Comparative Study of Organoids from Patient-Derived Normal and Tumor Colon and Rectal Tissue

Alba Costales-Carrera, Asunción Fernández-Barral, Pilar Bustamante-Madrid, Orlando Domínguez, Laura Guerra-Pastrián, Ramón Cantero, Luis Del Peso, Aurora Burgos, Antonio Barbáchano, Alberto Muñoz, Alba Costales-Carrera, Asunción Fernández-Barral, Pilar Bustamante-Madrid, Orlando Domínguez, Laura Guerra-Pastrián, Ramón Cantero, Luis Del Peso, Aurora Burgos, Antonio Barbáchano, Alberto Muñoz

Abstract

Colon and rectal tumors, often referred to as colorectal cancer, show different gene expression patterns in studies that analyze whole tissue biopsies containing a mix of tumor and non-tumor cells. To better characterize colon and rectal tumors, we investigated the gene expression profile of organoids generated from endoscopic biopsies of rectal tumors and adjacent normal colon and rectum mucosa from therapy-naive rectal cancer patients. We also studied the effect of vitamin D on these organoid types. Gene profiling was performed by RNA-sequencing. Organoids from a normal colon and rectum had a shared gene expression profile that profoundly differed from that of rectal tumor organoids. We identified a group of genes of the biosynthetic machinery as rectal tumor organoid-specific, including those encoding the RNA polymerase II subunits POLR2H and POLR2J. The active vitamin D metabolite 1α,25-dihydroxyvitamin D3/calcitriol upregulated stemness-related genes (LGR5, LRIG1, SMOC2, and MSI1) in normal rectum organoids, while it downregulated differentiation marker genes (TFF2 and MUC2). Normal colon and rectum organoids share similar gene expression patterns and respond similarly to calcitriol. Rectal tumor organoids display distinct and heterogeneous gene expression profiles, with differences with respect to those of colon tumor organoids, and respond differently to calcitriol than normal rectum organoids.

Keywords: colorectal cancer; patient-derived organoids; rectal tumors; stem cells; vitamin D.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Morphology and gene expression analysis of patient-derived normal and tumoral colon and rectum tissues. (a) Phase-contrast micrographs of each type of patient-derived organoid culture. Insets show hematoxylin and eosin (H&E) staining. Scale bar = 100 μm. (b) Principal component analysis (PCA) plot of the transcriptomes of organoid cultures derived from the colon, rectum, rectal tumor, and colon tumor. Additional RNA-seq data for normal and tumor colon organoids were included from a previous publication (accession number GSE100785) [33]. (c) Volcano plot comparing human colon and rectum RNA-seq signatures from six matched normal organoid cultures. The x-axis shows Log2 fold-change (Log2FC) and the y-axis shows the q-value (−Log10).
Figure 2
Figure 2
Mutational analysis and transcriptome profiles of human rectal tumor organoids. (a) Overview of the mutations found in the rectal tumor organoid cultures of six patients. (b) Volcano plot comparing normal rectum and rectal tumor RNA-seq signatures from six organoid cultures. The x-axis shows Log2FC and the y-axis shows the q-value (−Log10). Green/purple dots represent downregulated/upregulated (respectively) genes in rectal tumor organoids. The table lists the top 10 (lowest q-value) upregulated/downregulated genes in rectal tumor organoids ordered by their Log2FC.
Figure 3
Figure 3
Transcriptomic comparison of colon and rectal tumor organoids. (a) Gene Set Enrichment Analysis (GSEA) comparing the genes dysregulated in colon and rectal tumor organoids. (b) Heatmap showing the genes that behave distinctly during tumor progression in the two locations (FDR 5%). Clusters 1–3 group genes whose expression changes distinctly in colon and rectal tumors. The list to the right shows Gene Ontology analysis of Cluster 1 genes (only induced in rectal tumors) in several databases. (c) Heatmap showing the expression (cpm) of genes encoding ribosomal structural components distinctly dysregulated in colon and rectal tumor organoids (interaction study, FDR 5%). (d) GSEA comparing the MYC signature with the genes distinctly dysregulated in rectal tumor vs. colon tumor organoids. (e) Quantification of the expression level (cpm) of selected genes from Clusters 1 to 3 in (b).
