Conditional reprogramming in eyelid tumors: bridging the model gap in meibomian gland carcinoma

Abstract

Eyelid tumors, particularly sebaceous carcinoma and meibomian gland carcinoma (MGC), are rare but highly aggressive malignancies characterized by diagnostic difficulty, early dissemination, and limited therapeutic options. Progress in understanding their biology and developing effective treatments has been hampered by the scarcity of robust, patient-derived preclinical models. Conditional reprogramming (CR) technology, which combines Rho-associated kinase (ROCK) inhibition with feeder fibroblast co-culture, enables rapid and reversible expansion of primary epithelial cells while preserving their genetic stability and lineage-specific phenotypic. Over the past decade, CR has emerged as a powerful platform for cancer modeling, drug sensitivity testing, and mechanistic studies across multiple epithelial malignancies. However, its application in ocular oncology remains underexplored. This review summarizes the biological principles and technical features of CR technology, highlights its established applications in epithelial cancer research, and focuses on its emerging relevance to eyelid tumors, particularly MGC. We further address current challenges, including tissue acquisition, standardization and reconstruction of the tumor microenvironment, and the future perspectives integrating CR with organoid culture, multi-omics profiling, and artificial intelligence-based analyses to advance functional precision oncology in eyelid malignancies.

Keywords

Conditional reprogramming / Eyelid tumors / Meibomian gland carcinoma / Patient-derived model / Translational oncology

References

[1] Sa HS, Rubin ML, Xu S, Ning J, Tetzlaff M, Sagiv O, Kandl TJ, Esmaeli B. Prognostic factors for local recurrence, metastasis and survival for sebaceous carcinoma of the eyelid: observations in 100 patients. Br J Ophthalmol. 2019, 103: 980-984.

[2] Zhan H, Mao H, Wu D, Zhou J. Impact of clinicopathological features of meibomian gland adenocarcinoma on the outcomes of surgical resection combined with eyelid reconstruction. Am J Cancer Res. 2025, 15(6): 2765-2778.

[3] Yin VT, Merritt HA, Sniegowski M, Esmaeli B. Eyelid and ocular surface carcinoma: diagnosis and management. Clin Dermatol. 2015, 33: 159-169.

[4] Tripathi R, Chen Z, Li L, Bordeaux JS. Incidence and survival of sebaceous carcinoma in the United States. J Am Acad Dermatol. 2016, 75: 1210-1215.

[5] Cicinelli MV, Kaliki S. Ocular sebaceous gland carcinoma: an update of the literature. Int Ophthalmol. 2019, 39(5): 1187-1197.

[6] Martel A, Lassalle S, Picard-Gauci A, Gastaud L, Montaudie H, Bertolotto C, Nahon-Esteve S, Poissonnet G, Hofman P, Baillif S. New targeted therapies and immunotherapies for locally advanced periocular malignant tumours: towards a new 'eye-sparing' paradigm. Cancers (Basel). 2021, 13(11): 2822.

[7] Seago M, Hosking AM, Greenway HT, Kelley B. Extraocular sebaceous carcinoma treated with Mohs micrographic surgery-a 24-year retrospective review of tumor characteristics and treatment outcomes. Dermatol Surg. 2021, 47: 1195-1199.

[8] Boyack I, Berlied A, Peterson C. A potential role for c-MYC in the regulation of meibocyte cell stress. Cells. 2025, 1410. 709

[9] Jeong SU, Song JS, Lee HJ, Sa HS, Cho KJ. Prognostic significance of tumor-infiltrating lymphocytes and high-risk human papillomavirus in ocular sebaceous carcinoma: a comprehensive analysis. Mod Pathol. 2024, 374. 100449

[10] Peterson C, Hicks JL, De Marzo AM, Campbell AA, Eberhart CG, Dubielzig RR, Teixeira LB. Upregulated MYC expression and p53 mutations may contribute to the oncogenesis of canine Meibomian gland carcinomas. Vet Pathol. 2023, 602185-189.

[11] Rigas PK, Kase S, Rao NA. Expression of alpha-crystallins in human sebaceous carcinoma of the eyelid. Eur J Ophthalmol. 2009, 19(5): 702-707.

