A Contemporary Assessment of Osteosarcoma: Lessons from a Comparative Approach
Main Article Content
Abstract
This review will describe more than two decades of comparative research on primary bone cancer (osteosarcoma). Osteosarcoma is a chaotic disease present in a complex and variable microenvironment composed of many different cell types which interact with each other and lead to high transcriptional heterogeneity. Despite this heterogeneity, common transcriptional patterns can be observed in the bulk transcriptomes of these tumors; additionally, these patterns are associated with outcome, indicating their importance to the molecular biology of the disease. Work from our group and others has led to our current understanding of osteosarcoma as a disease where multiple pathological processes appear to converge into a limited array of tissue organizations with distinct biology. Recurrent as well as distinct events can lead to these states of tissue organization, explaining the heterogeneity of osteosarcoma that is observed among and within species. Yet, despite their chaotic genomes, osteosarcomas seem to be (relatively) genetically stable, with persistent maintenance of essentially the same chromothriptic karyotype throughout the developmental lifetime of the tumor. Importantly, the transcriptional variance between tumors can highlight the underlying biology of the malignant cells themselves, as well as the composition of the osteosarcoma microenvironment and the host response, both of which are prognostically significant for this disease. Initial single cell RNA-seq reports provide further evidence of the importance of the osteosarcoma microenvironment for tumor characterization. Our data suggest that improving patient outcomes in immunologically barren or “cold” osteosarcomas, necessitates generating immune permissive or “warmer” microenvironments within the tumor. Furthermore, the aging bone microenvironment may create specific niches that predispose to cancer, and identification of the drivers that lead to these variable transcriptional patterns will be essential to identify personalized, effective genomic therapy for osteosarcoma.
Keywords:
Osteosarcoma, Contemporary Assessment of Osteosarcoma, Comparative Approach of Osteosarcoma
Article Details
How to Cite
SARVER, Aaron L.; MAKIELSKI, Kelly M.; MODIANO, Jaime F..
A Contemporary Assessment of Osteosarcoma: Lessons from a Comparative Approach.
Medical Research Archives, [S.l.], v. 10, n. 11, nov. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3339>. Date accessed: 27 apr. 2024.
doi: https://doi.org/10.18103/mra.v10i11.3339.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. Makielski KM, Mills LJ, Sarver AL, et al. Risk Factors for Development of Canine and Human Osteosarcoma: A Comparative Review. Vet Sci. 2019;6(2):48.
3. Smeland S, Bielack SS, Whelan J, et al. Survival and prognosis with osteosarcoma: outcomes in more than 2000 patients in the EURAMOS-1 (European and American Osteosarcoma Study) cohort. Eur J Cancer. 2019;109:36-50.
4. Fenger JM, London CA, Kisseberth WC. Canine osteosarcoma: a naturally occurring disease to inform pediatric oncology. ILAR journal / National Research Council, Institute of Laboratory Animal Resources. 2014;55(1):69-85.
5. Beck J, Ren L, Huang S, et al. Canine and murine models of osteosarcoma. Vet Pathol. 2022;59(3):399-414.
6. Ek ET, Dass CR, Choong PF. Commonly used mouse models of osteosarcoma. Crit Rev Oncol Hematol. 2006;60(1):1-8.
7. Scott MC, Sarver AL, Tomiyasu H, et al. Aberrant Retinoblastoma (RB)-E2F Transcriptional Regulation Defines Molecular Phenotypes of Osteosarcoma. J Biol Chem. 2015;290(47):28070-28083.
8. Scott MC, Tomiyasu H, Garbe JR, et al. Heterotypic mouse models of canine osteosarcoma recapitulate tumor heterogeneity and biological behavior. Dis Model Mech. 2016;9(12):1435-1444.
9. Berman SD, Calo E, Landman AS, et al. Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage. Proc Natl Acad Sci U S A. 2008;105(33):11851-11856.
10. Walkley CR, Qudsi R, Sankaran VG, et al. Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease. Genes Dev. 2008;22(12):1662-1676.
11. Calo E, Quintero-Estades JA, Danielian PS, Nedelcu S, Berman SD, Lees JA. Rb regulates fate choice and lineage commitment in vivo. Nature. 2010;466(7310):1110-1114.
12. Moriarity BS, Otto GM, Rahrmann EP, et al. A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis. Nature genetics. 2015;47(6):615-624.
13. Perleberg C, Kind A, Schnieke A. Genetically engineered pigs as models for human disease. Dis Model Mech. 2018;11(1).
14. Mohseny AB, Hogendoorn PC. Zebrafish as a model for human osteosarcoma. Adv Exp Med Biol. 2014;804:221-236.
15. Guijarro MV, Ghivizzani SC, Gibbs CP. Animal models in osteosarcoma. Frontiers in oncology. 2014;4:189.
16. Langsten KL, Kim JH, Sarver AL, Dewhirst M, Modiano JF. Comparative Approach to the Temporo-Spatial Organization of the Tumor Microenvironment. Front Oncol. 2019;9:1185.
