Construction of Multicellular Tumor-On-A-Chip Models for Ovarian Cancer Research

Jiexian Ye; Hao Lin; Zilin Zhang; Shihui Xu; Feili Yang; Xuemei Zhuansun; Feng Ji; Yusha Zhang; Yuxin Zhu; Jing Zhang; Zaozao Chen; Zhongze Gu; Yang Shen

doi:10.1016/j.eng.2025.08.028

Engineering ›› DOI: 10.1016/j.eng.2025.08.028

review-article

Construction of Multicellular Tumor-On-A-Chip Models for Ovarian Cancer Research

Jiexian Ye ^a^,^c^,^#
, Hao Lin ^b^,^#
, Zilin Zhang ^a
, Shihui Xu ^a^,^c^,^d
, Feili Yang ^c
, Xuemei Zhuansun ^c
, Feng Ji ^b
, Yusha Zhang ^e
, Yuxin Zhu ^e
, Jing Zhang ^c
, Zaozao Chen ^a^,^c^,^*
, Zhongze Gu ^a^,^c^,^*
, Yang Shen ^e^,^*

Author information +

History +

PDF (4987KB)

Abstract

Ovarian cancer remains a highly lethal gynecologic malignancy. Early diagnosis poses significant challenges, and the five-year survival rate is consistently below 45 %. Current standard-of-care combines surgical resection with platinum-based chemotherapy. Emerging therapeutic modalities like chimeric antigen receptor-T (CAR-T) therapy show promise, though they face efficacy constraints due to tumor heterogeneity and immunosuppressive microenvironments. Conventional models including two-dimensional (2D) cultures and patient-derived xenografts are increasingly supplanted by organoid and tumor-on-a-chip technologies due to intrinsic limitations and poor clinical translatability. This study established multiple tumor-on-a-chip platforms derived from ovarian cancer organoids and conducted systematic in vitro drug sensitivity screening. Furthermore, by utilizing patient-derived organoids to engineer multicellular dynamic microenvironments, we achieved one of the extremely limited evaluations of CAR-T efficacy against solid tumors within ovarian cancer microfluidic systems. This work establishes an enhanced preclinical platform to advance therapeutic screening and personalized treatment development.

Keywords

Ovarian cancer / Chimeric antigen receptor-mesothelin-T / Organoid / Tumor-on-a-chip / Tumor microenvironment

Cite this article

Download citation ▾

Jiexian Ye, Hao Lin, Zilin Zhang, Shihui Xu, Feili Yang, Xuemei Zhuansun, Feng Ji, Yusha Zhang, Yuxin Zhu, Jing Zhang, Zaozao Chen, Zhongze Gu, Yang Shen. Construction of Multicellular Tumor-On-A-Chip Models for Ovarian Cancer Research. Engineering DOI:10.1016/j.eng.2025.08.028

登录浏览全文

4963

注册一个新账户忘记密码

References

Publishing order | Descend order by publishing year | Descend order by cited within

[1]	Torre LA, Islami F, Siegel RL, Ward EM, Jemal A.Global cancer in women: burden and trends.Cancer Epidemiol Biomarkers Prev 2017; 26(4):444-457.

[2]	Jiang X, Tang H, Chen T.Epidemiology of gynecologic cancers in China.J Gynecol Oncol 2018; 29(1):e7.

[3]	Tanyi JL, Haas AR, Beatty GL, Stashwick CJ, O MH’Hara, Morgan MA, et al.Anti-mesothelin chimeric antigen receptor T cells in patients with epithelial ovarian cancer. J Clin Oncol, 34 (15_suppl) (2016), p. 5511

[4]	Maru Y, Hippo Y.Current status of patient-derived ovarian cancer models.Cells 2019; 8(5):505.

[5]	Lee WS, Kim HY, Seok JY, Jang HH, Park YH, Kim SY, et al.Genomic profiling of patient-derived colon cancer xenograft models.Medicine 2014; 93(28):e298.

[6]	Wu Q, Liu J, Wang X, Feng L, Wu J, Zhu X, et al.Organ-on-a-chip: recent breakthroughs and future prospects.Biomed Eng Online 2020; 19(1):9.

