Tumor and α-SMA-expressing stromal cells in pancreatic neuroendocrine tumors have a distinct RNA profile depending on tumor grade.
Pancreatic neuroendocrine tumors
digital spatial profiling
gene expression
pathway enrichment analysis
tumor stroma
Journal
Molecular oncology
ISSN: 1878-0261
Titre abrégé: Mol Oncol
Pays: United States
ID NLM: 101308230
Informations de publication
Date de publication:
08 Sep 2024
08 Sep 2024
Historique:
revised:
12
07
2024
received:
07
09
2023
accepted:
22
08
2024
medline:
9
9
2024
pubmed:
9
9
2024
entrez:
8
9
2024
Statut:
aheadofprint
Résumé
Alpha-smooth muscle actin (α-SMA) expression in the stroma is linked to the presence of cancer-associated fibroblasts and is known to correlate with worse outcomes in various tumors. In this study, using a GeoMx digital spatial profiling approach, we characterized the gene expression of the tumor and α-SMA-expressing stromal cell compartments in pancreatic neuroendocrine tumors (PanNETs). The profiling was performed on tissues from eight retrospective cases (three grade 1, four grade 2, and one grade 3). Selected regions of interest were segmented geometrically based on tissue morphology and fluorescent signals from synaptophysin and α-SMA markers. The α-SMA-expressing stromal-cell-associated genes were involved in pathways of extracellular matrix modification, whereas, in tumor cells, the gene expression profiles were associated with pathways involved in cell proliferation. The comparison of gene expression profiles across all three PanNET grades revealed that the differences between grades are not only present at the level of the tumor but also in the α-SMA-expressing stromal cells. Furthermore, the tumor cells from regions with a rich presence of adjacent α-SMA-expressing stromal cells revealed an upregulation of matrix metalloproteinase-9 (MMP9) expression in grade 3 tumors. This study provides an in-depth characterization of gene expression profiles in α-SMA-expressing stromal and tumor cells, and outlines potential crosstalk mechanisms.
Identifiants
pubmed: 39245631
doi: 10.1002/1878-0261.13727
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : European Union's Recovery and Resilience Mechanism project: Consolidation of the Latvian Institute of Organic Synthesis and the Latvian Biomedical Research and Study Centre
ID : 5.2.1.1.i.0/2/24/I/CFLA/001
Organisme : Pauls Stradins Clinical University Hospital
ID : SKUS442/22
Informations de copyright
© 2024 The Author(s). Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Références
Oberg K, Castellano D. Current knowledge on diagnosis and staging of neuroendocrine tumors. Cancer Metastasis Rev. 2011;30(Suppl 1):3–7.
Perri G, Prakash LR, Katz MHG. Pancreatic neuroendocrine tumors. Curr Opin Gastroenterol. 2019;35:468–477.
Di Domenico A, Pipinikas CP, Maire RS, Bräutigam K, Simillion C, Dettmer MS, et al. Epigenetic landscape of pancreatic neuroendocrine tumours reveals distinct cells of origin and means of tumour progression. Commun Biol. 2020;3:740.
Ro C, Chai W, Yu VE, Yu R. Pancreatic neuroendocrine tumors: biology, diagnosis, and treatment. Chin J Cancer. 2013;32:312–324.
Massironi S, Rossi RE, Zilli A, Casazza G, Ciafardini C, Conte D. A wait‐and‐watch approach to small pancreatic neuroendocrine tumors: prognosis and survival. Oncotarget. 2016;7:18978–18983.
Bartolini I, Bencini L, Risaliti M, Ringressi MN, Moraldi L, Taddei A. Current management of pancreatic neuroendocrine tumors: from demolitive surgery to observation. Gastroenterol Res Pract. 2018;2018:9647247.
Khanna L, Prasad SR, Sunnapwar A, Kondapaneni S, Dasyam A, Tammisetti VS, et al. Pancreatic neuroendocrine neoplasms: 2020 update on pathologic and imaging findings and classification. Radiographics. 2020;40:1240–1262.
