Adipocytes promote pancreatic cancer migration and invasion through fatty acid metabolic reprogramming

Cai,Zhiwei; Li,Yang; Ma,Mingjian; Wang,Longxiang; Wang,Hongwei; Liu,Meng; Jiang,Chongyi

doi:10.3892/or.2023.8578

Adipocytes promote pancreatic cancer migration and invasion through fatty acid metabolic reprogramming

Authors:
- Zhiwei Cai
- Yang Li
- Mingjian Ma
- Longxiang Wang
- Hongwei Wang
- Meng Liu
- Chongyi Jiang
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Affiliations: Department of General Surgery, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, P.R. China
Published online on: June 1, 2023 https://doi.org/10.3892/or.2023.8578
Article Number: 141
Copyright: © Cai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Locally advanced and metastatic pancreatic cancer (PC) frequently grows in adipose tissue and has a poor prognosis. Although adipose tissue is largely composed of adipocytes, the mechanisms by which adipocytes impact PC are poorly understood. Using an in vitro coculture model, it was shown that adipocytes promoted tumor progression, and an intricate metabolic network between PC cells and adipocytes was identified and elucidated. First, the proteome of Panc‑1 PC cells cultured with or without mature adipocytes was identified. This revealed activated hypoxia signaling in cocultured Panc‑1 cells, which was confirmed by the increased expression of factors downstream of hypoxia signaling, such as ANGPTL4 and glycolytic genes, as determined by reverse transcription‑quantitative PCR and western blot analysis. In addition, it was demonstrated that coculture with cancer cells activated STAT3 and induced an insulin‑resistant phenotype in adipocytes. Furthermore, enhanced fatty acid β‑oxidation and increased lipid droplets (LDs) were observed in the cocultured cancer cells. In contrast, downregulated lipid metabolism and a decrease in the size of LDs were found in cocultured adipocytes. Finally, it was shown that the increase in LDs contributed to the increased metastatic capacity of the cocultured PC cells. These data demonstrated that interrupting the mechanisms of lipid uptake from adipocytes in the microenvironment may offer a potential strategy for attenuating PC metastasis.