[7]	Stewart JM, Shaw PA, Gedye C, Bernardini MQ, Neel BG, Ailles LE.Phenotypic heterogeneity and instability of human ovarian tumor-initiating cells.Proc Natl Acad Sci 2011; 108(16):6468-6473.

[8]	Dalerba P, Cho RW, Clarke MF.Cancer stem cells: models and concepts.Annu Rev Med 2007; 58(1):267-284.

[9]	Kryczek I, Liu S, Roh M, Vatan L, Szeliga W, Wei S, et al.Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells.Int J Cancer 2012; 130(1):29-39.

[10]	Drost J, Clevers H.Organoids in cancer research.Nat Rev Cancer 2018; 18(7):407-418.

[11]	Sun H, Wang H, Wang X, Aoki Y, Wang X, Yang Y, et al.Aurora-A/SOX8/FOXK1 signaling axis promotes chemoresistance via suppression of cell senescence and induction of glucose metabolism in ovarian cancer organoids and cells.Theranostics 2020; 10(15):6928-6945.

[12]	Maru Y, Tanaka N, Itami M, Hippo Y.Efficient use of patient-derived organoids as a preclinical model for gynecologic tumors.Gynecol Oncol 2019; 154(1):189-198.

[13]	Phan N, Hong JJ, Tofig B, Mapua M, Elashoff D, Moatamed NA, et al.A simple high-throughput approach identifies actionable drug sensitivities in patient-derived tumor organoids.Commun Biol 2019; 2(1):1-11.

[14]	Pauli C, Hopkins BD, Prandi D, Shaw R, Fedrizzi T, Sboner A, et al.Personalized in vitro and in vivo cancer models to guide precision medicine.Cancer Discov 2017; 7(5):462-477.

[15]	Tuveson D, Clevers H.Cancer modeling meets human organoid technology.Science 2019; 364(6444):952-955.

[16]	Aboulkheyr H Es, Montazeri L, Aref AR, Vosough M, Baharvand H.Personalized cancer medicine: an organoid approach.Trends Biotechnol 2018; 36(4):358-371.

[17]	Jin MZ, Han RR, Qiu GZ, Ju XC, Lou G, Jin WL.Organoids: an intermediate modeling platform in precision oncology.Cancer Lett 2018; 414:174-180.

[18]	Hill SJ, Decker B, Roberts EA, Horowitz NS, Muto MG, Worley MJJr, et al.Prediction of DNA repair inhibitor response in short-term patient-derived ovarian cancer organoids.Cancer Discov 2018; 8(11):1404-1421.

[19]	Li S, Lei N, Chen M, Guo R, Han L, Qiu L, et al.Exploration of organoids in ovarian cancer: from basic research to clinical translation.Transl Oncol 2024; 50:102130.

[20]	Joy JD, Malacrida B, Lafor Fêts, Kotantaki P, Maniati E, Manchanda R, et al.Human 3D ovarian cancer models reveal malignant cell-intrinsic and -extrinsic factors that influence CAR T-cell activity.Cancer Res 2024; 84(15):2432-2449.

[21]	Lal-Nag M, McGee L, Guha R, Lengyel E, Kenny HA, Ferrer M.A high-throughput screening model of the tumor microenvironment for ovarian cancer cell growth.SLAS Discov 2017; 22(5):494-506.

[22]	Ibrahim LI, Hajal C, Offeddu GS, Gillrie MR, Kamm RD.Omentum-on-a-chip: a multicellular, vascularized microfluidic model of the human peritoneum for the study of ovarian cancer metastases.Biomaterials 2022; 288:121728.

[23]	Dadgar N, Gonzalez-Suarez AM, Fattahi P, Hou X, Weroha JS, Gaspar-Maia A, et al.A microfluidic platform for cultivating ovarian cancer spheroids and testing their responses to chemotherapies.Microsyst Nanoeng 2020; 6(1):1-12.

[24]	Hietanen S, Oikkonen J, Hynninen J, Virtanen A, Häkkinen A, Hautaniemi S, et al.Longitudinal single-cell RNA-seq analysis reveals stress-promoted chemoresistance in metastatic ovarian cancer.Sci Adv 2022; 8(8):eabm1831.

[25]	Rajasekar S, Lin DSY, Abdul L, Liu A, Sotra A, Zhang F, et al.IFlowPlate-a customized 384-well plate for the culture of perfusable vascularized colon organoids.Adv Mater 2020; 32(46):e2002974.