Figure 4
Figure 4
Effect of calcitriol on human normal colon, rectum, and rectal tumor organoids. (a) Morphology analysis by H&E staining of each type of patient-derived organoids cultured for 96 h in the presence of 100 nM calcitriol or vehicle. Scale bar = 50 µm. (b) PCA of raw RNA-seq data from organoids treated with calcitriol or vehicle (17 patients/30 organoid cultures). * RNA-seq data (six patients) for normal and tumor colon organoids were included from a previous publication; transcriptome data from GSE100785 [33]. (c) Venn diagram showing the overlap among genes showing a significantly altered expression in normal and tumor organoids. The numbers of genes in each group are indicated. (d) Volcano plots showing calcitriol-regulated genes in organoids derived from a normal colon (blue), normal rectum (green), and rectal tumor (purple). Top-10 up/down regulated genes in normal colon, normal rectum, and rectal tumor organoids are listed. Common regulated genes in the three types of cultures are shown in bold.
Figure 5
Figure 5
Gene expression profiles induced by calcitriol in normal-tissue organoids. (a) Comparison of the calcitriol response of normal colon organoids in independent RNA-seq studies under the same conditions (Normal Colon X: n = 6, GSE100785 [33]; Normal Colon Y: n = 6, present study; total n = 12). Gray shading shows the calculated “correlation zone” according to the dispersion of the Log2FC induced by calcitriol in the replicate studies. (b) Comparison of the calcitriol response of normal colon organoids and normal rectum organoids. Genes in black within the gray-shaded correlation zone are not considered differentially regulated because the Log2FC difference does not exceed that of the replicate assays presented in panel (a); genes in red outside of the correlation zone are considered differentially regulated by calcitriol. (c) Violin plots showing the RNA expression (cpm = “counts per million”) of stemness and differentiation genes in colon and rectum organoids and their regulation by calcitriol.
Figure 6
Figure 6
Comparison of calcitriol effects on the gene expression profiles of rectal tumor and normal rectum organoids. (a) Comparison of the calcitriol response of rectal tumor and normal rectum organoids (n = 6 of each type). Genes showing differential regulation between the two organoid types are shown in red. (b) Comparison of the calcitriol response in colon tumor and rectal tumor organoids (n = 6 of each type). Genes in black within the gray-shaded correlation zone are not considered differentially regulated because the Log2FC difference does not exceed that of the replicate assays presented in Figure 5a. (c) Heatmap showing genes differentially regulated by calcitriol in normal and tumor organoids. The heatmap shows calcitriol regulation (Log2FC) in the transcriptome of 29 organoid cultures (colon, n = 12; colon tumor, n = 6; rectum, n = 6; rectal tumor, n = 5). The RNA-seq data for six of the normal colon organoid cultures and the six colon tumor organoid cultures were obtained from GSE100785 [33].

References

    1. Yamauchi M., Lochhead P., Morikawa T., Huttenhower C., Chan A.T., Giovannucci E., Fuchs C., Ogino S. Colorectal cancer: A tale of two sides or a continuum? Gut. 2012;61:794–797. doi: 10.1136/gutjnl-2012-302014.
    1. Hjartaker A., Aagnes B., Robsahm T.E., Langseth H., Bray F., Larsen I.K. Subsite-specific dietary risk factors for colorectal cancer: A review of cohort studies. J. Oncol. 2013;2013:703854. doi: 10.1155/2013/703854.
    1. Paschke S., Jafarov S., Staib L., Kreuser E.D., Maulbecker-Armstrong C., Roitman M., Holm T., Harris C.C., Link K.H., Kornmann M. Are Colon and Rectal Cancer Two Different Tumor Entities? A Proposal to Abandon the Term Colorectal Cancer. Int. J. Mol. Sci. 2018;19:2577. doi: 10.3390/ijms19092577.
    1. Murphy C.C., Wallace K., Sandler R.S., Baron J.A. Racial Disparities in Incidence of Young-Onset Colorectal Cancer and Patient Survival. Gastroenterology. 2019;156:958–965. doi: 10.1053/j.gastro.2018.11.060.
    1. Rezaianzadeh A., Rahimikazerooni S., Khazraei H., Tadayon S.M.K., Akool M.A., Rahimi M., Hosseini S.V. Do clinicopathologic features of rectal and colon cancer guide us towards distinct malignancies? J. Gastrointest. Oncol. 2019;10:203–208. doi: 10.21037/jgo.2019.02.16.
