Tumour heterogeneity

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Tumour heterogeneity describes the observation that different tumour cells can show distinct morphological and phenotypic profiles, including cellular morphology, gene expression, metabolism, motility, proliferation, and metastatic potential. [1] This phenomenon occurs both between tumours (inter-tumour heterogeneity) and within tumours (intra-tumour heterogeneity). A minimal level of intra-tumour heterogeneity is a simple consequence of the imperfection of DNA replication: whenever a cell (normal or cancerous) divides, a few mutations are acquired [2] —leading to a diverse population of cancer cells. [3] The heterogeneity of cancer cells introduces significant challenges in designing effective treatment strategies. However, research into understanding and characterizing heterogeneity can allow for a better understanding of the causes and progression of disease. In turn, this has the potential to guide the creation of more refined treatment strategies that incorporate knowledge of heterogeneity to yield higher efficacy. [4]

Contents

Tumour heterogeneity has been observed in leukemias, [5] breast, [6] prostate, [7] [8] [9] colon, [10] [11] [12] brain, [13] esophagus, [14] head and neck, [15] bladder [16] and gynecological carcinomas, [17] liposarcoma, [18] and multiple myeloma. [19]

Models of heterogeneity

There are two models used to explain the heterogeneity of tumour cells. These are the cancer stem cell model and the clonal evolution model. The models are not mutually exclusive, and it is believed that they both contribute to heterogeneity in varying amounts across different tumour types. [20]

Ability of cancer cells to form tumours under the cancer stem cell and clonal evolution models of heterogeneity. Tumour heterogeneity CSC vs stochastic.pdf
Ability of cancer cells to form tumours under the cancer stem cell and clonal evolution models of heterogeneity.

Cancer stem cells

The cancer stem cell model asserts that within a population of tumour cells, there is only a small subset of cells that are tumourigenic (able to form tumours). These cells are termed cancer stem cells (CSCs), and are marked by the ability to both self-renew and differentiate into non-tumourigenic progeny. The CSC model posits that the heterogeneity observed between tumour cells is the result of differences in the stem cells from which they originated. Stem cell variability is often caused by epigenetic changes, but can also result from clonal evolution of the CSC population where advantageous genetic mutations can accumulate in CSCs and their progeny (see below). [20]

Evidence of the cancer stem cell model has been demonstrated in multiple tumour types including leukemias, [21] [22] glioblastoma, [23] breast cancer, [24] and prostate cancer. [25]

However, the existence of CSCs is still under debate. One reason for this is that markers for CSCs have been difficult to reproduce across multiple tumours. Further, methods for determining tumourigenic potential utilize xenograft models. These methods suffer from inherent limitations such as the need to control immune response in the transplant animal, and the significant difference in environmental conditions from the primary tumour site to the xenograft site (e.g. absence of required exogenous molecules or cofactors). [26] This has caused some doubt about the accuracy of CSC results and the conclusions about which cells have tumourigenic potential.[ citation needed ]

Clonal evolution

The clonal evolution model was first proposed in 1976 by Peter Nowell. [27] In this model, tumours arise from a single mutated cell, accumulating additional mutations as it progresses. These changes give rise to additional subpopulations, and each of these subpopulations has the ability to divide and mutate further. This heterogeneity may give rise to subclones that possess an evolutionary advantage over the others within the tumour environment, and these subclones may become dominant in the tumour over time. [28] [29] When proposed, this model allowed for the understanding of tumour growth, treatment failure, and tumour aggression that occurs during the natural process of tumour formation. [28]

Branched evolution is more likely to contribute to tumour heterogeneity. Tumour heterogeneity linear vs branched.pdf
Branched evolution is more likely to contribute to tumour heterogeneity.

Evolution of the initial tumour cell may occur by two methods:

Linear expansion

Sequentially ordered mutations accumulate in driver genes, tumour suppressor genes, and DNA repair enzymes, resulting in clonal expansion of tumour cells. Linear expansion is less likely to reflect the endpoint of a malignant tumour [30] because the accumulation of mutations is stochastic in heterogeneic tumours.

Branched expansion

Expansion into multiple subclonal populations occurs through a splitting mechanism. [28] This method is more associated with tumour heterogeneity than linear expansion. The acquisition of mutations is random as a result of increased genomic instability with each successive generation. The long-term mutational accumulation may provide a selective advantage during certain stages of tumour progression. The tumor microenvironment may also contribute to tumour expansion, as it is capable of altering the selective pressures that the tumour cells are exposed to. [30]

Types and causes of heterogeneity

Multiple types of heterogeneity have been observed between tumour cells, stemming from both genetic and non-genetic variability. [31]