17. Chen X, Bahrami A, Pappo A, et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 2014;7(1):104-112.
18. Kovac M, Blattmann C, Ribi S, et al. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nature communications. 2015;6:8940.
19. Perry JA, Kiezun A, Tonzi P, et al. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci U S A. 2014;111(51):E5564-5573.
20. Sayles LC, Breese MR, Koehne AL, et al. Genome-Informed Targeted Therapy for Osteosarcoma. Cancer Discov. 2019;9(1):46-63.
21. Rajan S, Zaccaria S, Cannon MV, et al. Structurally complex osteosarcoma genomes exhibit limited heterogeneity within individual tumors and across evolutionary time. bioRxiv. 2022:2021.2008.2030.458268.
22. Sakthikumar S, Elvers I, Kim J, et al. SETD2 Is Recurrently Mutated in Whole-Exome Sequenced Canine Osteosarcoma. Cancer Res. 2018;78(13):3421-3431.
23. Gardner HL, Sivaprakasam K, Briones N, et al. Canine osteosarcoma genome sequencing identifies recurrent mutations in DMD and the histone methyltransferase gene SETD2. Commun Biol. 2019;2:266.
24. Alsaihati BA, Ho KL, Watson J, et al. Canine tumor mutational burden is correlated with TP53 mutation across tumor types and breeds. Nature communications. 2021;12(1):4670.
25. Das S, Idate R, Regan D, et al. Whole exome sequencing and gene expression analysis of canine osteosarcomas identify mutant TP53 and enriched immune pathways associated with longer survival. Research Square. 2021;PREPRINT (Version 1) - This preprint has not been peer reviewed.
26. Chu S, Skidmore ZL, Kunisaki J, et al. Unraveling the chaotic genomic landscape of primary and metastatic canine appendicular osteosarcoma with current sequencing technologies and bioinformatic approaches. PloS one. 2021;16(2):e0246443.
27. Hameed M, Mandelker D. Tumor Syndromes Predisposing to Osteosarcoma. Adv Anat Pathol. 2018;25(4):217-222.
28. Ribi S, Baumhoer D, Lee K, et al. TP53 intron 1 hotspot rearrangements are specific to sporadic osteosarcoma and can cause Li-Fraumeni syndrome. Oncotarget. 2015;6(10):7727-7740.
29. Diessner BJ, Pankratz N, Hooten AJ, et al. Nearly Half of TP53 Germline Variants Predicted To Be Pathogenic in Patients With Osteosarcoma Are De Novo: A Report From the Children's Oncology Group. JCO Precis Oncol. 2020;4.
30. Mohseny AB, Tieken C, van der Velden PA, et al. Small deletions but not methylation underlie CDKN2A/p16 loss of expression in conventional osteosarcoma. Genes, Chromosomes and Cancer. 2010;49(12):1095-1103.
31. Shao YW, Wood GA, Lu J, et al. Cross-species genomics identifies DLG2 as a tumor suppressor in osteosarcoma. Oncogene. 2019;38(2):291-298.
32. Thomas R, Wang HJ, Tsai PC, et al. Influence of genetic background on tumor karyotypes: evidence for breed-associated cytogenetic aberrations in canine appendicular osteosarcoma. Chromosome Res. 2009;17(3):365-377.
33. Karlsson EK, Sigurdsson S, Ivansson E, et al. Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B. Genome biology. 2013;14(12):R132.
34. Letko A, Minor KM, Norton EM, et al. Genome-Wide Analyses for Osteosarcoma in Leonberger Dogs Reveal the CDKN2A/B Gene Locus as a Major Risk Locus. Genes (Basel). 2021;12(12).
35. Mohseny AB, Szuhai K, Romeo S, et al. Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2. J Pathol. 2009;219(3):294-305.
36. Freeman SS, Allen SW, Ganti R, et al. Copy number gains in EGFR and copy number losses in PTEN are common events in osteosarcoma tumors. Cancer. 2008;113(6):1453-1461.
37. Angstadt AY, Motsinger-Reif A, Thomas R, et al. Characterization of canine osteosarcoma by array comparative genomic hybridization and RT-qPCR: signatures of genomic imbalance in canine osteosarcoma parallel the human counterpart. Genes Chromosomes Cancer. 2011;50(11):859-874.
38. Zhou J, Xiao X, Wang W, Luo Y. Association between PTEN and clinical-pathological features of osteosarcoma. Biosci Rep. 2019;39(7).
39. Smida J, Xu H, Zhang Y, et al. Genome-wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma. Int J Cancer. 2017;141(4):816-828.
40. Lafleur EA, Koshkina NV, Stewart J, et al. Increased Fas expression reduces the metastatic potential of human osteosarcoma cells. Clin Cancer Res. 2004;10(23):8114-8119.