    1. Kornmann M., Staib L., Wiegel T., Kron M., Henne-Bruns D., Link K.H., Formentini A., Study Group Oncology of Gastrointestinal Tumors Long-term results of 2 adjuvant trials reveal differences in chemosensitivity and the pattern of metastases between colon cancer and rectal cancer. Clin. Colorectal Cancer. 2013;12:54–61. doi: 10.1016/j.clcc.2012.07.005.
    1. van der Sijp M.P., Bastiaannet E., Mesker W.E., van der Geest L.G., Breugom A.J., Steup W.H., Marinelli A.W., Tseng L.N., Tollenaar R.A., van de Velde C.J., et al. Differences between colon and rectal cancer in complications, short-term survival and recurrences. Int. J. Colorectal Dis. 2016;31:1683–1691. doi: 10.1007/s00384-016-2633-3.
    1. Guraya S.Y. Pattern, Stage, and Time of Recurrent Colorectal Cancer After Curative Surgery. Clin. Colorectal Cancer. 2019;18:e223–e228. doi: 10.1016/j.clcc.2019.01.003.
    1. Iqbal A., George T.J. Randomized Clinical Trials in Colon and Rectal Cancer. Surg. Oncol. Clin. 2017;26:689–704. doi: 10.1016/j.soc.2017.05.008.
    1. Delattre O., Olschwang S., Law D.J., Melot T., Remvikos Y., Salmon R.J., Sastre X., Validire P., Feinberg A.P., Thomas G. Multiple genetic alterations in distal and proximal colorectal cancer. Lancet. 1989;2:353–356. doi: 10.1016/S0140-6736(89)90537-0.
    1. Bauer K.M., Hummon A.B., Buechler S. Right-side and left-side colon cancer follow different pathways to relapse. Mol. Carcinog. 2012;51:411–421. doi: 10.1002/mc.20804.
    1. Guinney J., Dienstmann R., Wang X., de Reynies A., Schlicker A., Soneson C., Marisa L., Roepman P., Nyamundanda G., Angelino P., et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 2015;21:1350–1356. doi: 10.1038/nm.3967.
    1. Yaeger R., Chatila W.K., Lipsyc M.D., Hechtman J.F., Cercek A., Sanchez-Vega F., Jayakumaran G., Middha S., Zehir A., Donoghue M.T.A., et al. Clinical Sequencing Defines the Genomic Landscape of Metastatic Colorectal Cancer. Cancer Cell. 2018;33:125–136. doi: 10.1016/j.ccell.2017.12.004.
    1. Sanz-Pamplona R., Cordero D., Berenguer A., Lejbkowicz F., Rennert H., Salazar R., Biondo S., Sanjuan X., Pujana M.A., Rozek L., et al. Gene expression differences between colon and rectum tumors. Clin. Cancer Res. 2011;17:7303–7312. doi: 10.1158/1078-0432.CCR-11-1570.
    1. Wei C., Chen J., Pande M., Lynch P.M., Frazier M.L. A pilot study comparing protein expression in different segments of the normal colon and rectum and in normal colon versus adenoma in patients with Lynch syndrome. J. Cancer Res. Clin. Oncol. 2013;139:1241–1250. doi: 10.1007/s00432-013-1437-x.
    1. Barker N., Ridgway R.A., van Es J.H., van de Wetering M., Begthel H., van den Born M., Danenberg E., Clarke A.R., Sansom O.J., Clevers H. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature. 2009;457:608–611. doi: 10.1038/nature07602.
    1. Barbachano A., Fernandez-Barral A., Ferrer-Mayorga G., Costales-Carrera A., Larriba M.J., Munoz A. The endocrine vitamin D system in the gut. Mol. Cell Endocrinol. 2017;453:79–87. doi: 10.1016/j.mce.2016.11.028.
    1. Lee J.E., Li H., Chan A.T., Hollis B.W., Lee I.M., Stampfer M.J., Wu K., Giovannucci E., Ma J. Circulating levels of vitamin D and colon and rectal cancer: The Physicians’ Health Study and a meta-analysis of prospective studies. Cancer Prev. Res. 2011;4:735–743. doi: 10.1158/1940-6207.CAPR-10-0289.
