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Journal of Translational Medicine
Published in: Journal of Translational Medicine 1/2021

Open Access 01-12-2021 | Regorafenib | Research

The role of PDGFRA as a therapeutic target in young colorectal cancer patients

Authors: Tae Won Kim, Hye Kyung Hong, Chung Lee, Sunmin Kim, Woo Yong Lee, Seong Hyeon Yun, Hee Cheol Kim, Jung Wook Huh, Yoon Ah Park, Je-Gun Joung, Woong-Yang Park, Yong Beom Cho

Published in: Journal of Translational Medicine | Issue 1/2021

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Abstract

Background

Young patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment. However, the underlying molecular characteristics are still unclear.

Methods

We conducted a comprehensive analysis of 49 CRC patients without hereditary CRC using the whole-exome and RNA sequencing with tumor and matched normal samples. A total of 594 TCGA samples and 4 patient-derived cells were utilized for validation.

Results

Consensus molecular subtype 4 (CMS4) (53.85%) and CMS2 (38.46%) were enriched in the young (≤ 40 years) and old (> 60 years) age groups, respectively. A CMS4-associated gene, platelet-derived growth factor receptor α (PDGFRA), was significantly upregulated in young patients with CRC (FC = 3.21, p = 0.0001) and was negatively correlated with age (p = 0.0001, R = − 0.526). Moreover, PDGFRA showed a positive co-expression with metastasis-related genes in young CRC patients. In vitro validation confirmed that young patient-derived cells (PDCs) showed an enriched expression of PDGFRA compared to old PDCs and a reduced proliferation rate by knockdown of PDGFRA. Furthermore, young CRC patients were more sensitive to regorafenib, a PDGFRA-targeting drug, than old CRC patients.