Xu W, Yan H, Xu L, Li M, Gao W, Jiang K, et al. Correlation between radiologic features on contrast‐enhanced CT and pathological tumor grades in pancreatic neuroendocrine neoplasms. J Biomed Res. 2020;35:179–188.
Ro C, Chai W, Yu VE, Yu R. Pancreatic neuroendocrine tumors: biology, diagnosis,and treatment. Chin J Cancer. 2013;32:312–324.
Maharjan CK, Ear PH, Tran CG, Howe JR, Chandrasekharan C, Quelle DE. Pancreatic neuroendocrine tumors: molecular mechanisms and therapeutic targets. Cancers (Basel). 2021;13:5117.
Shen X, Wang X, Lu X, Zhao Y, Guan W. Molecular biology of pancreatic neuroendocrine tumors: from mechanism to translation. Front Oncol. 2022;12:967071.
Zhang J, Francois R, Iyer R, Seshadri M, Zajac‐Kaye M, Hochwald SN. Current understanding of the molecular biology of pancreatic neuroendocrine tumors. J Natl Cancer Inst. 2013;105:1005–1017.
Heaphy CM, Singhi AD. Reprint of: the diagnostic and prognostic utility of incorporating DAXX, ATRX, and alternative lengthening of telomeres (ALT) to the evaluation of pancreatic neuroendocrine tumors (PanNETs). Hum Pathol. 2023;132:1–11.
Gisder DM, Overheu O, Keller J, Nöpel‐Dünnebacke S, Uhl W, Reinacher‐Schick A, et al. DAXX, ATRX, and MSI in PanNET and their metastases: correlation with histopathological data and prognosis. Pathobiology. 2023;90:71–80.
Anderson NM, Simon MC. The tumor microenvironment. Curr Biol. 2020;30:R921–R925.
Guo S, Deng C‐X. Effect of stromal cells in tumor microenvironment on metastasis initiation. Int J Biol Sci. 2018;14:2083–2093.
Sinn M, Denkert C, Striefler JK, Pelzer U, Stieler JM, Bahra M, et al. α‐Smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO‐001 study. Br J Cancer. 2014;111:1917–1923.
Vathiotis IA, Moutafi MK, Divakar P, Aung TN, Qing T, Fernandez A, et al. Alpha‐smooth muscle actin expression in the stroma predicts resistance to trastuzumab in patients with early‐stage HER2‐positive breast cancer. Clin Cancer Res. 2021;27:6156–6163.
Muchlińska A, Nagel A, Popęda M, Szade J, Niemira M, Zieliński J, et al. Alpha‐smooth muscle actin‐positive cancer‐associated fibroblasts secreting osteopontin promote growth of luminal breast cancer. Cell Mol Biol Lett. 2022;27:45.
Ping Q, Yan R, Cheng X, Wang W, Zhong Y, Hou Z, et al. Cancer‐associated fibroblasts: overview, progress, challenges, and directions. Cancer Gene Ther. 2021;28:984–999.
Cives M, Pelle' E, Quaresmini D, Rizzo FM, Tucci M, Silvestris F. The tumor microenvironment in neuroendocrine tumors: biology and therapeutic implications. Neuroendocrinology. 2019;109:83–99.
Simbolo M, Bilotta M, Mafficini A, Luchini C, Furlan D, Inzani F, et al. Gene expression profiling of pancreas neuroendocrine tumors with different Ki67‐based grades. Cancers (Basel). 2021;13:2054.
Wong H‐L, Yang KC, Shen Y, Zhao EY, Loree JM, Kennecke HF, et al. Molecular characterization of metastatic pancreatic neuroendocrine tumors (PNETs) using whole‐genome and transcriptome sequencing. Cold Spring Harb Mol Case Stud. 2018;4:a002329.
Li X, Wang C‐Y. From bulk, single‐cell to spatial RNA sequencing. Int J Oral Sci. 2021;13:36.