Genetic heterogeneity

Genetic heterogeneity is a common feature of tumour genomes, and can arise from multiple sources. Some cancers are initiated when exogenous factors introduce mutations, such as ultraviolet radiation (skin cancers) and tobacco (lung cancer). A more common source is genomic instability, which often arises when key regulatory pathways are disrupted in the cells. Some examples include impaired DNA repair mechanisms which can lead to increased replication errors, and defects in the mitosis machinery that allow for large-scale gain or loss of entire chromosomes. [32] Furthermore, it is possible for genetic variability to be further increased by some cancer therapies (e.g. treatment with temozolomide and other chemotherapy drugs). [33] [34]

Mutational tumor heterogeneity refers to variations in mutation frequency in different genes and samples and can be explored by MutSig Archived 2017-10-03 at the Wayback Machine . The etiology of mutational processes can considerably vary between tumor samples from the same or different cancer types and can be manifested in different context-dependent mutational profiles. It can be explored by COSMIC mutational signatures or MutaGene.

Other heterogeneity

Tumour cells can also show heterogeneity between their expression profiles. This is often caused by underlying epigenetic changes. [31] Variation in expression signatures have been detected in different regions of tumour samples within an individual. Researchers have shown that convergent mutations affecting H3K36 methyltransferase SETD2 and histone H3K4 demethylase KDM5C arose in spatially separated tumour sections. Similarly, MTOR, a gene encoding a cell regulatory kinase, has shown to be constitutively active, thereby increasing S6 phosphorylation. This active phosphorylation may serve as a biomarker in clear-cell carcinoma. [30]

Mechanochemical heterogeneity is a hallmark of living eukaryotic cells. It has an impact on epigenetic gene regulation. The heterogeneous dynamic mechanochemical processes regulate interrelationships within the group of cellular surfaces through adhesion. [35] Tumour development and spreading is accompanied by change in heterogeneous chaotic dynamics of mechanochemical interaction process in the group cells, including cells within tumour, and is hierarchical for the host of cancer patients. [36] The biological phenomena of mechanochemical heterogeneity maybe used for differential gastric cancer diagnostics against patients with inflammation of gastric mucosa [37] and for increasing antimetastatic activity of dendritic cells based on vaccines when mechanically heterogenized microparticles of tumor cells are used for their loading. [38] There is also a possible methodical approach based on the simultaneous ultrasound imaging diagnostic techniques and therapy, regarding the mechanochemical effect on nanobubles conglomerates with drugs in the tumour. [39] [40]

Redox processes in cancer cells induce changes in mechanochemical tumor heterogeneity by modifying bonds which influence the spatial arrangement of molecules in cell structures. This leads to the formation of regions with different biomechanical and biochemical properties within the tumor. [41]

Tumour microenvironment

Heterogeneity between tumour cells can be further increased due to heterogeneity in the tumour microenvironment. Regional differences in the tumour (e.g. availability of oxygen) impose different selective pressures on tumour cells, leading to a wider spectrum of dominant subclones in different spatial regions of the tumour. The influence of microenvironment on clonal dominance is also a likely reason for the heterogeneity between primary and metastatic tumours seen in many patients, as well as the inter-tumour heterogeneity observed between patients with the same tumour type. [42]

Implications and challenges

Treatment resistance

Heterogeneic tumours may exhibit different sensitivities to cytotoxic drugs among different clonal populations. This is attributed to clonal interactions that may inhibit or alter therapeutic efficacy, posing a challenge for successful therapies in heterogeneic tumours (and their heterogeneic metastases). [1]

Drug administration in heterogeneic tumours will seldom kill all tumour cells. The initial heterogeneic tumour population may bottleneck, such that few drug resistant cells (if any) will survive. This allows resistant tumour populations to replicate and grow a new tumour through the branching evolution mechanism (see above). The resulting repopulated tumour is heterogeneic and resistant to the initial drug therapy used. The repopulated tumour may also return in a more aggressive manner.[ citation needed ]

The administration of cytotoxic drugs often results in initial tumour shrinkage. This represents the destruction of initial non-resistant subclonal populations within a heterogeneic tumour, leaving only resistant clones. These resistant clones now contain a selective advantage and can replicate to repopulate the tumour. Replication will likely occur through branching evolution, contributing to tumour heterogeneity. The repopulated tumour may appear to be more aggressive. This is attributed to the drug-resistant selective advantage of the tumour cells.[ citation needed ]

Drug treatment induces a bottleneck effect, where resistant subclones will survive and propagate to re-form a heterogeneous tumour. Tumour heterogeneity treatment bottleneck.pdf
Drug treatment induces a bottleneck effect, where resistant subclones will survive and propagate to re-form a heterogeneous tumour.