    1. Touvier M., Chan D.S., Lau R., Aune D., Vieira R., Greenwood D.C., Kampman E., Riboli E., Hercberg S., Norat T. Meta-analyses of vitamin D intake, 25-hydroxyvitamin D status, vitamin D receptor polymorphisms, and colorectal cancer risk. Cancer Epidemiol. Biomark. Prev. 2011;20:1003–1016. doi: 10.1158/1055-9965.EPI-10-1141.
    1. Heath A.K., Hodge A.M., Ebeling P.R., Eyles D.W., Kvaskoff D., Buchanan D.D., Giles G.G., Williamson E.J., English D.R. Circulating 25-Hydroxyvitamin D Concentration and Risk of Breast, Prostate, and Colorectal Cancers: The Melbourne Collaborative Cohort Study. Cancer Epidemiol. Biomark. Prev. 2019;28:900–908. doi: 10.1158/1055-9965.EPI-18-1155.
    1. Ma Y., Zhang P., Wang F., Yang J., Liu Z., Qin H. Association between vitamin D and risk of colorectal cancer: A systematic review of prospective studies. J. Clin. Oncol. 2011;29:3775–3782. doi: 10.1200/JCO.2011.35.7566.
    1. Zgaga L., Theodoratou E., Farrington S.M., Din F.V., Ooi L.Y., Glodzik D., Johnston S., Tenesa A., Campbell H., Dunlop M.G. Plasma vitamin D concentration influences survival outcome after a diagnosis of colorectal cancer. J. Clin. Oncol. 2014;32:2430–2439. doi: 10.1200/JCO.2013.54.5947.
    1. Weinstein S.J., Purdue M.P., Smith-Warner S.A., Mondul A.M., Black A., Ahn J., Huang W.Y., Horst R.L., Kopp W., Rager H., et al. Serum 25-hydroxyvitamin D, vitamin D binding protein and risk of colorectal cancer in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Int. J. Cancer. 2015;136:E654–E664. doi: 10.1002/ijc.29157.
    1. McCullough M.L., Zoltick E.S., Weinstein S.J., Fedirko V., Wang M., Cook N.R., Eliassen A.H., Zeleniuch-Jacquotte A., Agnoli C., Albanes D., et al. Circulating Vitamin D and Colorectal Cancer Risk: An International Pooling Project of 17 Cohorts. J. Nat. Cancer Inst. 2019;111:158–169. doi: 10.1093/jnci/djy087.
    1. Vaughan-Shaw P.G., Zgaga L., Theodoratou E., Blackmur J.P., Dunlop M.G. Whether vitamin D supplementation protects against colorectal cancer risk remains an open question. Eur. J. Cancer. 2019;115:1–3. doi: 10.1016/j.ejca.2019.03.024.
    1. Zhu K., Knuiman M., Divitini M., Hung J., Lim E.M., Cooke B.R., Walsh J.P. Lower serum 25-hydroxyvitamin D is associated with colorectal and breast cancer, but not overall cancer risk: A 20-year cohort study. Nutr. Res. 2019;67:100–107. doi: 10.1016/j.nutres.2019.03.010.
    1. Abrahamsson H., Porojnicu A.C., Lindstrom J.C., Dueland S., Flatmark K., Hole K.H., Seierstad T., Moan J., Redalen K.R., Meltzer S., et al. High level of circulating vitamin D during neoadjuvant therapy may lower risk of metastatic progression in high-risk rectal cancer. BMC Cancer. 2019;19:488. doi: 10.1186/s12885-019-5724-z.
    1. Markotic A., Langer S., Kelava T., Vucic K., Turcic P., Tokic T., Stefancic L., Radetic E., Farrington S., Timofeeva M., et al. Higher Post-Operative Serum Vitamin D Level is Associated with Better Survival Outcome in Colorectal Cancer Patients. Nutr. Cancer. 2019;71:1078–1085. doi: 10.1080/01635581.2019.1597135.
    1. Ng K., Nimeiri H.S., McCleary N.J., Abrams T.A., Yurgelun M.B., Cleary J.M., Rubinson D.A., Schrag D., Miksad R., Bullock A.J., et al. Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer: The SUNSHINE Randomized Clinical Trial. JAMA. 2019;321:1370–1379. doi: 10.1001/jama.2019.2402.
