The study of predicting individual response to chemotherapy for colorectal cancer patients based on tumoroids living biobank_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

CHEN Hao , PAN Xiaofei , ZHANG Haogang , WANG Fujing ,  QIAO Pengfei

Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, P. R. China;

Corresponding author：

QIAO Pengfei, Email: lunwenqpf@126.com

Keywords：

colorectal cancer; tumoroid; living biobank; chemotherapy

DOI：

10.7507/1007-9424.202208018

Video：

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Objective In this study, we present a living biobank of patient-derived tumoroids from advanced colorectal cancer (CRC) patients and show examples of how these tumoroids can be used to simulate cancer behavior ex vivo and provide more evidence for tumoroids could be utilized as a predictive platform during chemotherapy to identify the chemotherapy response. Methods The tumor tissues of CRC patients were collected to isolate and culture tumoroids, and the histomorphology of tumoroids was evaluated. Further, tumoroids were treated with drugs of different chemotherapy schemes, and the drug sensitivity of tumoroids was evaluated by using CellTiter-GIo 3D cell viability assay, and the clinical efficacy was compared with that of patients. Results The tumoroids were still highly consistent with the original tumor histomorphology after continuous passage. The consistency between the drug sensitivity of tumoroids from different patients and the clinical efficacy of corresponding CRC patients was 91.18% (31/34). The drug inhibition rate of tumoroids was positively correlated with the progression free survival (PFS) of CRC patients (r_s=0.412, P=0.016), while the area under the cell activity drug concentration curve of tumoroids was negatively correlated with the PFS of CRC patients (r_s=–0.479, P=0.004). Conclusion This study established a biological sample bank of tumoroids for CRC patients, and suggested that tumoroids had the potential to be used as preclinical experimental models and predict the chemotherapy effect of CRC patients.

Citation： CHEN Hao, PAN Xiaofei, ZHANG Haogang, WANG Fujing, QIAO Pengfei. The study of predicting individual response to chemotherapy for colorectal cancer patients based on tumoroids living biobank. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2023, 30(2): 167-174. doi: 10.7507/1007-9424.202208018 Copy

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9.	Fleming M, Ravula S, Tatishchev SF, et al. Colorectal carcinoma: pathologic aspects. J Gastrointest Oncol, 2012, 3(3): 153-173.
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12.	Nakano T, Ando S, Takata N, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell, 2012, 10(6): 771-785.
13.	Lancaster MA, Renner M, Martin CA, et al. Cerebral organoids model human brain development and microcephaly. Nature, 2013, 501(7467): 373-379.
14.	Quadrato G, Nguyen T, Macosko EZ, et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature, 2017, 545(7652): 48-53.
15.	Paşca AM, Sloan SA, Clarke LE, et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods, 2015, 12(7): 671-678.
16.	Sakaguchi H, Kadoshima T, Soen M, et al. Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun, 2015, 6: 8896. doi: 10.1038/ncomms9896.
17.	Koehler KR, Nie J, Longworth-Mills E, et al. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat Biotechnol, 2017, 35(6): 583-589.
18.	Miller AJ, Dye BR, Ferrer-Torres D, et al. Generation of lung organoids from human pluripotent stem cells in vitro. Nat Protoc, 2019, 14(2): 518-540.
19.	McCracken KW, Catá EM, Crawford CM, et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature, 2014, 516(7531): 400-404.
20.	Hu H, Gehart H, Artegiani B, et al. Long-term expansion of functional mouse and human hepatocytes as 3D organoids. Cell, 2018, 175(6): 1591-1606.
21.	Hohwieler M, Illing A, Hermann PC, et al. Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling. Gut, 2017, 66(3): 473-486.
22.	Bleijs M, van de Wetering M, Clevers H, et al. Xenograft and organoid model systems in cancer research. EMBO J, 2019, 38(15): e101654. doi: 10.15252/embj.2019101654.
23.	Nanki K, Toshimitsu K, Takano A, et al. Divergent routes toward wnt and r-spondin niche independency during human gastric carcinogenesis. Cell, 2018, 174(4): 856-869.
24.	Smith RC, Tabar V. Constructing and deconstructing cancers using human pluripotent stem cells and organoids. Cell Stem Cell, 2019, 24(1): 12-24.
25.	Sato T, Stange DE, Ferrante M, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology, 2011, 141(5): 1762-1772.
26.	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(6): 827-838.
27.	Sachs N, de Ligt J, Kopper O, et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell, 2018, 172(1-2): 373-386.
28.	Qu Y, Han B, Gao B, et al. Differentiation of human induced pluripotent stem cells to mammary-like organoids. Stem Cell Reports, 2017, 8(2): 205-215.
29.	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(12): 1424-1435.
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32.	Boretto M, Maenhoudt N, Luo X, et al. Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening. Nat Cell Biol, 2019, 21(8): 1041-1051.
33.	Seidlitz T, Merker SR, Rothe A, et al. Human gastric cancer modelling using organoids. Gut, 2019, 68(2): 207-217.
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35.	Vlachogiannis G, Hedayat S, Vatsiou A, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science, 2018, 359(6378): 920-926.
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39.	Yokota E, Iwai M, Yukawa T, et al. Clinical application of a lung cancer organoid (tumoroid) culture system. NPJ Precis Oncol, 2021, 5(1): 29. doi: 10.1038/s41698-021-00166-3.
40.	Bregenzer M, Horst E, Mehta P, et al. The role of the tumor microenvironment in csc enrichment and chemoresistance: 3D co-culture methods. Methods Mol Biol, 2022, 2424: 217-245.
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42.	Dzobo K, Rowe A, Senthebane DA, et al. Three-dimensional organoids in cancer research: the search for the holy grail of preclinical cancer modeling. OMICS, 2018, 22(12): 733-748.
43.	Zanoni M, Cortesi M, Zamagni A, et al. Modeling neoplastic disease with spheroids and organoids. J Hematol Oncol, 2020, 13(1): 97. doi: 10.1186/s13045-020-00931-0.
44.	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(513): eaay2574. doi: 10.1126/scitranslmed.aay2574.

