).
Ashburner, M. et al. Gene ontology: tool for the unification of biology. The Gene Ontology Consortium. Nat. Genet. 25, 25–29 (2000).
Gene Ontology Consortium et al. The gene ontology knowledgebase in 2023. Genetics 224, iyad031 (2023).
Maddipati, R. & Stanger, B. Z. Pancreatic cancer metastases harbor evidence of polyclonality. Cancer Discov. 5, 1086–1097 (2015).
Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12, 954–961 (1992).
Dekkers, J. F. et al. Long-term culture, genetic manipulation and xenotransplantation of human normal and breast cancer organoids. Nat. Protoc. 16, 1936–1965 (2021).
Picon-Ruiz, M., Marchal, J. A. & Slingerland, J. M. Obtaining human breast adipose cells for breast cancer cell co-culture studies. STAR Protoc. 1, 100197 (2020).
Shalabi, S. F. et al. Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations. Nat. Aging 1, 838–849 (2021).
Gray, G. K. et al. A human breast atlas integrating single-cell proteomics and transcriptomics. Dev. Cell 57, 1400–1420.e7 (2022).
Nyitray, C. E., Chavez, M. G. & Desai, T. A. Compliant 3D microenvironment improves β-cell cluster insulin expression through mechanosensing and β-catenin signaling. Tissue Eng. Part A 20, 1888–1895 (2014).
Jeong, G. S. et al. Viscoelastic lithography for fabricating self-organizing soft micro-honeycomb structures with ultra-high aspect ratios. Nat. Commun. 7, 11269 (2016).
Girgin, M. U. et al. Bioengineered embryoids mimic post-implantation development in vitro. Nat. Commun. 12, 5140 (2021).
Wise, K. D. & Najafi, K. Microfabrication techniques for integrated sensors and microsystems. Science 254, 1335–1342 (1991).
Leong, T. G., Zarafshar, A. M. & Gracias, D. H. Three-dimensional fabrication at small size scales. Small 6, 792–806 (2010).
Steedman, M. R., Tao, S. L., Klassen, H. & Desai, T. A. Enhanced differentiation of retinal progenitor cells using microfabricated topographical cues. Biomed. Microdevices 12, 363–369 (2010).
Kharbikar, B. N., Kumar, S. H., Kr, S. & Srivastava, R. Hollow silicon microneedle array based trans-epidermal antiemetic patch for efficient management of chemotherapy induced nausea and vomiting. In Micro + Nano Materials, Devices, and Systems Vol. 9668 (eds Eggleton, B. J. & Palomba, S.) 256–272 (SPIE, 2015).
Bernards, D. A. et al. Injectable devices for delivery of liquid or solid protein formulations. ACS Materials Au 3, 255–264 (2023).
Kharbikar, B. N., Chendke, G. S. & Desai, T. A. Modulating the foreign body response of implants for diabetes treatment. Adv. Drug Deliv. Rev. 174, 87–113 (2021).
Kharbikar, B. N., Mohindra, P. & Desai, T. A. Biomaterials to enhance stem cell transplantation. Cell Stem Cell 29, 692–721 (2022).
Shukla, L., Yuan, Y., Shayan, R., Greening, D. W. & Karnezis, T. Fat therapeutics: the clinical capacity of adipose-derived stem cells and exosomes for human disease and tissue regeneration. Front. Pharmacol. 11, 158 (2020).
White, J. D., Dewal, R. S. & Stanford, K. I. The beneficial effects of brown adipose tissue transplantation. Mol. Aspects Med. 68, 74–81 (2019).
Liu, X. et al. Brown adipose tissue transplantation improves whole-body energy metabolism. Cell Res. 23, 851–854 (2013).
Stanford, K. I. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J. Clin. Invest. 123, 215–223 (2013).
Liu, X. et al. Brown adipose tissue transplantation reverses obesity in Ob/Ob mice. Endocrinology 156, 2461–2469 (2015).