    1. Calderwood A.H., Baron J.A., Mott L.A., Ahnen D.J., Bostick R.M., Figueiredo J.C., Passarelli M.N., Rees J.R., Robertson D.J., Barry E.L. No Evidence for Posttreatment Effects of Vitamin D and Calcium Supplementation on Risk of Colorectal Adenomas in a Randomized Trial. Cancer Prev. Res. 2019;12:295–304. doi: 10.1158/1940-6207.CAPR-19-0023.
    1. Thomas M.G., Tebbutt S., Williamson R.C. Vitamin D and its metabolites inhibit cell proliferation in human rectal mucosa and a colon cancer cell line. Gut. 1992;33:1660–1663. doi: 10.1136/gut.33.12.1660.
    1. Palmer H.G., Gonzalez-Sancho J.M., Espada J., Berciano M.T., Puig I., Baulida J., Quintanilla M., Cano A., de Herreros A.G., Lafarga M., et al. Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. J. Cell Biol. 2001;154:369–387. doi: 10.1083/jcb.200102028.
    1. Fernandez-Barral A., Costales-Carrera A., Buira S.P., Jung P., Ferrer-Mayorga G., Larriba M.J., Bustamante-Madrid P., Dominguez O., Real F.X., Guerra-Pastrian L., et al. Vitamin D differentially regulates colon stem cells in patient-derived normal and tumor organoids. FEBS J. 2020;287:53–72. doi: 10.1111/febs.14998.
    1. Ganesh K., Wu C., O’Rourke K.P., Szeglin B.C., Zheng Y., Sauve C.G., Adileh M., Wasserman I., Marco M.R., Kim A.S., et al. A rectal cancer organoid platform to study individual responses to chemoradiation. Nat. Med. 2019;25:1607–1614. doi: 10.1038/s41591-019-0584-2.
    1. Yao Y., Xu X., Yang L., Zhu J., Wan J., Shen L., Xia F., Fu G., Deng Y., Pan M., et al. Patient-Derived Organoids Predict Chemoradiation Responses of Locally Advanced Rectal Cancer. Cell Stem Cell. 2020;26:17–26. doi: 10.1016/j.stem.2019.10.010.
    1. Lee K., Lindsey A.S., Li N., Gary B., Andrews J., Keeton A.B., Piazza G.A. beta-catenin nuclear translocation in colorectal cancer cells is suppressed by PDE10A inhibition, cGMP elevation, and activation of PKG. Oncotarget. 2016;7:5353–5365. doi: 10.18632/oncotarget.6705.
    1. Romano G., Santi L., Bianco M.R., Giuffre M.R., Pettinato M., Bugarin C., Garanzini C., Savarese L., Leoni S., Cerrito M.G., et al. The TGF-beta pathway is activated by 5-fluorouracil treatment in drug resistant colorectal carcinoma cells. Oncotarget. 2016;7:22077–22091. doi: 10.18632/oncotarget.7895.
    1. Hassan M.K., Kumar D., Naik M., Dixit M. The expression profile and prognostic significance of eukaryotic translation elongation factors in different cancers. PLoS ONE. 2018;13:e0191377. doi: 10.1371/journal.pone.0191377.
    1. Losada A., Munoz-Alonso M.J., Martinez-Diez M., Gago F., Dominguez J.M., Martinez-Leal J.F., Galmarini C.M. Binding of eEF1A2 to the RNA-dependent protein kinase PKR modulates its activity and promotes tumour cell survival. Br. J. Cancer. 2018;119:1410–1420. doi: 10.1038/s41416-018-0336-y.
    1. Losada A., Munoz-Alonso M.J., Garcia C., Sanchez-Murcia P.A., Martinez-Leal J.F., Dominguez J.M., Lillo M.P., Gago F., Galmarini C.M. Translation Elongation Factor eEF1A2 is a Novel Anticancer Target for the Marine Natural Product Plitidepsin. Sci. Rep. 2016;6:35100. doi: 10.1038/srep35100.
    1. van Riggelen J., Yetil A., Felsher D.W. MYC as a regulator of ribosome biogenesis and protein synthesis. Nat. Rev. Cancer. 2010;10:301–309. doi: 10.1038/nrc2819.
    1. Muncan V., Sansom O.J., Tertoolen L., Phesse T.J., Begthel H., Sancho E., Cole A.M., Gregorieff A., de Alboran I.M., Clevers H., et al. Rapid loss of intestinal crypts upon conditional deletion of the Wnt/Tcf-4 target gene c-Myc. Mol. Cell Biol. 2006;26:8418–8426. doi: 10.1128/MCB.00821-06.