[26]	Maenhoudt N, Defraye C, Boretto M, Jan Z, Heremans R, Boeckx B, et al.Developing organoids from ovarian cancer as experimental and preclinical models.Stem Cell Rep 2020; 14(4):717-729.

[27]	Kopper O, de CJWitte, L Kõhmussaar, Valle-Inclan JE, Hami N, Kester L, et al.An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity.Nat Med 2019; 25(5):27.

[28]	L Kõhmussaar, Kopper O, Korving J, Begthel H, Vreuls CPH, Van JHEs, et al.Assessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids.Nat Commun 2020; 11(1):2660.

[29]	Senkowski W, Gall-Mas L, Falco MM, Li Y, Lavikka K, Kriegbaum MC, et al.A platform for efficient establishment and drug-response profiling of high-grade serous ovarian cancer organoids.Dev Cell 2023; 58(12):1106-1121.e7.

[30]	Mayr D, Hirschmann A, Löhrs U, Diebold J.KRAS and BRAF mutations in ovarian tumors: a comprehensive study of invasive carcinomas, borderline tumors and extraovarian implants.Gynecol Oncol 2006; 103(3):883-887.

[31]	T CGA Research Network.Integrated genomic analyses of ovarian carcinoma. Nature 2011;474(7353):609–15.

[32]	Adamson AW, Ding YC, Steele L, Leong LA, Morgan R, Wakabayashi MT, et al.Genomic analyses of germline and somatic variation in high-grade serous ovarian cancer.J Ovarian Res 2023; 16(1):141.

[33]	Chen Z, Ma N, Sun X, Li Q, Zeng Y, Chen F, et al.Automated evaluation of tumor spheroid behavior in 3D culture using deep learning-based recognition.Biomaterials 2021; 272:120770.

[34]	Gengenbacher N, Singhal M, Augustin HG.Preclinical mouse solid tumour models: status quo, challenges and perspectives.Nat Rev Cancer 2017; 17(12):751-765.

[35]	Zhang F, Zhu Y, Chen J, Kuang W, Huang R, Duan F, et al.Efficient endothelial and smooth muscle cell differentiation from human pluripotent stem cells through a simplified insulin-free culture system.Biomaterials 2021; 271:120713.

[36]	Kamatar A, Gunay G, Acar H.Natural and synthetic biomaterials for engineering multicellular tumor spheroids.Polymers 2020; 12(11):2506.

[37]	Doyle AD, Yamada KM.Mechanosensing via cell-matrix adhesions in 3D microenvironments.Exp Cell Res 2016; 343(1):60-66.

[38]	Khawar IA, Park JK, Jung ES, Lee MA, Chang S, Kuh HJ.Three dimensional mixed-cell spheroids mimic stroma-mediated chemoresistance and invasive migration in hepatocellular carcinoma.Neoplasia 2018; 20(8):800-812.

[39]	Gunay G, Kirit HA, Kamatar A, Baghdasaryan O, Hamsici S, Acar H.The effects of size and shape of the ovarian cancer spheroids on the drug resistance and migration.Gynecol Oncol 2020; 159(2):563-572.

[40]	Rafehi S, Ramos YValdes, Bertrand M, McGee J, Pr Méfontaine, Sugimoto A, et al.TGFβ signaling regulates epithelial-mesenchymal plasticity in ovarian cancer ascites-derived spheroids.Endocr Relat Cancer 2016; 23(3):147-159.

[41]	Mehta G, Hsiao AY, Ingram M, Luker GD, Takayama S.Opportunities and challenges for use of tumor spheroids as models to test drug delivery and efficacy.J Control Release 2012; 164(2):192-204.

[42]	Vukicevic S, Kleinman HK, Luyten FP, Roberts AB, Roche NS, Reddi AH.Identification of multiple active growth factors in basement membrane matrigel suggests caution in interpretation of cellular activity related to extracellular matrix components.Exp Cell Res 1992; 202(1):1-8.

[43]	Maruhashi T, Sugiura D, Okazaki IM, Okazaki T.LAG-3: from molecular functions to clinical applications.J Immunother Cancer 2020; 8(2):e001014.

[44]	Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, et al.Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives.Mol Cancer 2021; 20(1):131.