Conclusions

Our study suggests that CRC in young patients is associated with CMS4 and PDGFRA. In addition, PDGFRA may serve potential of novel therapeutic strategies and represent a predictive biomarker of response to regorafenib for young CRC patients.
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Literature
1.
Hubbard JM, Grothey A. Colorectal cancer in 2014: progress in defining first-line and maintenance therapies. Nat Rev Clin Oncol. 2015;12(2):73–4.PubMedCrossRef
2.
Lee YS, Kim SY, Song SJ, Hong HK, Lee Y, Oh BY, et al. Crosstalk between CCL7 and CCR3 promotes metastasis of colon cancer cells via ERK-JNK signaling pathways. Oncotarget. 2016;7(24):36842–53.PubMedPubMedCentralCrossRef
3.
Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):104–17.PubMedCrossRef
4.
Hong HK, Pyo DH, Kim TW, Yun NH, Lee YS, Song SJ, et al. Efficient primary culture model of patientderived tumor cells from colorectal cancer using a Rho-associated protein kinase inhibitor and feeder cells. Oncol Rep. 2019;42(5):2029–38.PubMed
5.
Chew MH, Koh PK, Ng KH, Eu KW. Improved survival in an Asian cohort of young colorectal cancer patients: an analysis of 523 patients from a single institution. Int J Colorectal Dis. 2009;24(9):1075–83.PubMedCrossRef
6.
O’Connell JB, Maggard MA, Liu JH, Etzioni DA, Livingston EH, Ko CY. Rates of colon and rectal cancers are increasing in young adults. Am Surg. 2003;69(10):866–72.PubMed
7.
Chan KK, Dassanayake B, Deen R, Wickramarachchi RE, Kumarage SK, Samita S, et al. Young patients with colorectal cancer have poor survival in the first twenty months after operation and predictable survival in the medium and long-term: analysis of survival and prognostic markers. World J Surg Oncol. 2010;8:82.PubMedPubMedCentralCrossRef
8.
Cusack JC, Giacco GG, Cleary K, Davidson BS, Izzo F, Skibber J, et al. Survival factors in 186 patients younger than 40 years old with colorectal adenocarcinoma. J Am Coll Surg. 1996;183(2):105–12.PubMed
9.
Endreseth BH, Romundstad P, Myrvold HE, Hestvik UE, Bjerkeset T, Wibe A, et al. Rectal cancer in the young patient. Dis Colon Rectum. 2006;49(7):993–1001.PubMedCrossRef
10.
Pearlman R, Frankel WL, Swanson B, Zhao W, Yilmaz A, Miller K, et al. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol. 2017;3(4):464–71.PubMedPubMedCentralCrossRef
11.
Berg M, Danielsen SA, Ahlquist T, Merok MA, Agesen TH, Vatn MH, et al. DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTEN-TP53 related to age at disease onset. PLoS One. 2010;5(11):e13978.PubMedPubMedCentralCrossRef
12.
Hong Y, Ho KS, Eu KW, Cheah PY. A susceptibility gene set for early onset colorectal cancer that integrates diverse signaling pathways: implication for tumorigenesis. Clin Cancer Res. 2007;13(4):1107–14.PubMedCrossRef
13.
14.
Ozsolak F, Milos PM. RNA sequencing: advances, challenges and opportunities. Nat Rev Genet. 2011;12(2):87–98.PubMedCrossRef
15.
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487(7407):330–7.CrossRef
16.
Roepman P, Schlicker A, Tabernero J, Majewski I, Tian S, Moreno V, et al. Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int J Cancer. 2014;134(3):552–62.PubMedCrossRef
17.
Budinska E, Popovici V, Tejpar S, D’Ario G, Lapique N, Sikora KO, et al. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J Pathol. 2013;231(1):63–76.PubMedPubMedCentralCrossRef
18.
Sadanandam A, Lyssiotis CA, Homicsko K, Collisson EA, Gibb WJ, Wullschleger S, et al. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat Med. 2013;19(5):619–25.PubMedPubMedCentralCrossRef
19.
Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–6.PubMedPubMedCentralCrossRef
20.
Thanki K, Nicholls ME, Gajjar A, Senagore AJ, Qiu S, Szabo C, et al. Consensus molecular subtypes of colorectal cancer and their clinical implications. Int Biol Biomed J. 2017;3(3):105–11.PubMedPubMedCentral
21.
Sveen A, Bruun J, Eide PW, Eilertsen IA, Ramirez L, Murumagi A, et al. Colorectal cancer consensus molecular subtypes translated to preclinical models uncover potentially targetable cancer cell dependencies. Clin Cancer Res. 2018;24(4):794–806.PubMedCrossRef
22.
Linnekamp JF, Hooff SRV, Prasetyanti PR, Kandimalla R, Buikhuisen JY, Fessler E, et al. Consensus molecular subtypes of colorectal cancer are recapitulated in in vitro and in vivo models. Cell Death Differ. 2018;25(3):616–33.PubMedPubMedCentralCrossRef
23.
Becht E, de Reynies A, Giraldo NA, Pilati C, Buttard B, Lacroix L, et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin Cancer Res. 2016;22(16):4057–66.PubMedCrossRef
24.
25.
DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491–8.PubMedPubMedCentralCrossRef
26.
Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31(3):213–9.PubMedPubMedCentralCrossRef
27.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164.PubMedPubMedCentralCrossRef
28.
Magi A, Tattini L, Cifola I, D’Aurizio R, Benelli M, Mangano E, et al. EXCAVATOR: detecting copy number variants from whole-exome sequencing data. Genome Biol. 2013;14(10):R120.PubMedCentralCrossRefPubMed
29.
Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R, Getz G. GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011;12(4):R41.PubMedPubMedCentralCrossRef
30.
Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–21.CrossRefPubMed
31.
32.
33.
Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40.PubMedCrossRef
34.
Wu G, Dawson E, Duong A, Haw R, Stein L. ReactomeFIViz: a Cytoscape app for pathway and network-based data analysis. F1000Res. 2014;3:146.PubMedPubMedCentral
35.
van de Wetering M, Francies HE, Francis JM, Bounova G, Iorio F, Pronk A, et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell. 2015;161(4):933–45.PubMedPubMedCentralCrossRef
36.
