Drug repurposing screening and mechanism analysis based on human colorectal cancer organoids

  • Yunuo Mao 1,2,5 ,
  • Wei Wang 1,2 ,
  • Jingwei Yang 1,2 ,
  • Xin Zhou 1,4 ,
  • Yongqu Lu 1,4 ,
  • Junpeng Gao 1,2 ,
  • Xiao Wang 1 ,
  • Lu Wen 1,2 ,
  • Wei Fu , 1,4 ,
  • Fuchou Tang , 1,2,3
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  • 1. School of Life Sciences, Biomedical Pioneering Innovation Center, Department of General Surgery, Third Hospital, Peking University, Beijing 100871, China
  • 2. Beijing Advanced Innovation Center for Genomics (ICG), Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China
  • 3. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China
  • 4. Peking University Third Hospital Cancer Center, Beijing 100871, China
  • 5. The Research Center of Stem Cell and Regenerative Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China
fuwei@bjmu.edu.cn
tangfuchou@pku.edu.cn

Received date: 05 Dec 2022

Accepted date: 22 May 2023

Published date: 15 Apr 2024

Copyright

2023 The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.

Abstract

Colorectal cancer (CRC) is a highly heterogeneous cancer and exploring novel therapeutic options is a pressing issue that needs to be addressed. Here, we established human CRC tumor-derived organoids that well represent both morphological and molecular heterogeneities of original tumors. To efficiently identify repurposed drugs for CRC, we developed a robust organoid-based drug screening system. By combining the repurposed drug library and computation-based drug prediction, 335 drugs were tested and 34 drugs with anti-CRC effects were identified. More importantly, we conducted a detailed transcriptome analysis of drug responses and divided the drug response signatures into five representative patterns: differentiation induction, growth inhibition, metabolism inhibition, immune response promotion, and cell cycle inhibition. The anticancer activities of drug candidates were further validated in the established patient-derived organoids-based xenograft (PDOX) system in vivo. We found that fedratinib, trametinib, and bortezomib exhibited effective anticancer effects. Furthermore, the concordance and discordance of drug response signatures between organoids in vitro and pairwise PDOX in vivo were evaluated. Our study offers an innovative approach for drug discovery, and the representative transcriptome features of drug responses provide valuable resources for developing novel clinical treatments for CRC.

Cite this article

Yunuo Mao , Wei Wang , Jingwei Yang , Xin Zhou , Yongqu Lu , Junpeng Gao , Xiao Wang , Lu Wen , Wei Fu , Fuchou Tang . Drug repurposing screening and mechanism analysis based on human colorectal cancer organoids[J]. Protein & Cell, 2024 , 15(4) : 285 -304 . DOI: 10.1093/procel/pwad038

1
Arnold M, Sierra MS, Laversanne M et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut 2017;66:683–6691.

DOI

2
Basu A, Bodycombe NE, Cheah JH et al. An interactive resource to identify cancer genetic and lineage dependencies targeted by small molecules. Cell 2013;154:1151–1161.

DOI

3
Ben-David U, Ha G, Tseng YY et al. Patient-derived xenografts undergo mouse-specific tumor evolution. Nat Genet 2017;49:1567–1575.

DOI

4
Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal cancer: a review. JAMA 2021;325:669–685.

DOI

5
Bonfils C, Kalita A, Dubay M et al. Evaluation of the pharmacodynamic effects of MGCD0103 from preclinical models to human using a novel HDAC enzyme assay. Clin Cancer Res 2008;14:3441–3449.

DOI

6
Broutier L, Mastrogiovanni G, Verstegen MM et al. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat Med 2017;23:1424–1435.

DOI

7
Chiavarina B, Costanza B, Ronca R et al. Metastatic colorectal cancer cells maintain the TGF beta program and use TGFBI to fuel angiogenesis. Theranostics 2021;11:1626–1640.

DOI

8
Dizdar L, Werner TA, Drusenheimer JC et al. BRAF(V600E) mutation: a promising target in colorectal neuroendocrine carcinoma. Int J Cancer 2019;144:1379–1390.

DOI

9
Driehuis E, Kretzschmar K, Clevers H. Establishment of patient-derived cancer organoids for drug-screening applications. Nat Protoc 2020;15:3380–3409.

DOI

10
Duan SY, Huang WQ, Liu XT et al. IMPDH2 promotes colorectal cancer progression through activation of the PI3K/AKT/mTOR and PI3K/AKT/FOXO1 signaling pathways. J Exp Clin Cancer Res 2018;37:304.

DOI

11
Etchin J, Sanda T, Mansour MR et al. KPT-330 inhibitor of CRM1 (XPO1)-mediated nuclear export has selective anti-leukaemic activity in preclinical models of T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia. Br J Haematol 2013;161:117–1127.

DOI

12
Fujii M, Shimokawa M, Date S et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 2016;18:827–838.

DOI

13
Fumagalli A, Oost KC, Kester L et al. Plasticity of Lgr5-negative cancer cells drives metastasis in colorectal cancer. Cell Stem Cell 2020;26:569–578 e567.

DOI

14
Geeleher P, Cox NJ, Huang RS. Clinical drug response can be predicted using baseline gene expression levels and in vitro drug sensitivity in cell lines. Genome Biol 2014;15:R47.

DOI

15
Geron I, Abrahamsson AE, Barroga CF et al. Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors. Cancer Cell 2008;13:321–330.

DOI

16
Gonzalez-Fierro A, Duenas-Gonzalez A. Drug repurposing for cancer therapy, easier said than done. Semin Cancer Biol 2021;68:123–131.