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1	Mizrahi JD, Surana R, Valle JW and Shroff RT: Pancreatic cancer. Lancet. 395:2008–2020. 2020. View Article : Google Scholar : PubMed/NCBI
2	Sahai E: Illuminating the metastatic process. Nat Rev Cancer. 7:737–749. 2007. View Article : Google Scholar : PubMed/NCBI
3	Feig C, Gopinathan A, Neesse A, Chan DS, Cook N and Tuveson DA: The pancreas cancer microenvironment. Clin Cancer Res. 18:4266–4276. 2012. View Article : Google Scholar : PubMed/NCBI
4	Klein AP: Pancreatic cancer epidemiology: Understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol. 18:493–502. 2021. View Article : Google Scholar : PubMed/NCBI
5	Chung KM, Singh J, Lawres L, Dorans KJ, Garcia C, Burkhardt DB, Robbins R, Bhutkar A, Cardone R, Zhao X, et al: Endocrine-Exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma. Cell. 181:832–847.e18. 2020. View Article : Google Scholar : PubMed/NCBI
6	Okumura T, Ohuchida K, Sada M, Abe T, Endo S, Koikawa K, Iwamoto C, Miura D, Mizuuchi Y, Moriyama T, et al: Extra-pancreatic invasion induces lipolytic and fibrotic changes in the adipose microenvironment, with released fatty acids enhancing the invasiveness of pancreatic cancer cells. Oncotarget. 8:18280–18295. 2017. View Article : Google Scholar : PubMed/NCBI
7	Hori M, Takahashi M, Hiraoka N, Yamaji T, Mutoh M, Ishigamori R, Furuta K, Okusaka T, Shimada K, Kosuge T, et al: Association of pancreatic Fatty infiltration with pancreatic ductal adenocarcinoma. Clin Transl Gastroenterol. 5:e532014. View Article : Google Scholar : PubMed/NCBI
8	Incio J, Liu H, Suboj P, Chin SM, Chen IX, Pinter M, Ng MR, Nia HT, Grahovac J, Kao S, et al: Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov. 6:852–869. 2016. View Article : Google Scholar : PubMed/NCBI
9	Quail DF and Dannenberg AJ: The obese adipose tissue microenvironment in cancer development and progression. Nat Rev Endocrinol. 15:139–154. 2019. View Article : Google Scholar : PubMed/NCBI
10	O'Sullivan J, Lysaght J, Donohoe CL and Reynolds JV: Obesity and gastrointestinal cancer: The interrelationship of adipose and tumour microenvironments. Nat Rev Gastroenterol Hepatol. 15:699–714. 2018. View Article : Google Scholar : PubMed/NCBI
11	Cai Z, Liang Y, Xing C, Wang H, Hu P, Li J, Huang H, Wang W and Jiang C: Cancer-associated adipocytes exhibit distinct phenotypes and facilitate tumor progression in pancreatic cancer. Oncol Rep. 42:2537–2549. 2019.PubMed/NCBI
12	Wang YY, Attané C, Milhas D, Dirat B, Dauvillier S, Guerard A, Gilhodes J, Lazar I, Alet N, Laurent V, et al: Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight. 2:e874892017. View Article : Google Scholar : PubMed/NCBI
13	Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, Romero IL, Carey MS, Mills GB, Hotamisligil GS, et al: Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 17:1498–1503. 2011. View Article : Google Scholar : PubMed/NCBI
14	Zhang M, Di Martino JS, Bowman RL, Campbell NR, Baksh SC, Simon-Vermot T, Kim IS, Haldeman P, Mondal C, Yong-Gonzales V, et al: Adipocyte-derived lipids mediate melanoma progression via FATP proteins. Cancer Discov. 8:1006–1025. 2018. View Article : Google Scholar : PubMed/NCBI
15	Wen YA, Xing X, Harris JW, Zaytseva YY, Mitov MI, Napier DL, Weiss HL, Mark Evers B and Gao T: Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer. Cell Death Dis. 8:e25932017. View Article : Google Scholar : PubMed/NCBI
16	Qian SW, Tang Y, Li X, Liu Y, Zhang YY, Huang HY, Xue RD, Yu HY, Guo L, Gao HD, et al: BMP4-mediated brown fat-like changes in white adipose tissue alter glucose and energy homeostasis. Proc Natl Acad Sci USA. 110:E798–E807. 2013. View Article : Google Scholar : PubMed/NCBI
17	Takehara M, Sato Y, Kimura T, Noda K, Miyamoto H, Fujino Y, Miyoshi J, Nakamura F, Wada H, Bando Y, et al: Cancer-associated adipocytes promote pancreatic cancer progression through SAA1 expression. Cancer Sci. 111:2883–2894. 2020. View Article : Google Scholar : PubMed/NCBI
18	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
19	Zhou B, Wu D, Liu H, Du LT, Wang YS, Xu JW, Qiu FB, Hu SY and Zhan HX: Obesity and pancreatic cancer: An update of epidemiological evidence and molecular mechanisms. Pancreatology. 19:941–950. 2019. View Article : Google Scholar : PubMed/NCBI
20	Shuff S, Oyama Y, Walker L and Eckle T: Circadian Angiopoietin-Like-4 as a Novel Therapy in Cardiovascular Disease. Trends Mol Med. 27:627–629. 2021. View Article : Google Scholar : PubMed/NCBI
21	Qiao G, Wu A, Chen X, Tian Y and Lin X: Enolase 1, a moonlighting protein, as a potential target for cancer treatment. Int J Biol Sci. 17:3981–3992. 2021. View Article : Google Scholar : PubMed/NCBI
22	Sharma D, Singh M and Rani R: Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics. Semin Cancer Biol. 87:184–195. 2022. View Article : Google Scholar : PubMed/NCBI