    1. Piazzi M., Bavelloni A., Gallo A., Faenza I., Blalock W.L. Signal Transduction in Ribosome Biogenesis: A Recipe to Avoid Disaster. Int. J. Mol. Sci. 2019;20:2718. doi: 10.3390/ijms20112718.
    1. Daniels D.L., Mendez J., Mosley A.L., Ramisetty S.R., Murphy N., Benink H., Wood K.V., Urh M., Washburn M.P. Examining the complexity of human RNA polymerase complexes using HaloTag technology coupled to label free quantitative proteomics. J. Proteome Res. 2012;11:564–575. doi: 10.1021/pr200459c.
    1. Proshkin S.A., Shematorova E.K., Shpakovski G.V. The Human Isoform of RNA Polymerase II Subunit hRPB11balpha Specifically Interacts with Transcription Factor ATF4. Int. J. Mol. Sci. 2019;21:135. doi: 10.3390/ijms21010135.
    1. Proshkin S.A., Shematorova E.K., Souslova E.A., Proshkina G.M., Shpakovski G.V. A minor isoform of the human RNA polymerase II subunit hRPB11 (POLR2J) interacts with several components of the translation initiation factor eIF3. Biochem. 2011;76:976–980. doi: 10.1134/S0006297911080141.
    1. Jishage M., Yu X., Shi Y., Ganesan S.J., Chen W.Y., Sali A., Chait B.T., Asturias F.J., Roeder R.G. Architecture of Pol II(G) and molecular mechanism of transcription regulation by Gdown1. Nat. Struct. Mol. Biol. 2018;25:859–867. doi: 10.1038/s41594-018-0118-5.
    1. Stevens P.D., Wen Y.A., Xiong X., Zaytseva Y.Y., Li A.T., Wang C., Stevens A.T., Farmer T.N., Gan T., Weiss H.L., et al. Erbin Suppresses KSR1-Mediated RAS/RAF Signaling and Tumorigenesis in Colorectal Cancer. Cancer Res. 2018;78:4839–4852. doi: 10.1158/0008-5472.CAN-17-3629.
    1. Mu Z., Wang L., Deng W., Wang J., Wu G. Structural insight into the Ragulator complex which anchors mTORC1 to the lysosomal membrane. Cell Discov. 2017;3:17049. doi: 10.1038/celldisc.2017.49.
    1. Mo D., Liu W., Li Y., Cui W. Long Non-coding RNA Zinc Finger Antisense 1 (ZFAS1) Regulates Proliferation, Migration, Invasion, and Apoptosis by Targeting MiR-7-5p in Colorectal Cancer. Med. Sci. Monit. 2019;25:5150–5158. doi: 10.12659/MSM.916619.
    1. Neme A., Seuter S., Malinen M., Nurmi T., Tuomainen T.P., Virtanen J.K., Carlberg C. In vivo transcriptome changes of human white blood cells in response to vitamin D. J. Steroid Biochem. Mol. Biol. 2019;188:71–76. doi: 10.1016/j.jsbmb.2018.11.019.
    1. Lou X., Sun B., Song J., Wang Y., Jiang J., Xu Y., Ren Z., Su C. Human sulfatase 1 exerts anti-tumor activity by inhibiting the AKT/ CDK4 signaling pathway in melanoma. Oncotarget. 2016;7:84486–84495. doi: 10.18632/oncotarget.12996.
    1. Lee H.Y., Yeh B.W., Chan T.C., Yang K.F., Li W.M., Huang C.N., Ke H.L., Li C.C., Yeh H.C., Liang P.I., et al. Sulfatase-1 overexpression indicates poor prognosis in urothelial carcinoma of the urinary bladder and upper tract. Oncotarget. 2017;8:47216–47229. doi: 10.18632/oncotarget.17590.
    1. Krishnakumar K., Chakravorty I., Foy W., Allen S., Justo T., Mukherjee A., Dhoot G.K. Multi-tasking Sulf1/Sulf2 enzymes do not only facilitate extracellular cell signalling but also participate in cell cycle related nuclear events. Exp. Cell Res. 2018;364:16–27. doi: 10.1016/j.yexcr.2018.01.022.