1. 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(3): 209-249.
2. Esin E, Yalcin S. Maintenance strategy in metastatic colorectal cancer: a systematic review. Cancer Treat Rev, 2016, 42: 82-90.
3. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer, 2013, 49(6): 1374-1403.
4. Pernot S, Velut G, Kourie RH, et al. 5-FU or mitomycin C hepatic arterial infusion after failure of arterial oxaliplatin in patients with colorectal cancer unresectable liver metastases. Clin Res Hepatol Gastroenterol, 2018, 42(3): 255-260.
5. 金晶, 顾晋, 沈琳. 结直肠癌肺转移多学科综合治疗专家共识(2018版). 实用肿瘤杂志, 2018, 33(6): 487-501.
6. Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science, 2014, 345(6194): 1247125. doi: 10.1126/science.1247125.
7. Smith JD, Ruby JA, Goodman KA, et al. Nonoperative management of rectal cancer with complete clinical response after neoadjuvant therapy. Ann Surg, 2012, 256(6): 965-972.
8. Ganesh K, Wu C, O’Rourke KP, et al. A rectal cancer organoid platform to study individual responses to chemoradiation. Nat Med, 2019, 25(10): 1607-1614.
9. Fleming M, Ravula S, Tatishchev SF, et al. Colorectal carcinoma: pathologic aspects. J Gastrointest Oncol, 2012, 3(3): 153-173.
10. Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: a randomized clinical trial. JAMA, 2017, 317(23): 2392-2401.
11. Sato T, Vries RG, Snippert HJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature, 2009, 459(7244): 262-265.
12. Nakano T, Ando S, Takata N, et al. Self-formation of optic cups and storable stratified neural retina from human ESCs. Cell Stem Cell, 2012, 10(6): 771-785.
13. Lancaster MA, Renner M, Martin CA, et al. Cerebral organoids model human brain development and microcephaly. Nature, 2013, 501(7467): 373-379.
14. Quadrato G, Nguyen T, Macosko EZ, et al. Cell diversity and network dynamics in photosensitive human brain organoids. Nature, 2017, 545(7652): 48-53.
15. Paşca AM, Sloan SA, Clarke LE, et al. Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods, 2015, 12(7): 671-678.
16. Sakaguchi H, Kadoshima T, Soen M, et al. Generation of functional hippocampal neurons from self-organizing human embryonic stem cell-derived dorsomedial telencephalic tissue. Nat Commun, 2015, 6: 8896. doi: 10.1038/ncomms9896.
17. Koehler KR, Nie J, Longworth-Mills E, et al. Generation of inner ear organoids containing functional hair cells from human pluripotent stem cells. Nat Biotechnol, 2017, 35(6): 583-589.
18. Miller AJ, Dye BR, Ferrer-Torres D, et al. Generation of lung organoids from human pluripotent stem cells in vitro. Nat Protoc, 2019, 14(2): 518-540.
19. McCracken KW, Catá EM, Crawford CM, et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature, 2014, 516(7531): 400-404.
20. Hu H, Gehart H, Artegiani B, et al. Long-term expansion of functional mouse and human hepatocytes as 3D organoids. Cell, 2018, 175(6): 1591-1606.
21. Hohwieler M, Illing A, Hermann PC, et al. Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling. Gut, 2017, 66(3): 473-486.
22. Bleijs M, van de Wetering M, Clevers H, et al. Xenograft and organoid model systems in cancer research. EMBO J, 2019, 38(15): e101654. doi: 10.15252/embj.2019101654.