41. Koshkina NV, Khanna C, Mendoza A, Guan H, DeLauter L, Kleinerman ES. Fas-negative osteosarcoma tumor cells are selected during metastasis to the lungs: the role of the Fas pathway in the metastatic process of osteosarcoma. Mol Cancer Res. 2007;5(10):991-999.
42. Worth LL, Lafleur EA, Jia SF, Kleinerman ES. Fas expression inversely correlates with metastatic potential in osteosarcoma cells. Oncol Rep. 2002;9(4):823-827.
43. Modiano JF, Bellgrau D, Cutter GR, et al. Inflammation, apoptosis, and necrosis induced by neoadjuvant fas ligand gene therapy improves survival of dogs with spontaneous bone cancer. Mol Ther. 2012;20(12):2234-2243.
44. Modiano JF, Bellgrau D. Fas ligand based immunotherapy: A potent and effective neoadjuvant with checkpoint inhibitor properties, or a systemically toxic promoter of tumor growth? Discov Med. 2016;21(114):109-116.
45. Filtz EA, Emery A, Lu H, Forster CL, Karasch C, Hallstrom TC. Rb1 and Pten Co-Deletion in Osteoblast Precursor Cells Causes Rapid Lipoma Formation in Mice. PloS one. 2015;10(8):e0136729.
46. Ng AJ, Mutsaers AJ, Baker EK, Walkley CR. Genetically engineered mouse models and human osteosarcoma. Clin Sarcoma Res. 2012;2(1):19.
47. Temiz NA, Moriarity BS, Wolf NK, et al. RNA sequencing of Sleeping Beauty transposon-induced tumors detects transposon-RNA fusions in forward genetic cancer screens. Genome Res. 2016;26(1):119-129.
48. Mavrakis KJ, McDonald ER, 3rd, Schlabach MR, et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science. 2016;351(6278):1208-1213.
49. Kryukov GV, Wilson FH, Ruth JR, et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science. 2016;351(6278):1214-1218.
50. Tseng YY, Moriarity BS, Gong W, et al. PVT1 dependence in cancer with MYC copy-number increase. Nature. 2014;512(7512):82-86.
51. Zhou Y, Yang D, Yang Q, et al. Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma. Nature communications. 2020;11(1):6322.
52. Baccin C, Al-Sabah J, Velten L, et al. Combined single-cell and spatial transcriptomics reveal the molecular, cellular and spatial bone marrow niche organization. Nat Cell Biol. 2020;22(1):38-48.
53. Scott MC, Temiz NA, Sarver AE, et al. Comparative Transcriptome Analysis Quantifies Immune Cell Transcript Levels, Metastatic Progression, and Survival in Osteosarcoma. Cancer Res. 2018;78(2):326-337.
54. Scott MC, Sarver AL, Gavin KJ, et al. Molecular subtypes of osteosarcoma identified by reducing tumor heterogeneity through an interspecies comparative approach. Bone. 2011;49(3):356-367.
55. Thayanithy V, Sarver AL, Kartha RV, et al. Perturbation of 14q32 miRNAs-cMYC gene network in osteosarcoma. Bone. 2012;50(1):171-181.
56. Lesluyes T, Delespaul L, Coindre JM, Chibon F. The CINSARC signature as a prognostic marker for clinical outcome in multiple neoplasms. Sci Rep. 2017;7(1):5480.
57. Thayanithy V, Park C, Sarver AL, et al. Combinatorial treatment of DNA and chromatin-modifying drugs cause cell death in human and canine osteosarcoma cell lines. PloS one. 2012;7(9):e43720.
58. Sarver AL, Thayanithy V, Scott MC, et al. MicroRNAs at the human 14q32 locus have prognostic significance in osteosarcoma. Orphanet journal of rare diseases. 2013;8:7.
59. Kelly AD, Haibe-Kains B, Janeway KA, et al. MicroRNA paraffin-based studies in osteosarcoma reveal reproducible independent prognostic profiles at 14q32. Genome Med. 2013;5(1):2.
60. Terashima A, Takayanagi H. The role of bone cells in immune regulation during the course of infection. Semin Immunopathol. 2019;41(5):619-626.
61. Sarver AL, Xie C, Riddle MJ, et al. Retinoblastoma tumor cell proliferation is negatively associated with an immune gene expression signature and increased immune cells. Lab Invest. 2021;101(6):701-718.
62. Lascelles BD, Dernell WS, Correa MT, et al. Improved survival associated with postoperative wound infection in dogs treated with limb-salvage surgery for osteosarcoma. Annals of surgical oncology. 2005;12(12):1073-1083.
63. Jeys LM, Grimer RJ, Carter SR, Tillman RM, Abudu A. Post operative infection and increased survival in osteosarcoma patients: are they associated? Annals of surgical oncology. 2007;14(10):2887-2895.
64. Wycislo KL, Fan TM. The immunotherapy of canine osteosarcoma: a historical and systematic review. J Vet Intern Med. 2015;29(3):759-769.
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