[12] Zhang C, Zhu L, Liu X, Jiang M, Tang Q, Xu F, Lin T, He Y. Establishment of a human meibomian gland carcinoma cell model and analysis of differently expressed genes. Exp Eye Res. 2022, 219. 108983

[13] Gallo RA, Lang SH, Gomez A, Sabater AL, Tse DT, Pelaez D, Rong AJ. Effects of mitomycin-C and 5-fluorouracil on ocular adnexal sebaceous carcinoma cells. Am J Ophthalmol. 2022, 240: 14-22.

[14] Lee SH, Jung YH, Yoo JY, Park HJ. A case report of recurrent metastatic sebaceous carcinoma which showed favorable response Tt non-fluorouracil based chemotherapy. Am J Case Rep. 2018, 19: 1192-1196.

[15] Utikal J, Nagel P, Müller V, Becker JC, Dippel E, Frisman A, Gschnell M, Griewank K, Hadaschik E, Helbig D, Hillen U, Leiter U, Pföhler C, Krönig L, Ziemer M, Ugurel S. S1-Guideline Sebaceous Carcinoma. JDDG J Dtsch Dermatol Ges. 2024, 22(5): 730-747.

[16] Zhu X, Xu M, Portal C, Lin Y, Ferdinand A, Peng T, Morrisey EE, Dlugosz AA, Castellano JM, Lee V, Seykora JT, Wong SY, Iomini C, Millar SE. Identification of meibomian gland stem cell populations and mechanisms of aging. Nat Commun. 2025, 16(1. 1663

[17] Song X, Fan J, Jia R, Zhou Y, Ge S, Zhang G, Wang H, Fan X. Identification and regulation pattern analysis of long noncoding RNAs in meibomian gland carcinoma. Epigenomics. 2019, 114): 381-400.

[18] Na HY, Park JH, Shin SA, Lee S, Lee H, Chae H, Choung H, Kim N, Chung JH, Kim JE. Targeted sequencing revealed distinct mutational profiles of ocular and extraocular sebaceous carcinomas. Cancers (Basel). 2021, 13(19): 4810.

[19] Jayaraj P, Ray D, Goel K, Singh A, Kant N, Sen S. Molecular landscape of eyelid sebaceous gland carcinoma: a comprehensive review. Indian J Ophthalmol. 2024, 72101393-1403.

[20] Liu X, Ory V, Chapman S, Yuan H, Albanese C, Kallakury B, Timofeeva OA, Nealon C, Dakic A, Simic V, Haddad BR, Rhim JS, Dritschilo A, Riegel A, McBride A, Schlegel R. Rock inhibitor and feeder cells induce the conditional reprogramming of epithelial cells. Am J Pathol. 2012, 180(2): 599-607.

[21] Jin L, Qu Y, Gomez LJ, Chung S, Han B, Gao B, Yue Y, Gong Y, Liu X, Amersi F, Dang C, Giuliano AE, Cui X. Characterization of primary human mammary epithelial cells isolated and propagated by conditional reprogrammed cell culture. Oncotarget. 2017, 9(14): 11503-11514.

[22] Li D, Thomas C, Shrivastava N, Gersten A, Gadsden N, Schlecht N, Kawachi N, Schiff BA, Smith RV, Rosenblatt G, Augustine S, Gavathiotis E, Burk R, Prystowsky MB, Guha C, Mehta V, Ow TJ. Establishment of a diverse head and neck squamous cancer cell bank using conditional reprogramming culture methods. J Med Virol. 2023, 95(2. e28388

[23] Zhao W, Liu K, Sun Z, Wang L, Liu B, Liu L, Qu X, Cao Z, Sun J, Chai J. Application research of individualized conditional reprogramming system to guide treatment of gastric cancer. Front Oncol. 2021, 11. 709511

[24] Liu X, Krawczyk E, Suprynowicz FA, Palechor-Ceron N, Yuan H, Dakic A, Simic V, Zheng YL, Sripadhan P, Chen C, Lu J, Hou TW, Choudhury S, Kallakury B, Tang DG, Darling T, Thangapazham R, Timofeeva O, Dritschilo A, Randell SH, Albanese C, Agarwal S, Schlegel R. Conditional reprogramming and long-term expansion of normal and tumor cells from human biospecimens. Nat Protoc. 2017, 122): 439-451.