Prognosis in multiple myeloma

In multiple myeloma, genetic analyzes of the tumor is used to detect risks markers such as specific mutation, deletion, insertion etc. Helping to assess the Prognosis of the patient. But there is a discrepancy between patients, some patients associated with a good risk will relapse earlier than expected. In addition, in some patients, risks anomaly will only be observed at relapse. A study from 2023 [43] using single cell showed that subclones with risks marker are present in some patients from the diagnosis but in such low frequency that they are not detectable by standard genetic routine assessment. Furthermore, this study indicated that patients with risks markers detectable only at relapse are indeed associated with a bad prognosis. With some risk anomaly there is no difference in the life expectancy (overall survival) between patients with the anomaly detected from the diagnosis and those with the anomaly only detected at relapse. Open question remains about the effect of the treatment on clonal selection. The therapeutic implication of this result is extensively developed in a paper : "Thus, sensitive detection approaches are required to detect these subclones at diagnosis together with innovative treatment strategies to eradicate low-frequency, high-risk subclones and prevent them from becoming dominant. [...] Finally, the described phenomenon is highly unlikely to be restricted to MM" [44] (Multiple Myeloma).

Biomarker discovery

Due to the genetic differences within and between tumours, biomarkers that may predict treatment response or prognosis may not be widely applicable. However, it has been suggested that the level of heterogeneity can itself be used as a biomarker since more heterogeneous tumours may be more likely to contain treatment-resistant subclones. [31] Further research into developing biomarkers that account for heterogeneity is still in progress.

Model systems

Current model systems typically lack the heterogeneity seen in human cancers. [45] In order to accurately study tumour heterogeneity, we must develop more accurate preclinical models. One such model, the patient derived tumour xenograft, has shown excellent utility in preserving tumour heterogeneity whilst allowing detailed study of the drivers of clonal fitness. [46] However, even this model cannot capture the full complexity of cancer.

Current strategies

While the problem of identifying, characterizing, and treating tumour heterogeneity is still under active research, some effective strategies have been proposed, including both experimental and computational solutions.[ citation needed ]

