Preview

Vavilov Journal of Genetics and Breeding

Advanced search

Intratumor heterogeneity: models of malignancy emergence and evolution

https://doi.org/10.18699/VJGB-23-94

Abstract

Cancer is a complex and heterogeneous disease characterized by the accumulation of genetic alterations that drive uncontrolled cell growth and proliferation. Evolutionary dynamics plays a crucial role in the emergence and development of tumors, shaping the heterogeneity and adaptability of cancer cells. From the perspective of evolutionary theory, tumors are complex ecosystems that evolve through a process of microevolution influenced by genetic mutations, epigenetic changes, tumor microenvironment factors, and therapy­induced changes. This dynamic nature of tumors poses significant challenges for effective cancer treatment, and understanding it is essential for developing effective and personalized therapies. By uncovering the mechanisms that determine tumor heterogeneity, researchers can identify key genetic and epigenetic changes that contribute to tumor progression and resistance to treatment. This knowledge enables the development of innovative strategies for targeting specific tumor clones, minimizing the risk of recurrence and improving patient outcomes. To investigate the evolutionary dynamics of cancer, researchers employ a wide range of experimental and computational approaches. Traditional experimental methods involve genomic profiling techniques such as next­generation sequencing and fluorescence in situ hybridization. These techniques enable the identification of somatic mutations, copy number alterations, and structural rearrangements within cancer genomes. Furthermore, single­cell sequencing methods have emerged as powerful tools for dissecting intratumoral heterogeneity and tracing clonal evolution. In parallel, computational models and algorithms have been developed to simulate and analyze cancer evolution. These models integrate data from multiple sources to predict tumor growth patterns, identify driver mutations, and infer evolutionary trajectories. In this paper, we set out to describe the current approaches to address this evolutionary complexity and theories of its occurrence.

About the Authors

R. A. Ivanov
Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences
Russian Federation

Novosibirsk



S. A. Lashin
Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Novosibirsk State University
Russian Federation

Novosibirsk



References

1. Augustin R.C., Delgoffe G.M., Najjar Y.G. Characteristics of the tumor microenvironment that influence immune cell functions: hypoxia, oxidative stress, metabolic alterations. Cancers (Basel). 2020; 12(12):3802. DOI 10.3390/cancers12123802

2. Baca S.C., Prandi D., Lawrence M.S., Mosquera J.M., Romanel A., Drier Y., Park K., Kitabayashi N., MacDonald T.Y., Ghandi M., Van Allen E., Kryukov G.V., Sboner A., Theurillat J.-P., Soong T.D., Nickerson E., Auclair D., Tewari A., Beltran H., Onofrio R.C., Boysen G., Guiducci C., Barbieri C.E., Cibulskis K., Sivachenko A., Carter S.L., Saksena G., Voet D., Ramos A.H., Winckler W., Cipicchio M., Ardlie K., Kantoff P.W., Berger M.F., Gabriel S.B., Golub T.R., Meyerson M., Lander E.S., Elemento O., Getz G., Demichelis F., Rubin M.A., Garraway L.A. Punctuated evolution of prostate cancer genomes. Cell. 2013;153(3):666-677. DOI 10.1016/j.cell.2013.03.021

3. Besse A., Clapp G.D., Bernard S., Nicolini F.E., Levy D., Lepoutre T. Stability analysis of a model of interaction between the immune system and cancer cells in chronic myelogenous leukemia. Bull. Math. Biol. 2018;80(5):1084-1110. DOI 10.1007/s11538-017-0272-7

4. Bonnet D., Dick J.E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 1997;3(7):730-737. DOI 10.1038/nm0797-730

5. Deng G., Zhang X., Chen Y., Liang S., Liu S., Yu Z., Lü M. Singlecell transcriptome sequencing reveals heterogeneity of gastric cancer: progress and prospects. Front. Oncol. 2023;13:1074268. DOI 10.3389/fonc.2023.1074268