[25] Cerneckis J, Cai H, Shi Y. Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications. Signal Transduct Target Ther. 2024, 9(1. 112

[26] Liu Y, Wu W, Cai C, Zhang H, Shen H, Han Y. Patient-derived xenograft models in cancer therapy: technologies and applications. Signal Transduct Target Ther. 2023, 81. 160

[27] Kettunen K, Boström PJ, Lamminen T, Heinosalo T, West G, Saarinen I, Kaipio K, Rantala J, Albanese C, Poutanen M, Taimen P. Personalized drug sensitivity screening for bladder cancer using conditionally reprogrammed patient-derived cells. Eur Urol. 2019, 764): 430-434.

[28] Timofeeva OA, Palechor-Ceron N, Li G, Yuan H, Krawczyk E, Zhong X, Liu G, Upadhyay G, Dakic A, Yu S, Fang S, Choudhury S, Zhang X, Ju A, Lee MS, Dan HC, Ji Y, Hou Y, Zheng YL, Albanese C, Rhim J, Schlegel R, Dritschilo A, Liu X. Conditionally reprogrammed normal and primary tumor prostate epithelial cells: a novel patient-derived cell model for studies of human prostate cancer. Oncotarget. 2017, 8(14): 22741-22758.

[29] Li Y, Guo D, Zhang Y, Wang L, Sun T, Li Z, Zhang X, Wang S, Chen Y, Wu A. Rapid screening for individualized chemotherapy optimization of colorectal cancer: a novel conditional reprogramming technology-based functional diagnostic assay. Transl Oncol. 2021, 14(1. 100935

[30] Ligaba SB, Khurana A, Graham G, Krawczyk E, Jablonski S, Petricoin EF, Glazer RI, Upadhyay G. Multifactorial analysis of conditional reprogramming of human keratinocytes. PLoS ONE. 2015, 102. e0116755

[31] Matsumoto N, Ueha S, Ueha R, Koyama M, Yamakawa K, Sato T, Goto T, Kono T, Shichino S, Matsushima K, Kondo K. HPV6-induced gene expression signature in recurrent respiratory papillomatosis. Laryngoscope. 2025, 13510): 3732-3739.

[32] Xing B, Pu C, Chen Y, Sheng Y, Zhang B, Cui J, Wu G, Zhao Y. Insights into the characteristics of primary radioresistant cervical cancer using single-cell transcriptomics. Hum Cell. 2023, 36(3): 1135-1146.

[33] Noel S, Servel N, Hatton A, Golec A, Rodrat M, Ng DRS, Li H, Pranke I, Hinzpeter A, Edelman A, Sheppard DN, Sermet-Gaudelus I. Correlating genotype with phenotype using CFTR-mediated whole-cell Cl- currents in human nasal epithelial cells. J Physiol. 2022, 600(6): 1515-1531.

[34] Alkhilaiwi F, Wang L, Zhou D, Raudsepp T, Ghosh S, Paul S, Palechor-Ceron N, Brandt S, Luff J, Liu X, Schlegel R, Yuan H. Long-term expansion of primary equine keratinocytes that maintain the ability to differentiate into stratified epidermis. Stem Cell Res Ther. 2018, 9(1. 181

[35] Wang L, Ye L, Wei G, Chen Y, Ye L, Wu X, Zeng Z, Wang Y, Yin G, Long X, Li H. Conditional reprogrammed human limbal epithelial cells represent a novel in vitro cell model for drug responses. Biochem Biophys Res Commun. 2018, 4994): 735-742.

[36] Woogeng IN, Kaczkowski B, Abugessaisa I, Hu H, Tachibana A, Sahara Y, Hon CC, Hasegawa A, Sakai N, Nishida M, Sanyal H, Sho J, Kajita K, Kasukawa T, Takasato M, Carninci P, Maeda A, Mandai M, Arner E, Takahashi M, Kime C. Inducing human retinal pigment epithelium-like cells from somatic tissue. Stem Cell Reports. 2022, 17(2): 289-306.