Hernandez S, Lazcano R, Serrano A, Powell S, Kostousov L, Mehta J, et al. Challenges and opportunities for immunoprofiling using a spatial high‐plex technology: the NanoString GeoMx(®) digital spatial profiler. Front Oncol. 2022;12:890410.
Nagtegaal ID, Odze RD, Klimstra D, Paradis V, Rugge M, Schirmacher P, et al. The 2019 WHO classification of tumours of the digestive system. Histopathology. 2020;76:182–188.
Hackeng WM, Brosens LAA, Kim JY, O'Sullivan R, Sung Y‐N, Liu T‐C, et al. Non‐functional pancreatic neuroendocrine tumours: ATRX/DAXX and alternative lengthening of telomeres (ALT) are prognostically independent from ARX/PDX1 expression and tumour size. Gut. 2022;71:961–973.
Danaher P, Kim Y, Nelson B, Griswold M, Yang Z, Piazza E, et al. Advances in mixed cell deconvolution enable quantification of cell types in spatial transcriptomic data. Nat Commun. 2022;13:385.
Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, et al. The STRING database in 2023: protein‐protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51:D638–D646.
De Boeck A, Hendrix A, Maynard D, Van Bockstal M, Daniëls A, Pauwels P, et al. Differential secretome analysis of cancer‐associated fibroblasts and bone marrow‐derived precursors to identify microenvironmental regulators of colon cancer progression. Proteomics. 2013;13:379–388.
Miki Y, Yashiro M, Moyano‐Galceran L, Sugimoto A, Ohira M, Lehti K. Crosstalk between cancer associated fibroblasts and cancer cells in scirrhous type gastric cancer. Front Oncol. 2020;10:568557.
Erdogan B, Webb DJ. Cancer‐associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Biochem Soc Trans. 2017;45:229–236.
Wu X, Tao P, Zhou Q, Li J, Yu Z, Wang X, et al. IL‐6 secreted by cancer‐associated fibroblasts promotes epithelial‐mesenchymal transition and metastasis of gastric cancer via JAK2/STAT3 signaling pathway. Oncotarget. 2017;8:20741–20750.
Stuelten CH, DaCosta Byfield S, Arany PR, Karpova TS, Stetler‐Stevenson WG, Roberts AB. Breast cancer cells induce stromal fibroblasts to express MMP‐9 via secretion of TNF‐alpha and TGF‐beta. J Cell Sci. 2005;118:2143–2153.
Attieh Y, Clark AG, Grass C, Richon S, Pocard M, Mariani P, et al. Cancer‐associated fibroblasts lead tumor invasion through integrin‐β3‐dependent fibronectin assembly. J Cell Biol. 2017;216:3509–3520.
Remsing Rix LL, Sumi NJ, Hu Q, Desai B, Bryant AT, Li X, et al. IGF‐binding proteins secreted by cancer‐associated fibroblasts induce context‐dependent drug sensitization of lung cancer cells. Sci Signal. 2022;15:eabj5879.
Wang H, Zhang J, Li H, Yu H, Chen S, Liu S, et al. FN1 is a prognostic biomarker and correlated with immune infiltrates in gastric cancers. Front Oncol. 2022;12:918719.
Huffman AP, Lin JH, Kim SI, Byrne KT, Vonderheide RH. CCL5 mediates CD40‐driven CD4+ T cell tumor infiltration and immunity. JCI Insight. 2020;5:e137263.
Zhang X‐X, Luo J‐H, Wu L‐Q. FN1 overexpression is correlated with unfavorable prognosis and immune infiltrates in breast cancer. Front Genet. 2022;13:913659.
Scoazec J‐Y. Angiogenesis in neuroendocrine tumors: therapeutic applications. Neuroendocrinology. 2013;97:45–56.
Simon T, Riemer P, Jarosch A, Detjen K, Di Domenico A, Bormann F, et al. DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas and pancreatic neuroendocrine tumors. Genome Med. 2022;14:1–14.