23. Nanki K, Toshimitsu K, Takano A, et al. Divergent routes toward wnt and r-spondin niche independency during human gastric carcinogenesis. Cell, 2018, 174(4): 856-869.
24. Smith RC, Tabar V. Constructing and deconstructing cancers using human pluripotent stem cells and organoids. Cell Stem Cell, 2019, 24(1): 12-24.
25. Sato T, Stange DE, Ferrante M, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology, 2011, 141(5): 1762-1772.
26. 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(6): 827-838.
27. Sachs N, de Ligt J, Kopper O, et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell, 2018, 172(1-2): 373-386.
28. Qu Y, Han B, Gao B, et al. Differentiation of human induced pluripotent stem cells to mammary-like organoids. Stem Cell Reports, 2017, 8(2): 205-215.
29. 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(12): 1424-1435.
30. Kim M, Mun H, Sung CO, et al. Patient-derived lung cancer organoids as in vitro cancer models for therapeutic screening. Nat Commun, 2019, 10(1): 3991. doi: 10.1038/s41467-019-11867-6.
31. Boj SF, Hwang CI, Baker LA, et al. Organoid models of human and mouse ductal pancreatic cancer. Cell, 2015, 160(1-2): 324-338.
32. Boretto M, Maenhoudt N, Luo X, et al. Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening. Nat Cell Biol, 2019, 21(8): 1041-1051.
33. Seidlitz T, Merker SR, Rothe A, et al. Human gastric cancer modelling using organoids. Gut, 2019, 68(2): 207-217.
34. van de Wetering M, Francies HE, Francis JM, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell, 2015, 161(4): 933-945.
35. Vlachogiannis G, Hedayat S, Vatsiou A, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science, 2018, 359(6378): 920-926.
36. Yao Y, Xu X, Yang L, et al. Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer. Cell Stem Cell, 2020, 26(1): 17-26.
37. Dutta D, Heo I, Clevers H. Disease modeling in stem cell-derived 3d organoid systems. Trends Mol Med, 2017, 23(5): 393-410.
38. Jin MZ, Han RR, Qiu GZ, et al. Organoids: an intermediate modeling platform in precision oncology. Cancer Lett, 2018, 414: 174-180.
39. Yokota E, Iwai M, Yukawa T, et al. Clinical application of a lung cancer organoid (tumoroid) culture system. NPJ Precis Oncol, 2021, 5(1): 29. doi: 10.1038/s41698-021-00166-3.
40. Bregenzer M, Horst E, Mehta P, et al. The role of the tumor microenvironment in csc enrichment and chemoresistance: 3D co-culture methods. Methods Mol Biol, 2022, 2424: 217-245.
41. Dzobo K. Taking a full snapshot of cancer biology: deciphering the tumor microenvironment for effective cancer therapy in the oncology clinic. OMICS, 2020, 24(4): 175-179.
42. Dzobo K, Rowe A, Senthebane DA, et al. Three-dimensional organoids in cancer research: the search for the holy grail of preclinical cancer modeling. OMICS, 2018, 22(12): 733-748.
43. Zanoni M, Cortesi M, Zamagni A, et al. Modeling neoplastic disease with spheroids and organoids. J Hematol Oncol, 2020, 13(1): 97. doi: 10.1186/s13045-020-00931-0.
44. 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(513): eaay2574. doi: 10.1126/scitranslmed.aay2574.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

The study of predicting individual response to chemotherapy for colorectal cancer patients based on tumoroids living biobank

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