[37] Zhou D, Wang A, Maxwell S, Schlegel R, Yuan H. Long-term culture of canine ocular cells that maintain canine papillomaviruses. Viruses. 2022, 14(12. 2675

[38] Wang L, Yu L, Li N, Wang Y, Yang M, Peng Y, Guo H, Ye L. Bromhexine elevates REP2 expression to stimulate secretion from human primary conjunctiva fornix epithelial cells. FEBS Lett. 2020, 5941): 153-160.

[39] Wang W, Wang H, Liu X, Xu F, Tang Q, Zhang C, Lin J, Zhu L, Lin T. E2F2(E2F transcription factor 2) as a potential therapeutic target in meibomian gland carcinoma: evidence from functional and epigenetic studies. BMC Cancer. 2025, 25(1. 880

[40] Liu R, Tu M, Xue J, Xiao B, Li J, Liang L. Oleic acid induces lipogenesis and NLRP3 inflammasome activation in organotypic mouse meibomian gland and human meibomian gland epithelial cells. Exp Eye Res. 2024, 241. 109851

[41] Bhardwaj M, Sen S, Sharma A, Kashyap S, Chosdol K, Pushker N, Bajaj MS, Bakhshi S. ZEB2/SIP1 as novel prognostic indicator in eyelid sebaceous gland carcinoma. Hum Pathol. 2015, 4610): 1437-1442.

[42] Ciaputa R, Szymerowski A, Zebrowski K, Dzimira S, Janus-Ziolkowska I, Kandefer-Gola M, Nowak M. Immunohistochemical and histopathological characteristics of adenomas and adenocarcinomas of Meibomian glands in dogs. Folia Histochem Cytobiol. 2025, 63(3): 142-148.

[43] Takeuchi D, Ishida M, Yasuda E, Ueda K, Hirose Y. Ocular and extraocular sebaceous carcinomas: a retrospective study with emphasis on the presence of in situ lesion and discussion and review of the histogenesis of extraocular sebaceous carcinoma. Oncol Lett. 2023, 26(2. 337

[44] Lee SC, Peterson C, Wang K, Alaali L, Eshleman J, Mahoney NR, Li E, Eberhart CG, Campbell AA. Establishment and characterization of three human ocular adnexal sebaceous carcinoma cell lines. Int J Mol Sci. 2024, 2518. 10183

[45] Li M, Wu XM, Li GD, Xia RN. Preliminary study on the establishment of the animal model and biological activity of human being meibomian gland carcinoma. Zhonghua Yan Ke Za Zhi. 2011, 473): 248-251

[46] Rong AJ, Gallo RA, Zhang MG, Doddapaneni R, Griswold AJ, Lee JY, Kurtenbach S, Dubovy SR, Tse DT, Pelaez D. Establishment and characterization of a novel human ocular adnexal sebaceous carcinoma cell line. Transl Vis Sci Technol. 2021, 106. 34

[47] Gu X, Huang Z, Chen J, Luo Y, Ge S, Jia R, Song X, Chai P, Xu S, Fan X. Establishment and characterization of a TP53-mutated eyelid sebaceous carcinoma cell line. Invest Ophthalmol Vis Sci. 2023, 6415. 16

[48] Peng A, Mao X, Zhong J, Fan S, Hu Y. Single-cell multi-omics and its prospective application in cancer biology. Proteomics. 2020, 2013. e1900271

[49] Hui S, Xie J, Dong L, Wei L, Dai W, Li D. Deep learning-based mobile application for efficient eyelid tumor recognition in clinical images. NPJ Digit Med. 2025, 81. 185

[50] Wang L, Dai X, Liu Z, Zhao Y, Sun Y, Mao B, Wu S, Zhu T, Huang F, Maimaiti N, Cai X, Li SZ, Sheng J, Guo T, Ye J. AI-driven eyelid tumor classification in ocular oncology using proteomic data. NPJ Precis Oncol. 2024, 81. 289

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