Experimental

Sequencing

See also

References

  1. 1 2 3 4 5 6 7 8 9 Marusyk, A; Polyak, K (2010). "Tumor heterogeneity: Causes and consequences". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1805 (1): 105–117. doi:10.1016/j.bbcan.2009.11.002. PMC   2814927 . PMID   19931353.
  2. Vogelstein, Bert; Papadopoulos, N.; Velculescu, V.E.; Zhou, S.; Diaz, L.A.; Kinzler, K.W. (2013). "Cancer Genome Landscapes". Science. 373 (6127): 1546–1556. Bibcode:2013Sci...339.1546V. doi:10.1126/science.1235122. PMC   3749880 . PMID   23539594.
  3. Heppner, G.A. (1984). "Tumor Heterogeneity". Cancer Research. 44 (6): 2259–2265. PMID   6372991.
  4. Reiter, Johannes G; Makohon-Moore, Alvin P; Gerold, Jeffrey M; Heyde, Alexander; Attiyeh, Marc A; Kohutek, Zachary A; Tokheim, Collin J; Brown, Alexia; DeBlasio, Rayne; Niyazov, Juliana; Zucker, Amanda; Karchin, Rachel; Kinzler, Kenneth W; Iacobuzio-Donahue, Christine A; Vogelstein, Bert; Nowak, Martin A (2018). "Minimal functional driver gene heterogeneity among untreated metastases". Science. 361 (6406): 1033–1037. Bibcode:2018Sci...361.1033R. doi:10.1126/science.aat7171. PMC   6329287 . PMID   30190408.
  5. Campbell, P. J.; Pleasance, E. D.; Stephens, P. J.; Dicks, E; Rance, R; Goodhead, I; Follows, G. A.; Green, A. R.; Futreal, P. A.; Stratton, M. R. (2008). "Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing". Proceedings of the National Academy of Sciences. 105 (35): 13081–13086. Bibcode:2008PNAS..10513081C. doi: 10.1073/pnas.0801523105 . PMC   2529122 . PMID   18723673.
  6. Shipitsin, M; Campbell, L. L.; Argani, P; Weremowicz, S; Bloushtain-Qimron, N; Yao, J; Nikolskaya, T; Serebryiskaya, T; Beroukhim, R; Hu, M; Halushka, M. K.; Sukumar, S; Parker, L. M.; Anderson, K. S.; Harris, L. N.; Garber, J. E.; Richardson, A. L.; Schnitt, S. J.; Nikolsky, Y; Gelman, R. S.; Polyak, K (2007). "Molecular definition of breast tumor heterogeneity". Cancer Cell. 11 (3): 259–273. doi: 10.1016/j.ccr.2007.01.013 . PMID   17349583.
  7. MacIntosh, C. A.; Stower, M; Reid, N; Maitland, N. J. (1998). "Precise microdissection of human prostate cancers reveals genotypic heterogeneity". Cancer Research. 58 (1): 23–28. PMID   9426051.
  8. Alvarado, C; Beitel, L. K.; Sircar, K; Aprikian, A; Trifiro, M; Gottlieb, B (2005). "Somatic mosaicism and cancer: A micro-genetic examination into the role of the androgen receptor gene in prostate cancer". Cancer Research. 65 (18): 8514–8518. doi: 10.1158/0008-5472.CAN-05-0399 . PMID   16166332.
  9. Konishi, N; Hiasa, Y; Matsuda, H; Tao, M; Tsuzuki, T; Hayashi, I; Kitahori, Y; Shiraishi, T; Yatani, R; Shimazaki, J (1995). "Intratumor cellular heterogeneity and alterations in ras oncogene and p53 tumor suppressor gene in human prostate carcinoma". The American Journal of Pathology. 147 (4): 1112–1122. PMC   1871010 . PMID   7573356.
  10. González-García, I; Solé, R. V.; Costa, J (2002). "Metapopulation dynamics and spatial heterogeneity in cancer". Proceedings of the National Academy of Sciences. 99 (20): 13085–13089. Bibcode:2002PNAS...9913085G. doi: 10.1073/pnas.202139299 . PMC   130590 . PMID   12351679.
  11. Samowitz, W. S.; Slattery, M. L. (1999). "Regional reproducibility of microsatellite instability in sporadic colorectal cancer". Genes, Chromosomes and Cancer. 26 (2): 106–114. doi:10.1002/(SICI)1098-2264(199910)26:2<106::AID-GCC2>3.0.CO;2-F. PMID   10469448. S2CID   5643190.
  12. Giaretti, W; Monaco, R; Pujic, N; Rapallo, A; Nigro, S; Geido, E (1996). "Intratumor heterogeneity of K-ras2 mutations in colorectal adenocarcinomas: Association with degree of DNA aneuploidy". The American Journal of Pathology. 149 (1): 237–245. PMC   1865212 . PMID   8686748.
  13. Heppner, G. H. (1984). "Tumor heterogeneity". Cancer Research. 44 (6): 2259–2265. PMID   6372991.
  14. Maley, C. C.; Galipeau, P. C.; Finley, J. C.; Wongsurawat, V. J.; Li, X; Sanchez, C. A.; Paulson, T. G.; Blount, P. L.; Risques, R. A.; Rabinovitch, P. S.; Reid, B. J. (2006). "Genetic clonal diversity predicts progression to esophageal adenocarcinoma". Nature Genetics. 38 (4): 468–473. doi:10.1038/ng1768. PMID   16565718. S2CID   1898396.
