Quantitative evaluation and reversion analysis of the attractor landscapes of an intracellular regulatory network for colorectal cancer
Tóm tắt
Cancer reversion, converting the phenotypes of a cancer cell into those of a normal cell, has been sporadically observed throughout history. However, no systematic analysis has been attempted so far. To investigate this from a systems biological perspective, we have constructed a logical network model of colorectal tumorigenesis by integrating key regulatory molecules and their interactions from previous experimental data. We identified molecular targets that can reverse cancerous cellular states to a normal state by systematically perturbing each molecular activity in the network and evaluating the resulting changes of the attractor landscape with respect to uncontrolled proliferation, EMT, and stemness. Intriguingly, many of the identified targets were well in accord with previous studies. We further revealed that the identified targets constitute stable network motifs that contribute to enhancing the robustness of attractors in cancerous cellular states against diverse regulatory signals. The proposed framework for systems analysis is applicable to the study of tumorigenesis and reversion of other types of cancer.
Tài liệu tham khảo
World Health Organization. WHO methods and data sources for global burden of disease estimates 2000–2011. World Health Organization; 2013. http://www.who.int/healthinfo/statistics/GlobalDALYmethods_2000_2011.pdf?ua=1.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.
Vincent MD. Cancer: beyond speciation. Adv Cancer Res. 2011;112:283–350.
Telerman A, Amson R. The molecular programme of tumour reversion: the steps beyond malignant transformation. Nat Rev Cancer. 2009;9(3):206–16.
Askanazy M. Die Teratome nach ihrem Bau, ihrem Verlauf, ihrer Genese und im Vergleich zum experimentellen Teratoid. Verhandl Dtsch Gesellsch Pathol. 1907;11:39–82.
Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007;445(7128):661–5.
Jain M, Arvanitis C, Chu K, Dewey W, Leonhardt E, Trinh M, Sundberg CD, Bishop JM, Felsher DW. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science. 2002;297(5578):102–4.
Friday BB, Adjei AA. K-ras as a target for cancer therapy. Biochim Biophys Acta. 2005;1756(2):127–44.
Sarraf P, Mueller E, Jones D, King FJ, Deangelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C. Differentiation and reversal of malignant changes in colon cancer through PPAR&ggr. Nat Med. 1998;4(9):1046–52.
Cho KH, Joo JI, Shin D, Kim D, Park SM. The reverse control of irreversible biological processes. Wiley Interdiscip Rev Syst Biol Med. 2016;8(5):366–77.
Cho K-H, Lee S, Kim D, Shin D, Joo JI, Park S-M. Cancer reversion, a renewed challenge in systems biology. Curr Opin Systs Biol. 2017;2:48–57.
Kauffman SA. Metabolic stability and epigenesis in randomly constructed genetic nets. J Theor Biol. 1969;22(3):437–67.
Barabasi A-L, Oltvai ZN. Network biology: understanding the cell’s functional organization. Nat Rev Genet. 2004;5(2):101–13.
Reva B, Antipin Y, Sander C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic acids Res. 2011;39(7):e118. gkr407.
Albert R, Jeong H, Barabási A-L. Error and attack tolerance of complex networks. Nature. 2000;406(6794):378–82.
Radisky D, Hagios C, Bissell MJ. Tumors are unique organs defined by abnormal signaling and context. Semin Cancer Biol. 2001;11:87–95.
Jan-Sing H, Shiu-Ru L, Mei-Yin C, Fang-Ming C, Chien-Yu L, Tsung-Jen H, Yu-Sheng H, Che-Jen H, Jaw-Yuan W. APC, K-ras, and p53 gene mutations in colorectal cancer patients: correlation to clinicopathologic features and postoperative surveillance. Am Surg. 2005;71(4):336–43.
Dow LE, O’Rourke KP, Simon J, Tschaharganeh DF, van Es JH, Clevers H, Lowe SW. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Cell. 2015;161(7):1539–52.
Fumiã HF, Martins ML. Boolean network model for cancer pathways: predicting carcinogenesis and targeted therapy outcomes. Plos One. 2013;8(7):e69008.
Cohen DP, Martignetti L, Robine S, Barillot E, Zinovyev A, Calzone L. Mathematical modelling of molecular pathways enabling tumour cell invasion and migration. Plos Comput Biol. 2015;11(11):e1004571.
Hwang WL, Yang MH, Tsai ML, Lan HY, Su SH, Chang SC, Teng HW, Yang SH, Lan YT, Chiou SH. SNAIL regulates interleukin-8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells. Gastroenterology. 2011;141(1):279–91. e275.