6. Durrett R., Foo J., Leder K., Mayberry J., Michor F. Intratumor heterogeneity in evolutionary models of tumor progression. Genetics. 2011;188(2):461-477. DOI 10.1534/genetics.110.125724

7. Fearon E.R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61(5):759-767. DOI 10.1016/0092-8674(90)90186-I

8. Flavahan W.A., Gaskell E., Bernstein B.E. Epigenetic plasticity and the hallmarks of cancer. Science. 2017;357(6348):eaal2380. DOI 10.1126/science.aal2380

9. Furukawa Y., Kikuchi J. Molecular basis of clonal evolution in multiple myeloma. Int. J. Hematol. 2020;111(4):496-511. DOI 10.1007/s12185-020-02829-6

10. Gawad C., Koh W., Quake S.R. Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics. Proc. Natl. Acad. Sci. USA. 2014;111(50):17947-17952. DOI 10.1073/pnas.1420822111

11. Gertz E.M., Chowdhury S.A., Lee W.-J., Wangsa D., HeselmeyerHaddad K., Ried T., Schwartz R., Schäffer A.A. FISHtrees 3.0: tumor phylogenetics using a ploidy probe. PLoS One. 2016;11(6): e0158569. DOI 10.1371/journal.pone.0158569

12. Graham T.A., Sottoriva A. Measuring cancer evolution from the genome. J. Pathol. 2017;241(2):183-191. DOI 10.1002/path.4821

13. Haffner M.C., Zwart W., Roudier M.P., True L.D., Nelson W.G., Epstein J.I., De Marzo A.M., Nelson P.S., Yegnasubramanian S. Genomic and phenotypic heterogeneity in prostate cancer. Nat. Rev. Urol. 2021;18(2):79-92. DOI 10.1038/s41585-020-00400-w

14. Hata M., Hayakawa Y., Koike K. Gastric stem cell and cellular origin of cancer. Biomedicines. 2018;6(4):100. DOI 10.3390/biomedicines6040100

15. Hausser J., Alon U. Tumour heterogeneity and the evolutionary tradeoffs of cancer. Nat. Rev. Cancer. 2020;20(4):247-257. DOI 10.1038/s41568-020-0241-6

16. Heinrich S., Craig A.J., Ma L., Heinrich B., Greten T.F., Wang X.W. Understanding tumour cell heterogeneity and its implication for immunotherapy in liver cancer using single-cell analysis. J. Hepatol. 2021;74(3):700-715. DOI 10.1016/j.jhep.2020.11.036

17. Koh G., Degasperi A., Zou X., Momen S., Nik-Zainal S. Mutational signatures: emerging concepts, caveats and clinical applications. Nat. Rev. Cancer. 2021;21(10):619-637. DOI 10.1038/s41568-021-00377-7

18. Lee T.K.-W., Guan X.-Y., Ma S. Cancer stem cells in hepatocellular carcinoma – from origin to clinical implications. Nat. Rev. Gastroenterol. Hepatol. 2022;19(1):26-44. DOI 10.1038/s41575-021-00508-3

19. Losic B., CraigA.J., Villacorta-Martin C., Martins-Filho S.N., Akers N., Chen X., Ahsen M.E., von Felden J., Labgaa I., DʹAvola D., Allette K., Lira S.A., Furtado G.C., Garcia-Lezana T., Restrepo P., Stueck A., Ward S.C., Fiel M.I., Hiotis S.P., Gunasekaran G., Sia D., Schadt E.E., Sebra R., Schwartz M., Llovet J.M., Thung S., Stolovitzky G., Villanueva A. Intratumoral heterogeneity and clonal evolution in liver cancer. Nat. Commun. 2020;11(1):291. DOI 10.1038/s41467-019-14050-z

20. Lüönd F., Tiede S., Christofori G. Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression. Br. J. Cancer. 2021;125(2):164-175. DOI 10.1038/s41416-021-01328-7

21. Meacham C.E., Morrison S.J. Tumour heterogeneity and cancer cell plasticity. Nature. 2013;501(7467):328-337. DOI 10.1038/nature12624