Liu Y, Sun J, Zhao M. ONGene: a literature-based database for human oncogenes. J Genet Genomics. 2017;44(2):119–21.PubMedCrossRef
37.
Zhao M, Kim P, Mitra R, Zhao J, Zhao Z. TSGene 2.0: an updated literature-based knowledgebase for tumor suppressor genes. Nucleic Acids Res. 2016;44(D1):D1023-31.PubMedCrossRef
38.
Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504.PubMedPubMedCentralCrossRef
39.
40.
41.
Qin Y, Conley AP, Grimm EA, Roszik J. A tool for discovering drug sensitivity and gene expression associations in cancer cells. PLoS ONE. 2017;12(4):e0176763.PubMedPubMedCentralCrossRef
42.
Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schutz G, et al. Regorafenib (BAY 73–4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. 2011;129(1):245–55.PubMedCrossRef
43.
Miura K, Satoh M, Kinouchi M, Yamamoto K, Hasegawa Y, Philchenkov A, et al. The preclinical development of regorafenib for the treatment of colorectal cancer. Expert Opin Drug Discov. 2014;9(9):1087–101.PubMedCrossRef
44.
Schroeder B, Li Z, Cranmer LD, Jones RL, Pollack SM. Targeting gastrointestinal stromal tumors: the role of regorafenib. Onco Targets Ther. 2016;9:3009–16.PubMedPubMedCentral
45.
46.
Venugopal A, Stoffel EM. Colorectal cancer in young adults. Curr Treat Options Gastroenterol. 2019;17(1):89–98.PubMedCrossRef
47.
Zhu B, Wang Y, Wang X, Wu S, Zhou L, Gong X, et al. Evaluation of the correlation of MACC1, CD44, Twist1, and KiSS-1 in the metastasis and prognosis for colon carcinoma. Diagn Pathol. 2018;13(1):45.PubMedPubMedCentralCrossRef
48.
Vatandoust S, Price TJ, Ullah S, Roy AC, Beeke C, Young JP, et al. Metastatic colorectal cancer in young adults: a study from the South Australian Population-based registry. Clin Colorectal Cancer. 2016;15(1):32–6.PubMedCrossRef
49.
Wang MJ, Ping J, Li Y, Adell G, Arbman G, Nodin B, et al. The prognostic factors and multiple biomarkers in young patients with colorectal cancer. Sci Rep. 2015;5:10645.PubMedPubMedCentralCrossRef
50.
Heldin CH, Lennartsson J. Structural and functional properties of platelet-derived growth factor and stem cell factor receptors. Cold Spring Harb Perspect Biol. 2013;5(8):a009100.PubMedPubMedCentralCrossRef
51.
Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P, et al. Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest. 2006;116(6):1561–70.PubMedPubMedCentralCrossRef
52.
Ball SG, Shuttleworth CA, Kielty CM. Vascular endothelial growth factor can signal through platelet-derived growth factor receptors. J Cell Biol. 2007;177(3):489–500.PubMedPubMedCentralCrossRef
53.
54.
Chen MC, Baskaran R, Lee NH, Hsu HH, Ho TJ, Tu CC, et al. CXCL2/CXCR2 axis induces cancer stem cell characteristics in CPT-11-resistant LoVo colon cancer cells via Galphai-2 and Galphaq/11. J Cell Physiol. 2019;234(7):11822–34.PubMedCrossRef
55.
Yamada K, Hamashima T, Ishii Y, Yamamoto S, Okuno N, Yoshida N, et al. Different PDGF receptor dimers drive distinct migration modes of the mouse skin fibroblast. Cell Physiol Biochem. 2018;51(3):1461–79.PubMedCrossRef
56.
Watts TL, Cui R, Szaniszlo P, Resto VA, Powell DW, Pinchuk IV. PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment. J Transl Med. 2016;14(1):337.PubMedPubMedCentralCrossRef
57.
Dai L, Chen X, Lu X, Wang F, Zhan Y, Song G, et al. Phosphoinositide-specific phospholipase Cgamma1 inhibition induces autophagy in human colon cancer and hepatocellular carcinoma cells. Sci Rep. 2017;7(1):13912.PubMedPubMedCentralCrossRef
58.
Cho HJ, Baek KE, Nam IK, Park SM, Kim IK, Park SH, et al. PLCgamma is required for RhoGDI2-mediated cisplatin resistance in gastric cancer. Biochem Biophys Res Commun. 2011;414(3):575–80.PubMedCrossRef
59.
Zhang B, Wang F, Dai L, Cai H, Zhan Y, Gang S, et al. Lentivirus-mediated PLCgamma1 gene short-hairpin RNA suppresses tumor growth and metastasis of human gastric adenocarcinoma. Oncotarget. 2016;7(7):8043–54.PubMedCentralCrossRefPubMed
60.
Li X, Ba Q, Liu Y, Yue Q, Chen P, Li J, et al. Dihydroartemisinin selectively inhibits PDGFRalpha-positive ovarian cancer growth and metastasis through inducing degradation of PDGFRalpha protein. Cell Discov. 2017;3:17042.PubMedPubMedCentralCrossRef
61.
62.
Ip CKM, Ng PKS, Jeong KJ, Shao SH, Ju Z, Leonard PG, et al. Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapies. Nat Commun. 2018;9(1):4583.PubMedPubMedCentralCrossRef
63.
Hofer MD, Fecko A, Shen R, Setlur SR, Pienta KG, Tomlins SA, et al. Expression of the platelet-derived growth factor receptor in prostate cancer and treatment implications with tyrosine kinase inhibitors. Neoplasia. 2004;6(5):503–12.PubMedPubMedCentralCrossRef
64.
Yurgelun MB, Masciari S, Joshi VA, Mercado RC, Lindor NM, Gallinger S, et al. Germline TP53 mutations in patients with early-onset colorectal cancer in the colon cancer family registry. JAMA Oncol. 2015;1(2):214–21.PubMedCrossRef
65.
Staub E, Grone J, Mennerich D, Ropcke S, Klamann I, Hinzmann B, et al. A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer. Mol Cancer. 2006;5:37.PubMedPubMedCentralCrossRef
66.
Srivastava S, Verma M, Henson DE. Biomarkers for early detection of colon cancer. Clin Cancer Res. 2001;7(5):1118–26.PubMed
67.
Al-Sohaily S, Biankin A, Leong R, Kohonen-Corish M, Warusavitarne J. Molecular pathways in colorectal cancer. J Gastroenterol Hepatol. 2012;27(9):1423–31.PubMedCrossRef
68.
69.
Metadata
Title
The role of PDGFRA as a therapeutic target in young colorectal cancer patients
Authors
Tae Won Kim
Hye Kyung Hong
Chung Lee
Sunmin Kim
Woo Yong Lee
Seong Hyeon Yun
Hee Cheol Kim
Jung Wook Huh
Yoon Ah Park
Je-Gun Joung
Woong-Yang Park
Yong Beom Cho
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Translational Medicine / Issue 1/2021
Electronic ISSN: 1479-5876
DOI
https://doi.org/10.1186/s12967-021-03088-7

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