Greene CS, Krishnan A, Wong AK, Ricciotti E, Zelaya RA, Himmelstein DS, Zhang R, Hartmann BM, Zaslavsky E, Sealfon SC. Understanding multicellular function and disease with human tissue-specific networks. Nat Genet. 2015;47(6):569–76.
Helikar T, Konvalina J, Heidel J, Rogers JA. Emergent decision-making in biological signal transduction networks. Proc Natl Acad Sci. 2008;105(6):1913–8.
Drost J, Van Jaarsveld RH, Ponsioen B, Zimberlin C, Van Boxtel R, Buijs A, Sachs N, Overmeer RM, Offerhaus GJ, Begthel H. Sequential cancer mutations in cultured human intestinal stem cells. Nature. 2015;521(7550):43–7.
Wang R-S, Saadatpour A, Albert R. Boolean modeling in systems biology: an overview of methodology and applications. Phys Biol. 2012;9(5):055001.
Kim J, Park S-M, Cho K-H. Discovery of a kernel for controlling biomolecular regulatory networks. Sci Rep. 2013;3:2223.
Steinway SN, Zañudo JG, Ding W, Rountree CB, Feith DJ, Loughran TP, Albert R. Network modeling of TGFβ signaling in hepatocellular carcinoma epithelial-to-mesenchymal transition reveals joint Sonic hedgehog and Wnt pathway activation. Cancer Res. 2014;74(21):5963–77.
Aldana M, Balleza E, Kauffman S, Resendiz O. Robustness and evolvability in genetic regulatory networks. J Theor Biol. 2007;245(3):433–48.
Guinney J, Dienstmann R, Wang X, De Reyniès A, Schlicker A, Soneson C, Marisa L, Roepman P, Nyamundanda G, Angelino P. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–6.
Sottoriva A, Kang H, Ma Z, Graham TA, Salomon MP, Zhao J, Marjoram P, Siegmund K, Press MF, Shibata D. A Big Bang model of human colorectal tumor growth. Nat Genet. 2015;47(3):209–16.
Christensen LL, Tobiasen H, Holm A, Schepeler T, Ostenfeld MS, Thorsen K, Rasmussen MH, Birkenkamp‐Demtroeder K, Sieber OM, Gibbs P. MiRNA- 362–3p induces cell cycle arrest through targeting of E2F1, USF2 and PTPN1 and is associated with recurrence of colorectal cancer. Int J Cancer. 2013;133(1):67–78.
Kim DJ, Reddy K, Kim MO, Li Y, Nadas J, Cho Y-Y, Kim J-E, Shim J-H, Song NR, Carper A. (3-Chloroacetyl)-indole, a novel allosteric AKT inhibitor, suppresses colon cancer growth in vitro and in vivo. Cancer Prev Res. 2011;4(11):1842–51.
Collins MA, Bednar F, Zhang Y, Brisset J-C, Galbán S, Galbán CJ, Rakshit S, Flannagan KS, Adsay NV, di Magliano MP. Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice. J Clin Invest. 2012;122(2):639–53.
Ukomadu C, Dutta A. p21-dependent inhibition of colon cancer cell growth by mevastatin is independent of inhibition of G1 cyclin-dependent kinases. J Biol Chem. 2003;278(44):43586–94.
Cristóbal I, Manso R, Rincón R, Caramés C, Senin C, Borrero A, Martínez-Useros J, Rodriguez M, Zazo S, Aguilera O. PP2A inhibition is a common event in colorectal cancer and its restoration using FTY720 shows promising therapeutic potential. Mol Cancer Ther. 2014;13(4):938–47.
Kim JH, Yoon SY, Kim C-N, Joo JH, Moon SK, Choe IS, Choe Y-K, Kim JW. The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16INK4a/p14ARF proteins. Cancer Lett. 2004;203(2):217–24.
Zucker S, Vacirca J. Role of matrix metalloproteinases (MMPs) in colorectal cancer. Cancer Metastasis Rev. 2004;23(1–2):101–17.
Phelan C, Iqbal J, Lynch H, Lubinski J, Gronwald J, Moller P, Ghadirian P, Foulkes W, Armel S, Eisen A. Incidence of colorectal cancer in BRCA1 and BRCA2 mutation carriers: results from a follow-up study. Br J Cancer. 2014;110(2):530–4.
Wang E, Zaman N, Mcgee S, Milanese JS, Masoudi-Nejad A, O’Connor-McCourt M. Predictive genomics: A cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data. Semin Cancer Biol. 2015;30:4–12.
Cho S-H, Park S-M, Lee H-S, Lee H-Y, Cho K-H. Attractor landscape analysis of colorectal tumorigenesis and its reversion. BMC Syst Biol. 2016;10(1):96.
Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell. 2002;108(2):153–64.