Lactate Promotes Cancer Stem-like Property of Oral Sequamous Cell Carcinoma

Abstract

Accumulation of lactate in tumor has been linked to poor prognosis of oral squamous cell carcinoma (OSCC), but the underlying mechanism remained largely uncertain. Previous studies have suggested that presence of cancer stem cells (CSCs) closely correlated with cellular malignancy of OSCC. Here, using 3D organoid culture model, we investigated whether lactate promoted CSCs phenotype in primary OSCC cells. We generated organoids using fresh OSCC specimens and verified that organoids recapitulated histopathology and cellular heterogeneity of parental tumor. Organoids were then transfected with a Wnt reporter to visualize Wnt activity. The sphere forming assay demonstrated that high Wnt activity functionally designated CSCs population in OSCC cells. Further investigations indicated that lactate treatment promoted Wnt activity and increased the expression of CSCs (i.e. CD133⁺ cells) in organoids. Moreover, silencing monocarboxylate transporter 1 (MCT1), the prominent path for lactate uptake in human tumor with siRNA significantly impaired organoid forming capacity of OSCC cells. Together, our study demonstrated that lactate can promote CSCs phenotype of OSCC, and MCT1 may be a therapeutic target against OSCC growth.

Keywords

oral squamous cell carcinoma / lactate / cancer stem cells / organoid / monocarboxylate transporter 1

References

[1] Vander HeidenMG, CantleyLC, ThompsonCB. Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation. Science, 2009, 324(5930): 1029-1033

[2] DohertyJR, ClevelandJL. Targeting lactate metabolism for cancer therapeutics. J Clin Invest, 2013, 123(9): 3685-3692

[3] FaubertB, LiKY, CaiL, et al.. Lactate Metabolism in Human Lung Tumors. Cell, 2017, 171: 358-371

[4] WildeL, RocheM, Domingo-VidalM, et al.. Metabolic Coupling and the Reverse Warburg Effect in Cancer, implications for novel biomarker and anticancer agent development. Semin Oncol, 2017, 44(3): 198-203

[5] SattlerUG, MeyerSS, QuennetV, et al.. Glycolytic metabolism and tumour response to fractionated irradiation. Radiother Oncol, 2010, 94(1): 102-109

[6] González-MolesMA, ScullyC, Ruiz-ÁvilaI, et al.. The cancer stem cell hypothesis applied to oral carcinoma. Oral Oncol, 2013, 49(8): 738-746

[7] SunS, LiuS, DuanSZ, et al.. Targeting the c-Met/FZD8 signaling axis eliminates patient-derived cancer stem-like cells in head and neck squamous carcinomas. Cancer Res, 2014, 74(24): 7546-7559

[8] SimpleM, SureshA, DasD, et al.. Cancer stem cells and field cancerization of oral squamous cell carcinoma. Oral Oncol, 2015, 51(7): 643-651

[9] BatlleE, CleversH. Cancer stem cells revisited. Nat Med, 2017, 23(10): 1124-1134

[10] MitraA, MishraL, LiS. Technologies for deriving primary tumor cells for use in personalized cancer therapy. Trends Biotechnol, 2013, 31(6): 347-354

[11] CenteneraMM, RajGV, KnudsenKE, et al.. Ex vivo culture of human prostate tissue and drug development. Nat Rev Urol, 2013, 10(8): 483-487

[12] DrostJ, CleversH. Organoids in cancer research. Nat Rev Cancer, 2018, 18(7): 407-418

[13] ShahAT, HeasterTM, SkalaMC. Metabolic Imaging of Head and Neck Cancer Organoids. PloS One, 2017, 12(1): e0170415

[14] QuY, HanB, GaoB, et al.. Differentiation of Human Induced Pluripotent Stem Cells to Mammary-like Organoids. Stem Cell Report, 2017, 8(2): 201-215

[15] SonveauxP, VégranF, SchroederT, et al.. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest, 2008, 118(12): 3930-3942

[16] ZhangQ, ShiS, YenY, et al.. A subpopulation of CD133⁺ cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer Lett, 2010, 289(2): 151-160

[17] NandaKD, RanganathanK, DeviU, et al.. Increased expression of CK8 and CK18 in leukoplakia, oral submucous fibrosis, and oral squamous cell carcinoma: An immunohistochemistry study. Oral Surg Oral Med Oral Pathol Oral Radiol, 2012, 113(2): 245-253

[18] VermeulenL, De Sousa E MeloF, van der HeijdenM, et al.. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol, 2010, 12(5): 468-476

[19] Int J Cancer, 2018, 142(6):

[20] TassoneP, Domingo-VidalM, Whitaker-MenezesD, et al.. Metformin Effects on Metabolic Coupling and Tumor Growth in Oral Cavity Squamous Cell Carcinoma Coinjection Xenografts. Otolaryngol Head Neck Surg, 2018, 158(5): 867-877

[21] SachsN, CleversH. Organoid cultures for the analysis of cancer phenotypes. Curr Opin Genet Dev, 2014, 24: 68-73

[22] LiL, LiC, WangS, et al.. Exosomes Derived from Hypoxic Oral Squamous Cell Carcinoma Cells Deliver miR-21 to Normoxic Cells to Elicit a Prometastatic Phenotype. Cancer Res, 2016, 76(7): 1770-1780

[23] Martinez-OutschoornUE, Peiris-PagèsM, PestellRG, et al.. Cancer metabolism: a therapeutic perspective. Nat Rev Clin Oncol, 2017, 14: 11-31

[24] Rodriguez-ColmanMJ, ScheweM, MeerloM, et al.. Interplay between metabolic identities in the intestinal crypt supports stem cell function. Nature, 2017, 543: 424-427