    1. Barbáchano A., Larriba M.J., Ferrer-Mayorga G., González-Sancho J.M., Muñoz A. Vitamin D and Colon Cancer. In: Feldman D., Pike J.W., Bouillon R., Giovannucci E., Goltzman D., Hewison M., editors. Vitamin D. 4th ed. Volume 2. Elsevier; London, UK: Academic Press; San Diego, CA, USA: 2018. pp. 837–862.
    1. Pendas-Franco N., Garcia J.M., Pena C., Valle N., Palmer H.G., Heinaniemi M., Carlberg C., Jimenez B., Bonilla F., Munoz A., et al. DICKKOPF-4 is induced by TCF/beta-catenin and upregulated in human colon cancer, promotes tumour cell invasion and angiogenesis and is repressed by 1alpha,25-dihydroxyvitamin D3. Oncogene. 2008;27:4467–4477. doi: 10.1038/onc.2008.88.
    1. Wang T., Qin Y., Lai H., Wei W., Li Z., Yang Y., Huang M., Chen J. The prognostic value of ADRA1 subfamily genes in gastric carcinoma. Oncol. Lett. 2019;18:3150–3158. doi: 10.3892/ol.2019.10660.
    1. Chakraborty S., Kumar A., Faheem M.M., Katoch A., Kumar A., Jamwal V.L., Nayak D., Golani A., Rasool R.U., Ahmad S.M., et al. Vimentin activation in early apoptotic cancer cells errands survival pathways during DNA damage inducer CPT treatment in colon carcinoma model. Cell Death Dis. 2019;10:467. doi: 10.1038/s41419-019-1690-2.
    1. van de Wetering M., Francies H.E., Francis J.M., Bounova G., Iorio F., Pronk A., van Houdt W., van Gorp J., Taylor-Weiner A., Kester L., et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell. 2015;161:933–945. doi: 10.1016/j.cell.2015.03.053.
    1. Fujii M., Shimokawa M., Date S., Takano A., Matano M., Nanki K., Ohta Y., Toshimitsu K., Nakazato Y., Kawasaki K., et al. A Colorectal Tumor Organoid Library Demonstrates Progressive Loss of Niche Factor Requirements during Tumorigenesis. Cell Stem Cell. 2016;18:827–838. doi: 10.1016/j.stem.2016.04.003.
    1. Knight J.M., Kim E., Ivanov I., Davidson L.A., Goldsby J.S., Hullar M.A., Randolph T.W., Kaz A.M., Levy L., Lampe J.W., et al. Comprehensive site-specific whole genome profiling of stromal and epithelial colonic gene signatures in human sigmoid colon and rectal tissue. Physiol. Genom. 2016;48:651–659. doi: 10.1152/physiolgenomics.00023.2016.
    1. Cramer J.M., Thompson T., Geskin A., LaFramboise W., Lagasse E. Distinct human stem cell populations in small and large intestine. PLoS ONE. 2015;10:e0118792. doi: 10.1371/journal.pone.0118792.
    1. Middendorp S., Schneeberger K., Wiegerinck C.L., Mokry M., Akkerman R.D., van Wijngaarden S., Clevers H., Nieuwenhuis E.E. Adult stem cells in the small intestine are intrinsically programmed with their location-specific function. Stem Cells. 2014;32:1083–1091. doi: 10.1002/stem.1655.
    1. Wang X., Yamamoto Y., Wilson L.H., Zhang T., Howitt B.E., Farrow M.A., Kern F., Ning G., Hong Y., Khor C.C., et al. Cloning and variation of ground state intestinal stem cells. Nature. 2015;522:173–178. doi: 10.1038/nature14484.
    1. Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–337. doi: 10.1038/nature11252.
    1. Penzo M., Montanaro L., Trere D., Derenzini M. The Ribosome Biogenesis-Cancer Connection. Cells. 2019;8:55. doi: 10.3390/cells8010055.
    1. Morral C., Stanisavljevic J., Hernando-Momblona X., Mereu E., Alvarez-Varela A., Cortina C., Stork D., Slebe F., Turon G., Whissell G., et al. Zonation of Ribosomal DNA Transcription Defines a Stem Cell Hierarchy in Colorectal Cancer. Cell Stem Cell. 2020;26:845–861.e12. doi: 10.1016/j.stem.2020.04.012.