  15. Califano, J; Van Der Riet, P; Westra, W; Nawroz, H; Clayman, G; Piantadosi, S; Corio, R; Lee, D; Greenberg, B; Koch, W; Sidransky, D (1996). "Genetic progression model for head and neck cancer: Implications for field cancerization". Cancer Research. 56 (11): 2488–2492. PMID   8653682.
  16. Sauter, G; Moch, H; Gasser, T. C.; Mihatsch, M. J.; Waldman, F. M. (1995). "Heterogeneity of chromosome 17 and erbB-2 gene copy number in primary and metastatic bladder cancer". Cytometry. 21 (1): 40–46. doi: 10.1002/cyto.990210109 . PMID   8529469.
  17. Fujii, H; Yoshida, M; Gong, Z. X.; Matsumoto, T; Hamano, Y; Fukunaga, M; Hruban, R. H.; Gabrielson, E; Shirai, T (2000). "Frequent genetic heterogeneity in the clonal evolution of gynecological carcinosarcoma and its influence on phenotypic diversity". Cancer Research. 60 (1): 114–120. PMID   10646862.
  18. Horvai, A. E.; Devries, S; Roy, R; O'Donnell, R. J.; Waldman, F (2009). "Similarity in genetic alterations between paired well-differentiated and dedifferentiated components of dedifferentiated liposarcoma". Modern Pathology. 22 (11): 1477–1488. doi: 10.1038/modpathol.2009.119 . PMID   19734852.
  19. Pantou, D; Rizou, H; Tsarouha, H; Pouli, A; Papanastasiou, K; Stamatellou, M; Trangas, T; Pandis, N; Bardi, G (2005). "Cytogenetic manifestations of multiple myeloma heterogeneity". Genes, Chromosomes and Cancer. 42 (1): 44–57. doi:10.1002/gcc.20114. PMID   15495197. S2CID   43218546.
  20. 1 2 Shackleton, M; Quintana, E; Fearon, E. R.; Morrison, S. J. (2009). "Heterogeneity in cancer: Cancer stem cells versus clonal evolution". Cell. 138 (5): 822–829. doi: 10.1016/j.cell.2009.08.017 . PMID   19737509.
  21. Lapidot, T; Sirard, C; Vormoor, J; Murdoch, B; Hoang, T; Caceres-Cortes, J; Minden, M; Paterson, B; Caligiuri, M. A.; Dick, J. E. (1994). "A cell initiating human acute myeloid leukaemia after transplantation into SCID mice". Nature. 367 (6464): 645–648. Bibcode:1994Natur.367..645L. doi:10.1038/367645a0. PMID   7509044. S2CID   4330788.
  22. Wang, J. C.; Lapidot, T; Cashman, J. D.; Doedens, M; Addy, L; Sutherland, D. R.; Nayar, R; Laraya, P; Minden, M; Keating, A; Eaves, A. C.; Eaves, C. J.; Dick, J. E. (1998). "High level engraftment of NOD/SCID mice by primitive normal and leukemic hematopoietic cells from patients with chronic myeloid leukemia in chronic phase". Blood. 91 (7): 2406–2414. doi: 10.1182/blood.V91.7.2406 . PMID   9516140.
  23. Singh, S. K.; Hawkins, C; Clarke, I. D.; Squire, J. A.; Bayani, J; Hide, T; Henkelman, R. M.; Cusimano, M. D.; Dirks, P. B. (2004). "Identification of human brain tumour initiating cells". Nature. 432 (7015): 396–401. Bibcode:2004Natur.432..396S. doi:10.1038/nature03128. PMID   15549107. S2CID   4430962.
  24. Al-Hajj, M; Wicha, M. S.; Benito-Hernandez, A; Morrison, S. J.; Clarke, M. F. (2003). "Prospective identification of tumorigenic breast cancer cells". Proceedings of the National Academy of Sciences. 100 (7): 3983–3988. Bibcode:2003PNAS..100.3983A. doi: 10.1073/pnas.0530291100 . PMC   153034 . PMID   12629218.
  25. Maitland, N. J.; Collins, A. T. (2008). "Prostate cancer stem cells: A new target for therapy". Journal of Clinical Oncology. 26 (17): 2862–2870. doi:10.1200/JCO.2007.15.1472. PMID   18539965.
  26. Meacham, C. E.; Morrison, S. J. (2013). "Tumour heterogeneity and cancer cell plasticity". Nature. 501 (7467): 328–337. Bibcode:2013Natur.501..328M. doi:10.1038/nature12624. PMC   4521623 . PMID   24048065.
  27. Nowell, P. C. (1976). "The clonal evolution of tumor cell populations". Science. 194 (4260): 23–28. Bibcode:1976Sci...194...23N. doi:10.1126/science.959840. PMID   959840. S2CID   38445059.
  28. 1 2 3 Swanton, C (2012). "Intratumor heterogeneity: Evolution through space and time". Cancer Research. 72 (19): 4875–4882. doi:10.1158/0008-5472.CAN-12-2217. PMC   3712191 . PMID   23002210.