Fujita H, Ohuchida K, Mizumoto K, Nakata K, Yu J, Kayashima T, et al. Alpha‐smooth muscle actin expressing stroma promotes an aggressive tumor biology in pancreatic ductal adenocarcinoma. Pancreas. 2010;39:1254–1262.
Bordignon P, Bottoni G, Xu X, Popescu AS, Truan Z, Guenova E, et al. Dualism of FGF and TGF‐β signaling in heterogeneous cancer‐associated fibroblast activation with ETV1 as a critical determinant. Cell Rep. 2019;28:2358–2372.e6.
Wu F, Yang J, Liu J, Wang Y, Mu J, Zeng Q, et al. Signaling pathways in cancer‐associated fibroblasts and targeted therapy for cancer. Signal Transduct Target Ther. 2021;6:218.
Rex J, Lutz A, Faletti LE, Albrecht U, Thomas M, Bode JG, et al. IL‐1β and TNFα differentially influence NF‐κB activity and FasL‐induced apoptosis in primary murine hepatocytes during LPS‐induced inflammation. Front Physiol. 2019;10:117.
Funa K, Papanicolaou V, Juhlin C, Rastad J, Akerström G, Heldin CH, et al. Expression of platelet‐derived growth factor beta‐receptors on stromal tissue cells in human carcinoid tumors. Cancer Res. 1990;50:748–753.
D'Assoro AB, Leon‐Ferre R, Braune E‐B, Lendahl U. Roles of notch signaling in the tumor microenvironment. Int J Mol Sci. 2022;23:6241.
Kayamori K, Katsube K‐I, Sakamoto K, Ohyama Y, Hirai H, Yukimori A, et al. NOTCH3 is induced in cancer‐associated fibroblasts and promotes angiogenesis in oral squamous cell carcinoma. PLoS One. 2016;11:e0154112.
Zhang C, Fei Y, Wang H, Hu S, Liu C, Hu R, et al. CAFs orchestrates tumor immune microenvironment‐a new target in cancer therapy? Front Pharmacol. 2023;14:1113378.
Nissen NI, Karsdal M, Willumsen N. Collagens and cancer associated fibroblasts in the reactive stroma and its relation to cancer biology. J Exp Clin Cancer Res. 2019;38:115.
Armstrong T, Packham G, Murphy LB, Bateman AC, Conti JA, Fine DR, et al. Type I collagen promotes the malignant phenotype of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2004;10:7427–7437.
Ucaryilmaz Metin C, Ozcan G. Comprehensive bioinformatic analysis reveals a cancer‐associated fibroblast gene signature as a poor prognostic factor and potential therapeutic target in gastric cancer. BMC Cancer. 2022;22:692.
Ghura H, Keimer M, von Au A, Hackl N, Klemis V, Nakchbandi IA. Inhibition of fibronectin accumulation suppresses tumor growth. Neoplasia. 2021;23:837–850.
Geng Q‐S, Huang T, Li L‐F, Shen Z‐B, Xue W‐H, Zhao J. Over‐expression and prognostic significance of FN1, correlating with immune infiltrates in thyroid cancer. Front Med. 2021;8:812278.
Maneshi P, Mason J, Dongre M, Öhlund D. Targeting tumor‐stromal interactions in pancreatic cancer: impact of collagens and mechanical traits. Front Cell Dev Biol. 2021;9:787485.
Wiechec E, Magan M, Matic N, Ansell‐Schultz A, Kankainen M, Monni O, et al. Cancer‐associated fibroblasts modulate transcriptional signatures involved in proliferation, differentiation and metastasis in head and neck squamous cell carcinoma. Cancers (Basel). 2021;13:3361.
Weigelt B, Peterse JL, van't Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5:591–602.
Lakis V, Lawlor RT, Newell F, Patch A‐M, Mafficini A, Sadanandam A, et al. DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association. Commun Biol. 2021;4:155.