Pogodzinski, D., Ostrowska, L., Smarkusz-Zarzecka, J. & Zysk, B. Secretome of adipose tissue as the key to understanding the endocrine function of adipose tissue. Int. J. Mol. Sci. 23, 2309 (2022).
Sun, T. et al. Engineered adipose-derived stem cells overexpressing RXFP1 via CRISPR activation ameliorate erectile dysfunction in diabetic rats. Antioxidants 12, 171 (2023).
Rudolph, M. C., Wellberg, E. A. & Anderson, S. M. Adipose-depleted mammary epithelial cells and organoids. J. Mammary Gland Biol. Neoplasia 14, 381–386 (2009).
Currie, C. J., Poole, C. D. & Gale, E. A. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52, 1766–1777 (2009).
Hemkens, L. G. et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52, 1732–1744 (2009).
Godsland, I. F. Insulin resistance and hyperinsulinaemia in the development and progression of cancer. Clin. Sci. (Lond) 118, 315–332 (2009).
Nasiri, A. R., Rodrigues, M. R., Li, Z., Leitner, B. P. & Perry, R. J. SGLT2 inhibition slows tumor growth in mice by reversing hyperinsulinemia. Cancer Metab. 7, 10 (2019).
Chondronikola, M. et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes 63, 4089–4099 (2014).
Chadt, A. & Al-Hasani, H. Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease. Pflugers Arch. 472, 1273–1298 (2020).
Kousteni, S. FoxO1, the transcriptional chief of staff of energy metabolism. Bone 50, 437–443 (2012).
Schilperoort, M. et al. The GPR120 agonist TUG-891 promotes metabolic health by stimulating mitochondrial respiration in brown fat. EMBO Mol. Med. 10, e8047 (2018).
Satapati, S. et al. GPR120 suppresses adipose tissue lipolysis and synergizes with GPR40 in antidiabetic efficacy. J. Lipid Res. 58, 1561–1578 (2017).
Nguyen, H. P. et al. Aifm2, a NADH oxidase, supports robust glycolysis and is required for cold- and diet-induced thermogenesis. Mol. Cell 77, 600–617.e4 (2020).
Wang, P., Mariman, E., Renes, J. & Keijer, J. The secretory function of adipocytes in the physiology of white adipose tissue. J. Cell. Physiol. 216, 3–13 (2008).
Bond, S. T., Calkin, A. C. & Drew, B. G. Adipose-derived extracellular vesicles: systemic messengers and metabolic regulators in health and disease. Front. Physiol. 13, 837001 (2022).
Matharu, N. et al. CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science 363, eaau0629 (2019).
Wang, X. et al. Evaluation and optimization of differentiation conditions for human primary brown adipocytes. Sci. Rep. 8, 5304 (2018).
Lowell, B. B. & Flier, J. S. Brown adipose tissue, β3-adrenergic receptors, and obesity. Annu. Rev. Med. 48, 307–316 (1997).
Sun, X. et al. Mirabegron displays anticancer effects by globally browning adipose tissues. Nat. Commun. 14, 7610 (2023).
Chen, J., Guo, Z., Tian, H. & Chen, X. Production and clinical development of nanoparticles for gene delivery. Mol. Ther. Methods Clin. Dev. 3, 16023 (2016).
Banskota, S. et al. Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins. Cell 185, 250–265.e16 (2022).
Tsagkaraki, E. et al. CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease. Nat. Commun. 12, 6931 (2021).
Steele, C. B. et al. Vital signs: trends in incidence of cancers associated with overweight and obesity—United States, 2005–2014. MMWR Morb. Mortal Wkly Rep. 66, 1052–1058 (2017).
Renehan, A. G., Zwahlen, M. & Egger, M. Adiposity and cancer risk: new mechanistic insights from epidemiology. Nat. Rev. Cancer 15, 484–498 (2015).
Paz-Filho, G., Lim, E. L., Wong, M. L. & Licinio, J. Associations between adipokines and obesity-related cancer. Front. Biosci. (Landmark Ed.) 16, 1634–1650 (2011).