  29. Merlo, L. M. F.; Pepper, J. W.; Reid, B. J.; Maley, C. C. (2006). "Cancer as an evolutionary and ecological process". Nature Reviews Cancer. 6 (12): 924–935. doi:10.1038/nrc2013. PMID   17109012. S2CID   8040576.
  30. 1 2 3 Gerlinger, M; Rowan, A. J.; Horswell, S; Larkin, J; Endesfelder, D; Gronroos, E; Martinez, P; Matthews, N; Stewart, A; Tarpey, P; Varela, I; Phillimore, B; Begum, S; McDonald, N. Q.; Butler, A; Jones, D; Raine, K; Latimer, C; Santos, C. R.; Nohadani, M; Eklund, A. C.; Spencer-Dene, B; Clark, G; Pickering, L; Stamp, G; Gore, M; Szallasi, Z; Downward, J; Futreal, P. A.; Swanton, C (2012). "Intratumor heterogeneity and branched evolution revealed by multiregion sequencing". New England Journal of Medicine. 366 (10): 883–892. doi:10.1056/NEJMoa1113205. PMC   4878653 . PMID   22397650.
  31. 1 2 3 Marusyk, A; Almendro, V; Polyak, K (2012). "Intra-tumour heterogeneity: A looking glass for cancer?". Nature Reviews Cancer. 12 (5): 323–334. doi:10.1038/nrc3261. PMID   22513401. S2CID   24420285.
  32. Burrell, R. A.; McGranahan, N; Bartek, J; Swanton, C (2013). "The causes and consequences of genetic heterogeneity in cancer evolution". Nature. 501 (7467): 338–345. Bibcode:2013Natur.501..338B. doi:10.1038/nature12625. PMID   24048066. S2CID   4457392.
  33. Johnson, B. E.; Mazor, T; Hong, C; Barnes, M; Aihara, K; McLean, C. Y.; Fouse, S. D.; Yamamoto, S; Ueda, H; Tatsuno, K; Asthana, S; Jalbert, L. E.; Nelson, S. J.; Bollen, A. W.; Gustafson, W. C.; Charron, E; Weiss, W. A.; Smirnov, I. V.; Song, J. S.; Olshen, A. B.; Cha, S; Zhao, Y; Moore, R. A.; Mungall, A. J.; Jones, S. J.; Hirst, M; Marra, M. A.; Saito, N; Aburatani, H; Mukasa, A (2014). "Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma". Science. 343 (6167): 189–193. Bibcode:2014Sci...343..189J. doi:10.1126/science.1239947. PMC   3998672 . PMID   24336570.
  34. 1 2 Ding, L; Ley, T. J.; Larson, D. E.; Miller, C. A.; Koboldt, D. C.; Welch, J. S.; Ritchey, J. K.; Young, M. A.; Lamprecht, T; McLellan, M. D.; McMichael, J. F.; Wallis, J. W.; Lu, C; Shen, D; Harris, C. C.; Dooling, D. J.; Fulton, R. S.; Fulton, L. L.; Chen, K; Schmidt, H; Kalicki-Veizer, J; Magrini, V. J.; Cook, L; McGrath, S. D.; Vickery, T. L.; Wendl, M. C.; Heath, S; Watson, M. A.; Link, D. C.; Tomasson, M. H. (2012). "Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing". Nature. 481 (7382): 506–510. Bibcode:2012Natur.481..506D. doi:10.1038/nature10738. PMC   3267864 . PMID   22237025.
  35. G.M.Edelman (1989). "Topobiology". Scientific American. 260 (5): 76–88. Bibcode:1989SciAm.260e..76E. doi:10.1038/scientificamerican0589-76. PMID   2717916.
  36. V.E. Orel; N.N Dzyatkovskaya; M.I. Danko; A.V. Romanov; Y.I. Mel'nik; Y.A. Grinevich; S.V. Martynenko (2004). "Spatial and mechanoemission chaos of mechanically deformed tumor cells". Journal of Mechanics in Medicine and Biology . 4 (1): 31–45. doi:10.1142/s0219519404000886.
  37. V.E. Orel; A.V. Romanov; N.N. Dzyatkovskaya; Yu.I. Mel’nik (2002). "The device and algorithm for estimation of the mechanoemisson chaos in blood of patients with gastric cancer". Medical Engineering & Physics. 24 (5): 365–371. doi:10.1016/s1350-4533(02)00022-x. PMID   12052364.
  38. N. Khranovskaya; V. Orel; Y. Grinevich; O. Alekseenko; A. Romanov; O. Skachkova; N.Dzyatkovskaya; A. Burlaka; S.Lukin (2012). "Mechanical heterogenization of Lewis lung carcinoma cells can improve antimetastatic effect of dendritic cells". Journal of Mechanics in Medicine and Biology. 3 (12): 22. doi:10.1142/S0219519411004757.
  39. Orel, Valerii B.; Papazoglou, Αndreas S.; Tsagkaris, Christos; Moysidis, Dimitrios V.; Papadakos, Stavros; Galkin, Olexander Yu.; Orel, Valerii E.; Syvak, Liubov A. (2023). "Nanotherapy based on magneto-mechanochemical modulation of tumor redox state". WIREs Nanomedicine and Nanobiotechnology. 15 (3): e1868. doi:10.1002/wnan.1868. ISSN   1939-0041. PMID   36289050.
  40. Orel, V. B.; Zabolotny, M. A.; Orel, V. E. (2017-05-01). "Heterogeneity of hypoxia in solid tumours and mechanochemical reactions with oxygen nanobubbles". Medical Hypotheses. 102: 82–86. doi:10.1016/j.mehy.2017.03.006. ISSN   0306-9877. PMID   28478838.