22. Merlo L.M.F., Pepper J.W., Reid B.J., Maley C.C. Cancer as an evolutionary and ecological process. Nat. Rev. Cancer. 2006;6(12):924-935. DOI 10.1038/nrc2013

23. Morris L.G.T., Riaz N., Desrichard A., Şenbabaoğlu Y., Hakimi A.A., Makarov V., Reis-Filho J.S., Chan T.A. Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival. Oncotarget. 2016;7(9):10051-10063. DOI 10.18632/oncotarget.7067

24. Mumenthaler S.M., Foo J., Choi N.C., Heise N., Leder K., Agus D.B., Pao W., Michor F., Mallick P. The impact of microenvironmental heterogeneity on the evolution of drug resistance in cancer cells. Cancer Inform. 2015;14(Suppl.4):19-31. DOI 10.4137/CIN.S19338

25. Navin N.E. The first five years of single-cell cancer genomics and beyond. Genome Res. 2015;25(10):1499-1507. DOI 10.1101/gr.191098.115

26. Nowell P. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23-28. DOI 10.1126/science.959840

27. Reya T., Morrison S.J., Clarke M.F., Weissman I.L. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105-111. DOI 10.1038/35102167

28. Robertson-Tessi M., Gillies R.J., Gatenby R.A., Anderson A.R.A. Impact of metabolic heterogeneity on tumor growth, invasion, and treatment outcomes. Cancer Res. 2015;75(8):1567-1579. DOI 10.1158/0008-5472.CAN-14-1428

29. Roma-Rodrigues C., Mendes R., Baptista P., Fernandes A. Targeting tumor microenvironment for cancer therapy. Int. J. Mol. Sci. 2019; 20(4):840. DOI 10.3390/ijms20040840

30. Vendramin R., Litchfield K., Swanton C. Cancer evolution: Darwin and beyond. EMBO J. 2021;40(18):e108389. DOI 10.15252/embj.2021108389

31. Vosberg S., Greif P.A. Clonal evolution of acute myeloid leukemia from diagnosis to relapse. Genes Chromosomes Cancer. 2019;58(12): 839-849. DOI 10.1002/gcc.22806

32. Walcher L., KistenmacherA.-K., Suo H., KitteR., Dluczek S., StraußA., Blaudszun A.-R., Yevsa T., Fricke S., Kossatz-Boehlert U. Cancer stem cells-origins and biomarkers: perspectives for targeted personalized therapies. Front. Immunol. 2020;11:1280. DOI 10.3389/fimmu.2020.01280

33. Wang Y., Waters J., Leung M.L., Unruh A., Roh W., Shi X., Chen K., Scheet P., Vattathil S., Liang H., Multani A., Zhang H., Zhao R., Michor F., Meric-Bernstam F., Navin N.E. Clonal evolution in breast cancer revealed by single nucleus genome sequencing. Nature. 2014;512(7513):155-160. DOI 10.1038/nature13600

34. Williams M.J., Werner B., Barnes C.P., Graham T.A., Sottoriva A. Identification of neutral tumor evolution across cancer types. Nat. Genet. 2016;48(3):238-244. DOI 10.1038/ng.3489

35. Yao J., Chen J., Li L.-Y., Wu M. Epigenetic plasticity of enhancers in cancer. Transcription. 2020;11(1):26-36. DOI 10.1080/21541264.2020.1713682

36. Zarzynska J.M. The role of stem cells in breast cancer. In: Breast Cancer – From Biology to Medicine. InTech, 2017. DOI 10.5772/66904

37. Zhao T., Chiang Z.D., Morriss J.W., LaFave L.M., Murray E.M., Del Priore I., Meli K., Lareau C.A., Nadaf N.M., Li J., Earl A.S., Macosko E.Z., Jacks T., Buenrostro J.D., Chen F. Spatial genomics enables multi-modal study of clonal heterogeneity in tissues. Nature. 2022;601(7891):85-91. DOI 10.1038/s41586-021-04217-4


Review

Views: 857


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 2500-3259 (Online)