[45]	Carmeliet P, Jain RK.Molecular mechanisms and clinical applications of angiogenesis.Nature 2011; 473(7347):298-307.

[46]	Ayala-Domínguez L, Olmedo-Nieva L, Muñoz-Bello JO, Contreras-Paredes A, Manzo-Merino J, Martínez-Ramírez I, et al.Mechanisms of vasculogenic mimicry in ovarian cancer.Front Oncol 2019; 9:998.

[47]	Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L.Angiogenic signaling pathways and anti-angiogenic therapy for cancer.Signal Transduct Target Ther 2023; 8(1):198.

[48]	Liu HD, Xia BR, Jin MZ, Lou G.Organoid of ovarian cancer: genomic analysis and drug screening.Clin Transl Oncol 2020; 22(8):1240-1251.

[49]	Bi J, Newtson AM, Zhang Y, Devor EJ, Samuelson MI, Thiel KW, et al.Successful patient-derived organoid culture of gynecologic cancers for disease modeling and drug sensitivity testing.Cancers 2021; 13(12):2901.

[50]	Mu N, Gu J, Huang T, Zhang C, Shu Z, Li M, et al.A novel NF-κB/YY1/microRNA-10a regulatory circuit in fibroblast-like synoviocytes regulates inflammation in rheumatoid arthritis.Sci Rep 2016; 6:20059.

[51]	Zhuang J, Zhang J, Wu M, Zhang Y.A dynamic 3D tumor spheroid chip enables more accurate nanomedicine uptake evaluation.Adv Sci 2019; 6(22):1901462.

[52]	Lv J, Li P.Mesothelin as a biomarker for targeted therapy.Biomark Res 2019; 7(1):18.

[53]	Hassan R, Thomas A, Alewine C, Le DT, Jaffee EM, Pastan I.Mesothelin immunotherapy for cancer: ready for prime time?.J Clin Oncol 2016; 34(34):4171-4179.

[54]	Zhao R, Cui Y, Zheng Y, Li S, Lv J, Wu Q, et al.Human hyaluronidase PH20 potentiates the antitumor activities of mesothelin-specific CAR-T cells against gastric cancer.Front Immunol 2021; 12:660488.

[55]	Zhang Q, Liu G, Liu J, Yang M, Fu J, Liu G, et al.The antitumor capacity of mesothelin-CAR-T cells in targeting solid tumors in mice.Mol Ther Oncolytics 2021; 20:556-568.

[56]	Klampatsa A, Dimou V, Albelda SM.Mesothelin-targeted CAR-T cell therapy for solid tumors.Expert Opin Biol Ther 2021; 21(4):473-486.

[57]	Molloy ME, Austin RJ, Lemon BD, Aaron WH, Ganti V, Jones A, et al.Preclinical characterization of HPN536, a trispecific, T-cell-activating protein construct for the treatment of mesothelin-expressing solid tumors.Clin Cancer Res 2021; 27(5):1452-1462.

[58]	Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z.GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses.Nucleic Acids Res 2017; 45(W1):W98-W.

[59]	Bellone M, Calcinotto A.Ways to enhance lymphocyte trafficking into tumors and fitness of tumor infiltrating lymphocytes.Front Oncol 2013; 3:231.

[60]	Calcinotto A, Grioni M, Jachetti E, Curnis F, Mondino A, Parmiani G, et al.Targeting TNF-α to neoangiogenic vessels enhances lymphocyte infiltration in tumors and increases the therapeutic potential of immunotherapy.J Immunol 2012; 1950(188):2687-2694.

[61]	Sumransub N, El NJurdi, Chiraphapphaiboon W, Maakaron JE.Putting function back in dysfunction: endothelial diseases and current therapies in hematopoietic stem cell transplantation and cellular therapies.Blood Rev 2022; 51:100883.

[62]	Mercogliano MF, Bruni S, Mauro F, Elizalde PV, Schillaci R.Harnessing tumor necrosis factor alpha to achieve effective cancer immunotherapy.Cancers 2021; 13(3):564.

[63]	Zhang TQ, Lv QY, Jin WL.The cellular-centered view of hypoxia tumor microenvironment: molecular mechanisms and therapeutic interventions.Biochim Biophys Acta 2024; 1879(5):189137.