  41. Orel, Valerii B.; Galkin, Olexander Yu.; Orel, Valerii E.; Dasyukevich, Olga Yo.; Rykhalskyi, Oleksandr Yu.; Kurapov, Yurii A.; Litvin, Stanislav A.; Yukhymchuk, Volodymyr O.; Isayeva, Oksana F.; Syvak, Liubov A.; Dedkov, Anatoliy G. (August 2023). "Mechanoluminescence of Walker-256 Carcinosarcoma Cells Induced by Magneto-Mechanomechanical Effects of Fe3O4–Au Nanocomposite". Journal of Mechanics in Medicine and Biology. 23 (6): 2340027. doi: 10.1142/S0219519423400274 . ISSN   0219-5194.
  42. Junttila, M. R.; De Sauvage, F. J. (2013). "Influence of tumour micro-environment heterogeneity on therapeutic response". Nature. 501 (7467): 346–354. Bibcode:2013Natur.501..346J. doi:10.1038/nature12626. PMID   24048067. S2CID   4452486.
  43. Lannes, Romain; Samur, Mehmet; Perrot, Aurore; Mazzotti, Celine; Divoux, Marion; Cazaubiel, Titouan; Leleu, Xavier; Schavgoulidze, Anaïs; Chretien, Marie-Lorraine; Manier, Salomon; Adiko, Didier; Orsini-Piocelle, Frederique; Lifermann, François; Brechignac, Sabine; Gastaud, Lauris; Bouscary, Didier; Macro, Margaret; Cleynen, Alice; Mohty, Mohamad; Munshi, Nikhil; Corre, Jill; Avet-Loiseau, Hervé (2023). "In Multiple Myeloma, High-Risk Secondary Genetic Events Observed at Relapse Are Present from Diagnosis in Tiny, Undetectable Subclonal Populations". Journal of Clinical Oncology. 41 (9): 1695–1702. doi:10.1200/JCO.21.01987. PMC   10043564 . PMID   36343306. S2CID   253395684.
  44. Boyle, Eileen M.; Davies, Faith E. (2023). "From little subclones grow mighty oaks". Nature Reviews Clinical Oncology. 20 (3): 141–142. doi:10.1038/s41571-022-00727-w. PMID   36624303. S2CID   255567626.
  45. Auman, James Todd; McLeod, Howard L. (2010-01-01). "Colorectal Cancer Cell Lines Lack the Molecular Heterogeneity of Clinical Colorectal Tumors". Clinical Colorectal Cancer. 9 (1): 40–47. doi:10.3816/ccc.2010.n.005. PMID   20100687.
  46. Cassidy, John W.; Caldas, Carlos; Bruna, Alejandra (2015-08-01). "Maintaining Tumor Heterogeneity in Patient-Derived Tumor Xenografts". Cancer Research. 75 (15): 2963–2968. doi:10.1158/0008-5472.CAN-15-0727. ISSN   0008-5472. PMC   4539570 . PMID   26180079.
  47. Bai H, Harmancı AS, Erson-Omay AZ, Li J, Coșkun S, Simon M, et al. (Nov 2015). "Integrated genomic characterization of IDH1-mutant glioma malignant progression". Nature Genetics. 48 (1): 59–66. doi:10.1038/ng.3457. PMC   4829945 . PMID   26618343.
  48. Bedard, P. L.; Hansen, A. R.; Ratain, M. J.; Siu, L. L. (2013). "Tumour heterogeneity in the clinic". Nature. 501 (7467): 355–364. Bibcode:2013Natur.501..355B. doi:10.1038/nature12627. PMC   5224525 . PMID   24048068.
  49. Dawson, S. J.; Tsui, D. W.; Murtaza, M; Biggs, H; Rueda, O. M.; Chin, S. F.; Dunning, M. J.; Gale, D; Forshew, T; Mahler-Araujo, B; Rajan, S; Humphray, S; Becq, J; Halsall, D; Wallis, M; Bentley, D; Caldas, C; Rosenfeld, N (2013). "Analysis of circulating tumor DNA to monitor metastatic breast cancer". New England Journal of Medicine. 368 (13): 1199–1209. doi: 10.1056/NEJMoa1213261 . PMID   23484797.
  50. Gatenby, R. A.; Silva, A. S.; Gillies, R. J.; Frieden, B. R. (2009). "Adaptive therapy". Cancer Research. 69 (11): 4894–4903. doi:10.1158/0008-5472.CAN-08-3658. PMC   3728826 . PMID   19487300.
  51. Cibulskis, K; Lawrence, M. S.; Carter, S. L.; Sivachenko, A; Jaffe, D; Sougnez, C; Gabriel, S; Meyerson, M; Lander, E. S.; Getz, G (2013). "Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples". Nature Biotechnology. 31 (3): 213–219. doi:10.1038/nbt.2514. PMC   3833702 . PMID   23396013.
  52. Koboldt, D. C.; Zhang, Q; Larson, D. E.; Shen, D; McLellan, M. D.; Lin, L; Miller, C. A.; Mardis, E. R.; Ding, L; Wilson, R. K. (2012). "Var Scan 2: Somatic mutation and copy number alteration discovery in cancer by exome sequencing". Genome Research. 22 (3): 568–576. doi:10.1101/gr.129684.111. PMC   3290792 . PMID   22300766.