DOI

17
Hafner M, Niepel M, Chung M et al. Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs. Nat Methods 2016;13:521–527.

DOI

18
Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinf 2013;14:7.

DOI

19
Hirt CK, Booij TH, Grob L et al. Drug screening and genome editing in human pancreatic cancer organoids identifies drug–gene interactions and candidates for off-label treatment. Cell Genom 2022;2:100095.

DOI

20
Jiang YY, Jiang Y, Li CQ et al. TP63, SOX2, and KLF5 Establish a core regulatory circuitry that controls epigenetic and transcription patterns in esophageal squamous cell carcinoma cell lines. Gastroenterology 2020;159:1311–1327. e19.

DOI

21
Kopper O, de Witte CJ, Lohmussaar K et al. An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity. Nat Med 2019;25:838–849.

DOI

22
Lamb J, Crawford ED, Peck D et al. Golub, The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science 2006;313:1929–1935.

DOI

23
Lee HO, Hong Y, Etlioglu HE et al. Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer. Nat Genet 2020;52:594–603.

DOI

24
Limagne E, Nuttin L, Thibaudin M et al. MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells. Cancer Cell 2022;40:136–152.e12.

DOI

25
Miyoshi H, Stappenbeck TS. In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nat Protoc 2013;8:2471–2482.

DOI

26
Mullally A, Hood J, Harrison C et al. Fedratinib in myelofibrosis. Blood Adv 2020;4:1792–1800.

DOI

27
Musa A, Tripathi S, Dehmer M et al. Systems pharmacogenomic landscape of drug similarities from LINCS data: Drug Association Networks. Sci Rep 2019;9:7849.

DOI

28
Ooft SN, Weeber F, Dijkstra KK et al. Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients. Sci Transl Med 2019;11:eaay2574.

DOI

29
Ordonez-Moran P, Dafflon C, Imajo M et al. HOXA5 counteracts stem cell traits by inhibiting Wnt signaling in colorectal cancer. Cancer Cell 2015;28:815–829.

DOI

30
Pushpakom S, Iorio F, Eyers PA et al. Drug repurposing: progress, challenges and recommendations. Nat Rev Drug Discov 2019;18:41–58.

DOI

31
Sachs N, de Ligt J, Kopper O et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 2018;172:373–386.e10.

DOI

32
Seashore-Ludlow B, Rees MG, Cheah JH et al. Harnessing connectivity in a large-scale small-molecule sensitivity dataset. Cancer Discov 2015;5:1210–1223.

DOI

33
Sillars-Hardebol AH, Carvalho B, Belien JA et al. BCL2L1 has a functional role in colorectal cancer and its protein expression is associated with chromosome 20q gain. J Pathol 2012;226:442–450.

DOI

34
Srivatsan SR, McFaline-Figueroa JL, Ramani V et al. Massively multiplex chemical transcriptomics at single-cell resolution. Science 2020;367:45–51.

DOI

35
Stewart E, Federico SM, Chen X et al. Orthotopic patient-derived xenografts of paediatric solid tumours. Nature 2017;549:96–100.

DOI

36
Subramanian A, Narayan R, Corsello SM et al. A Next Generation Connectivity Map: L1000 platform and the first 1,000,000 profiles. Cell 2017;171:1437–1452.e17.

37
Sung H, Ferlay J, Siegel RL et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71:209–249.

DOI

38
Sveen A, Kopetz S, Lothe RA. Biomarker-guided therapy for colorectal cancer: strength in complexity. Nat Rev Clin Oncol 2020;17:11–32.

DOI

39
Vlachogiannis G, Hedayat S, Vatsiou A et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science 2018;359:920–926.

DOI

40
Voorhees PM, Dees EC, O’Neil B et al. The proteasome as a target for cancer therapy. Clin Cancer Res 2003;9:6316–6325.

41
Wang Q, Zhou Y, Rychahou P et al. Ketogenesis contributes to intestinal cell differentiation. Cell Death Differ 2017;24:458–468.

DOI

42
Wang R, Mao Y, Wang W et al. Systematic evaluation of colorectal cancer organoid system by single-cell RNA-Seq analysis. Genome Biol 2022;23:106.

DOI

43
van de Wetering M, Francies HE, Francis JM et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 2015;161:933–945.

DOI

44
Yan HHN, Siu HC, Law S et al. A comprehensive human gastric cancer organoid biobank captures tumor subtype heterogeneity and enables therapeutic screening. Cell Stem Cell 2018;23:882–897.e11.

DOI

45
Yang W, Soares J, Greninger P et al. Genomics of Drug Sensitivity in Cancer (GDSC): a resource for therapeutic biomarker discovery in cancer cells. Nucleic Acids Res 2013;41:D955–D961.

DOI

46
Yao Y, Xu X, Yang L et al. Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer. Cell Stem Cell 2020;26:17–26.e6.

DOI

47
Yap TA, Parkes EE, Peng WHA et al. Development of immunotherapy combination strategies in cancer. Cancer Discov 2021;11:1368–1397.

DOI

48
Yin S, Xi R, Wu A et al. Patient-derived tumor-like cell clusters for drug testing in cancer therapy. Sci Transl Med 2020;12:eaaz1723.

DOI

49
Yu GC, Wang LG, Han YY et al. clusterProfiler: an R Package for comparing biological themes among gene clusters. Omics 2012;16:284–287.

DOI

50
Zhou Y, Zhou B, Pache L et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019;10:1523.

DOI

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