Obazee O, Capurso G, Tavano F, Archibugi L, De Bonis A, Greenhalf W, et al. Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms. Carcinogenesis. 2018;39:360–367.
Scott AT, Weitz M, Breheny PJ, Ear PH, Darbro B, Brown BJ, et al. Gene expression signatures identify novel therapeutics for metastatic pancreatic neuroendocrine tumors. Clin Cancer Res. 2020;26:2011–2021.
Yang KC, Kalloger SE, Aird JJ, Lee MKC, Rushton C, Mungall KL, et al. Proteotranscriptomic classification and characterization of pancreatic neuroendocrine neoplasms. Cell Rep. 2021;37:109817.
Dilley WG, Kalyanaraman S, Verma S, Cobb JP, Laramie JM, Lairmore TC. Global gene expression in neuroendocrine tumors from patients with the MEN1 syndrome. Mol Cancer. 2005;4:9.
Fei W, Chen L, Chen J, Shi Q, Zhang L, Liu S, et al. RBP4 and THBS2 are serum biomarkers for diagnosis of colorectal cancer. Oncotarget. 2017;8:92254–92264.
Wang Y, Qin C, Zhao B, Li Z, Li T, Yang X, et al. EGR1 induces EMT in pancreatic cancer via a P300/SNAI2 pathway. J Transl Med. 2023;21:201.
Hui DY. Group 1B phospholipase a(2) in metabolic and inflammatory disease modulation. Biochim Biophys Acta Mol Cell Biol Lipids. 2019;1864:784–788.
Lin T‐C. Functional roles of SPINK1 in cancers. Int J Mol Sci. 2021;22:3814.
Goto A, Niki T, Terado Y, Fukushima J, Fukayama M. Prevalence of CD99 protein expression in pancreatic endocrine tumours (PETs). Histopathology. 2004;45:384–392.
Zarebczan B, Chen H. Signaling mechanisms in neuroendocrine tumors as targets for therapy. Endocrinol Metab Clin N Am. 2010;39:801–810.
Braicu C, Buse M, Busuioc C, Drula R, Gulei D, Raduly L, et al. A comprehensive review on MAPK: a promising therapeutic target in cancer. Cancers (Basel). 2019;11:1618.
Abdel‐Rahman O. Vascular endothelial growth factor (VEGF) pathway and neuroendocrine neoplasms (NENs): prognostic and therapeutic considerations. Tumour Biol. 2014;35:10615–10625.
Zhang J, Jia Z, Li Q, Wang L, Rashid A, Zhu Z, et al. Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression‐free survival among patients with low‐grade neuroendocrine tumors. Cancer. 2007;109:1478–1486.
Cai Q, Brissova M, Reinert RB, Pan FC, Brahmachary P, Jeansson M, et al. Enhanced expression of VEGF‐A in β cells increases endothelial cell number but impairs islet morphogenesis and β cell proliferation. Dev Biol. 2012;367:40–54.
Liu J, Xiao Q, Xiao J, Niu C, Li Y, Zhang X, et al. Wnt/β‐catenin signalling: function, biological mechanisms, and therapeutic opportunities. Signal Transduct Target Ther. 2022;7:3.
Giralt I, Gallo‐Oller G, Navarro N, Zarzosa P, Pons G, Magdaleno A, et al. Dickkopf proteins and their role in cancer: a family of Wnt antagonists with a dual role. Pharmaceuticals (Basel). 2021;14:810.
Igbinigie E, Guo F, Jiang S‐W, Kelley C, Li J. Dkk1 involvement and its potential as a biomarker in pancreatic ductal adenocarcinoma. Clin Chim Acta. 2019;488:226–234.
Ouyang Y, Pan J, Tai Q, Ju J, Wang H. Transcriptomic changes associated with DKK4 overexpression in pancreatic cancer cells detected by RNA‐seq. Tumour Biol. 2016;37:10827–10838.