    1. Sarkissyan M., Wu Y., Chen Z., Mishra D.K., Sarkissyan S., Giannikopoulos I., Vadgama J.V. Vitamin D receptor FokI gene polymorphisms may be associated with colorectal cancer among African American and Hispanic participants. Cancer. 2014;120:1387–1393. doi: 10.1002/cncr.28565.
    1. Takeshige N., Yin G., Ohnaka K., Kono S., Ueki T., Tanaka M., Maehara Y., Okamura T., Ikejiri K., Maekawa T., et al. Associations between vitamin D receptor (VDR) gene polymorphisms and colorectal cancer risk and effect modifications of dietary calcium and vitamin D in a Japanese population. Asian Pac. J. Cancer Prev. 2015;16:2019–2026. doi: 10.7314/APJCP.2015.16.5.2019.
    1. Berger M.D., Stintzing S., Heinemann V., Cao S., Yang D., Sunakawa Y., Matsusaka S., Ning Y., Okazaki S., Miyamoto Y., et al. A Polymorphism within the Vitamin D Transporter Gene Predicts Outcome in Metastatic Colorectal Cancer Patients Treated with FOLFIRI/Bevacizumab or FOLFIRI/Cetuximab. Clin. Cancer Res. 2018;24:784–793. doi: 10.1158/1078-0432.CCR-17-1663.
    1. Zhu Y., Wang P.P., Zhai G., Bapat B., Savas S., Woodrow J.R., Sharma I., Li Y., Zhou X., Yang N., et al. Vitamin D receptor and calcium-sensing receptor polymorphisms and colorectal cancer survival in the Newfoundland population. Br. J. Cancer. 2017;117:898–906. doi: 10.1038/bjc.2017.242.
    1. Cho Y.A., Lee J., Oh J.H., Chang H.J., Sohn D.K., Shin A., Kim J. Vitamin D receptor FokI polymorphism and the risks of colorectal cancer, inflammatory bowel disease, and colorectal adenoma. Sci. Rep. 2018;8:12899. doi: 10.1038/s41598-018-31244-5.
    1. Yuan C., Sato K., Hollis B.W., Zhang S., Niedzwiecki D., Ou F.S., Chang I.W., O’Neil B.H., Innocenti F., Lenz H.J., et al. Plasma 25-Hydroxyvitamin D Levels and Survival in Patients with Advanced or Metastatic Colorectal Cancer: Findings from CALGB/SWOG 80405 (Alliance) Clin. Cancer Res. 2019;25:7497–7505. doi: 10.1158/1078-0432.CCR-19-0877.
    1. Cristobal A., van den Toorn H.W.P., van de Wetering M., Clevers H., Heck A.J.R., Mohammed S. Personalized Proteome Profiles of Healthy and Tumor Human Colon Organoids Reveal Both Individual Diversity and Basic Features of Colorectal Cancer. Cell Rep. 2017;18:263–274. doi: 10.1016/j.celrep.2016.12.016.
    1. Michels B.E., Mosa M.H., Grebbin B.M., Yepes D., Darvishi T., Hausmann J., Urlaub H., Zeuzem S., Kvasnicka H.M., Oellerich T., et al. Human colon organoids reveal distinct physiologic and oncogenic Wnt responses. J. Exp. Med. 2019;216:704–720. doi: 10.1084/jem.20180823.
    1. Bolhaqueiro A.C.F., Ponsioen B., Bakker B., Klaasen S.J., Kucukkose E., van Jaarsveld R.H., Vivie J., Verlaan-Klink I., Hami N., Spierings D.C.J., et al. Ongoing chromosomal instability and karyotype evolution in human colorectal cancer organoids. Nat. Genet. 2019;51:824–834. doi: 10.1038/s41588-019-0399-6.
    1. Kim D., Pertea G., Trapnell C., Pimentel H., Kelley R., Salzberg S.L. TopHat2: Accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14:R36. doi: 10.1186/gb-2013-14-4-r36.
    1. Love M.I., Huber W., Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550. doi: 10.1186/s13059-014-0550-8.
    1. Perez-Silva J.G., Araujo-Voces M., Quesada V. nVenn: Generalized, quasi-proportional Venn and Euler diagrams. Bioinformatics. 2018;34:2322–2324. doi: 10.1093/bioinformatics/bty109.

Source: PubMed

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