23	Pedroso JAB, Ramos-Lobo AM and Donato J Jr: SOCS3 as a future target to treat metabolic disorders. Hormones (Athens). 18:127–136. 2019. View Article : Google Scholar : PubMed/NCBI
24	Wunderlich CM, Hövelmeyer N and Wunderlich FT: Mechanisms of chronic JAK-STAT3-SOCS3 signaling in obesity. Jakstat. 2:e238782013.PubMed/NCBI
25	Wang T, Fahrmann JF, Lee H, Li YJ, Tripathi SC, Yue C, Zhang C, Lifshitz V, Song J, Yuan Y, et al: JAK/STAT3-regulated Fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab. 27:136–150.e5. 2018. View Article : Google Scholar : PubMed/NCBI
26	Garcia D and Shaw RJ: AMPK: Mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell. 66:789–800. 2017. View Article : Google Scholar : PubMed/NCBI
27	Rozeveld CN, Johnson KM, Zhang L and Razidlo GL: KRAS controls pancreatic cancer cell lipid metabolism and invasive potential through the lipase HSL. Cancer Res. 80:4932–4945. 2020. View Article : Google Scholar : PubMed/NCBI
28	Dumas JF and Brisson L: Interaction between adipose tissue and cancer cells: Role for cancer progression. Cancer Metastasis Rev. 40:31–46. 2021. View Article : Google Scholar : PubMed/NCBI
29	Lyssiotis CA and Kimmelman AC: Metabolic Interactions in the tumor microenvironment. Trends Cell Biol. 27:863–875. 2017. View Article : Google Scholar : PubMed/NCBI
30	Mukherjee A, Chiang CY, Daifotis HA, Nieman KM, Fahrmann JF, Lastra RR, Romero IL, Fiehn O and Lengyel E: Adipocyte-induced FABP4 expression in ovarian cancer cells promotes metastasis and mediates carboplatin resistance. Cancer Res. 80:1748–1761. 2020. View Article : Google Scholar : PubMed/NCBI
31	Ye H, Adane B, Khan N, Sullivan T, Minhajuddin M, Gasparetto M, Stevens B, Pei S, Balys M, Ashton JM, et al: Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell. 19:23–37. 2016. View Article : Google Scholar : PubMed/NCBI
32	Andersen DK, Korc M, Petersen GM, Eibl G, Li D, Rickels MR, Chari ST and Abbruzzese JL: Diabetes, pancreatogenic diabetes, and pancreatic cancer. Diabetes. 66:1103–1110. 2017. View Article : Google Scholar : PubMed/NCBI
33	Permert J, Ihse I, Jorfeldt L, von Schenck H, Arnquist HJ and Larsson J: Improved glucose metabolism after subtotal pancreatectomy for pancreatic cancer. Br J Surg. 80:1047–1050. 1993. View Article : Google Scholar : PubMed/NCBI
34	Pannala R, Basu A, Petersen GM and Chari ST: New-onset diabetes: A potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 10:88–95. 2009. View Article : Google Scholar : PubMed/NCBI
35	Basso D, Brigato L, Veronesi A, Panozzo MP, Amadori A and Plebani M: The pancreatic cancer cell line MIA PaCa2 produces one or more factors able to induce hyperglycemia in SCID mice. Anticancer Res. 15:2585–2588. 1995.PubMed/NCBI
36	Moldogazieva NT, Mokhosoev IM and Terentiev AA: Metabolic heterogeneity of cancer cells: An Interplay between HIF-1, GLUTs, and AMPK. Cancers (Basel). 12:8622020. View Article : Google Scholar : PubMed/NCBI
37	Fuentes NR, Phan J, Huang Y, Lin D and Taniguchi CM: Resolving the HIF paradox in pancreatic cancer. Cancer Lett. 489:50–55. 2020. View Article : Google Scholar : PubMed/NCBI
38	Diedrich JD, Rajagurubandara E, Herroon MK, Mahapatra G, Hüttemann M and Podgorski I: Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1α activation. Oncotarget. 7:64854–64877. 2016. View Article : Google Scholar : PubMed/NCBI
39	La Camera G, Gelsomino L, Malivindi R, Barone I, Panza S, De Rose D, Giordano F, D'Esposito V, Formisano P, Bonofiglio D, et al: Adipocyte-derived extracellular vesicles promote breast cancer cell malignancy through HIF-1α activity. Cancer Lett. 521:155–168. 2021. View Article : Google Scholar : PubMed/NCBI
40	Seo J, Jeong DW, Park JW, Lee KW, Fukuda J and Chun YS: Fatty-acid-induced FABP5/HIF-1 reprograms lipid metabolism and enhances the proliferation of liver cancer cells. Commun Biol. 3:6382020. View Article : Google Scholar : PubMed/NCBI
41	Cunniff B, McKenzie AJ, Heintz NH and Howe AK: AMPK activity regulates trafficking of mitochondria to the leading edge during cell migration and matrix invasion. Mol Biol Cell. 27:2662–2674. 2016. View Article : Google Scholar : PubMed/NCBI
42	Lin S, Huang C, Gunda V, Sun J, Chellappan SP, Li Z, Izumi V, Fang B, Koomen J, Singh PK, et al: Fascin controls metastatic colonization and mitochondrial oxidative phosphorylation by remodeling mitochondrial actin filaments. Cell Rep. 28:2824–2836.e8. 2019. View Article : Google Scholar : PubMed/NCBI
43	LeBleu VS, O'Connell JT, Gonzalez Herrera KN, Wikman H, Pantel K, Haigis MC, de Carvalho FM, Damascena A, Domingos Chinen LT, Rocha RM, et al: PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol. 16:992–1003. 2014. View Article : Google Scholar : PubMed/NCBI
44	Kelley LC, Chi Q, Cáceres R, Hastie E, Schindler AJ, Jiang Y, Matus DQ, Plastino J and Sherwood DR: Adaptive F-actin polymerization and localized ATP production drive basement membrane invasion in the absence of MMPs. Dev Cell. 48:313–328.e8. 2019. View Article : Google Scholar : PubMed/NCBI