Park, J., Morley, T. S., Kim, M., Clegg, D. J. & Scherer, P. E. Obesity and cancer—mechanisms underlying tumour progression and recurrence. Nat. Rev. Endocrinol. 10, 455–465 (2014).
Sirin, O. & Kolonin, M. G. Treatment of obesity as a potential complementary approach to cancer therapy. Drug Discov. Today 18, 567–573 (2013).
Khandekar, M. J., Cohen, P. & Spiegelman, B. M. Molecular mechanisms of cancer development in obesity. Nat. Rev. Cancer 11, 886–895 (2011).
Huffman, D. M. et al. Cancer progression in the transgenic adenocarcinoma of mouse prostate mouse is related to energy balance, body mass, and body composition, but not food intake. Cancer Res. 67, 417–424 (2007).
Zhang, Y. et al. Stromal progenitor cells from endogenous adipose tissue contribute to pericytes and adipocytes that populate the tumor microenvironment. Cancer Res. 72, 5198–5208 (2012).
Wang, Y. Y. et al. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight 2, e87489 (2017).
Rohrig, F. & Schulze, A. The multifaceted roles of fatty acid synthesis in cancer. Nat. Rev. Cancer 16, 732–749 (2016).
Beloribi-Djefaflia, S., Vasseur, S. & Guillaumond, F. Lipid metabolic reprogramming in cancer cells. Oncogenesis 5, e189 (2016).
Ye, H. et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell 19, 23–37 (2016).
Cypess, A. M. Reassessing human adipose tissue. N. Engl. J. Med. 386, 768–779 (2022).
Bashor, C. J., Hilton, I. B., Bandukwala, H., Smith, D. M. & Veiseh, O. Engineering the next generation of cell-based therapeutics. Nat. Rev. Drug Discov. 21, 655–675 (2022).
Chendke, G. S. et al. Replenishable prevascularized cell encapsulation devices increase graft survival and function in the subcutaneous space. Bioeng. Transl. Med. 8, e10520 (2023).
Kharbikar, B. N., Zhong, J. X., Cuylear, D. L., Perez, C. A. & Desai, T. A. Theranostic biomaterials for tissue engineering. Curr. Opin. Biomed. Eng. 19, 100299 (2021).
Herberts, C. A., Kwa, M. S. & Hermsen, H. P. Risk factors in the development of stem cell therapy. J. Transl. Med. 9, 29 (2011).
Buitinga, M. et al. Micro-fabricated scaffolds lead to efficient remission of diabetes in mice. Biomaterials 135, 10–22 (2017).
Carpenter, R. et al. Scaffold-assisted ectopic transplantation of internal organs and patient-derived tumors. ACS Biomater. Sci. Eng. 5, 6667–6678 (2019).
Cordeiro, P. G. Breast reconstruction after surgery for breast cancer. N. Engl. J. Med. 359, 1590–1601 (2008).
Juntunen, M. et al. Evaluation of the effect of donor weight on adipose stromal/stem cell characteristics by using weight-discordant monozygotic twin pairs. Stem Cell Res. Ther. 12, 516 (2021).
Chu, D. T. et al. Adipose tissue stem cells for therapy: an update on the progress of isolation, culture, storage, and clinical application. J. Clin. Med. 8, 917 (2019).
Doench, J. G. et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR–Cas9. Nat. Biotechnol. 34, 184–191 (2016).
Schindelin, J. et al. Fiji: an open-source platform for biological-image analysis. Nat. Methods 9, 676–682 (2012).
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
Law, C. W., Chen, Y., Shi, W. & Smyth, G. K. voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 15, R29 (2014).
H. P. Nguyen, et al. Project ID GSE246231. Gene Expression Omnibus https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE246231 (2024).
Qiu, W. & Su, G. H. Development of orthotopic pancreatic tumor mouse models. Methods Mol. Biol. 980, 215–223 (2013).
Rosenbluth, J. M. et al. Organoid cultures from normal and cancer-prone human breast tissues preserve complex epithelial lineages. Nat. Commun. 11, 1711 (2020).