  53. Saunders, C. T.; Wong, W. S.; Swamy, S; Becq, J; Murray, L. J.; Cheetham, R. K. (2012). "Strelka: Accurate somatic small-variant calling from sequenced tumor-normal sample pairs". Bioinformatics. 28 (14): 1811–1817. doi: 10.1093/bioinformatics/bts271 . PMID   22581179.
  54. Carter, S. L.; Cibulskis, K; Helman, E; McKenna, A; Shen, H; Zack, T; Laird, P. W.; Onofrio, R. C.; Winckler, W; Weir, B. A.; Beroukhim, R; Pellman, D; Levine, D. A.; Lander, E. S.; Meyerson, M; Getz, G (2012). "Absolute quantification of somatic DNA alterations in human cancer" (PDF). Nature Biotechnology. 30 (5): 413–421. doi:10.1038/nbt.2203. PMC   4383288 . PMID   22544022.
  55. Shah, S. P.; Roth, A; Goya, R; Oloumi, A; Ha, G; Zhao, Y; Turashvili, G; Ding, J; Tse, K; Haffari, G; Bashashati, A; Prentice, L. M.; Khattra, J; Burleigh, A; Yap, D; Bernard, V; McPherson, A; Shumansky, K; Crisan, A; Giuliany, R; Heravi-Moussavi, A; Rosner, J; Lai, D; Birol, I; Varhol, R; Tam, A; Dhalla, N; Zeng, T; Ma, K; Chan, S. K. (2012). "The clonal and mutational evolution spectrum of primary triple-negative breast cancers". Nature. 486 (7403): 395–399. Bibcode:2012Natur.486..395S. doi:10.1038/nature10933. PMC   3863681 . PMID   22495314.
  56. Gillies, Robert J.; Verduzco, Daniel; Gatenby, Robert A. (July 2012). "Evolutionary dynamics of carcinogenesis and why targeted therapy does not work". Nature Reviews Cancer. 12 (7): 487–493. doi:10.1038/nrc3298. PMC   4122506 . PMID   22695393.
  57. Navin, N; Kendall, J; Troge, J; Andrews, P; Rodgers, L; McIndoo, J; Cook, K; Stepansky, A; Levy, D; Esposito, D; Muthuswamy, L; Krasnitz, A; McCombie, W. R.; Hicks, J; Wigler, M (2011). "Tumour evolution inferred by single-cell sequencing". Nature. 472 (7341): 90–94. Bibcode:2011Natur.472...90N. doi:10.1038/nature09807. PMC   4504184 . PMID   21399628.
  58. Jahn, Katharina (2016). "Tree inference for single-cell data". Genome Biology. 17: 86. doi: 10.1186/s13059-016-0936-x . PMC   4858868 . PMID   27149953.
  59. Ross, Edith (2016). "OncoNEM: inferring tumor evolution from single-cell sequencing data". Genome Biology. 17: 69. doi: 10.1186/s13059-016-0929-9 . PMC   4832472 . PMID   27083415.
  60. Zafar, Hamim (2017). "SiFit: inferring tumor trees from single-cell sequencing data under finite-sites models". Genome Biology. 18 (1): 178. doi: 10.1186/s13059-017-1311-2 . PMC   5606061 . PMID   28927434.
  61. Zafar, Hamim (2019). "SiCloneFit: Bayesian inference of population structure, genotype, and phylogeny of tumor clones from single-cell genome sequencing data". Genome Research. 29 (11): 1847–1859. doi: 10.1101/gr.243121.118 . PMC   6836738 . PMID   31628257.
  62. Malikic, Salem; Rashidi Mehrabadi, Farid (2019). "PhISCS: a combinatorial approach for subperfect tumor phylogeny reconstruction via integrative use of single-cell and bulk sequencing data". Genome Research. 29 (11): 1860–1877. doi: 10.1101/gr.234435.118 . PMC   6836735 . PMID   31628256.
  63. Sadeqi Azer, Erfan; Rashidi Mehrabadi, Farid (2020). "PhISCS-BnB: a fast branch and bound algorithm for the perfect tumor phylogeny reconstruction problem". Bioinformatics. 36 (Supplement_1): i169 –i176. doi: 10.1093/bioinformatics/btaa464 . PMC   7355310 . PMID   32657358.
  64. Kızılkale, Can; Rashidi Mehrabadi, Farid; Sadeqi Azer, Erfan; Pérez-Guijarro, Eva; Marie, Kerrie L.; Lee, Maxwell P.; Day, Chi-Ping; Merlino, Glenn; Ergün, Funda; Buluç, Aydın; Sahinalp, S. Cenk; Malikić, Salem (September 2022). "Fast intratumor heterogeneity inference from single-cell sequencing data". Nature Computational Science. 2 (9): 577–583. doi:10.1038/s43588-022-00298-x. PMC   10765963 . PMID   38177468. S2CID   252171836.
  65. El-Kebir, Mohammed (2018). "SPhyR: Tumor phylogeny estimation from single-cell sequencing data under loss and error". Bioinformatics. 34 (17): i671 –i679. doi: 10.1093/bioinformatics/bty589 . PMC   6153375 . PMID   30423070.
  66. 1 2 Jahn, Katharina; Kuipers, Jack; Beerenwinkel, Niko (December 2016). "Tree inference for single-cell data". Genome Biology. 17 (1): 86. doi: 10.1186/s13059-016-0936-x . PMC   4858868 . PMID   27149953.
  67. Whidden, Chris; Matsen, Frederick A. (1 May 2015). "Quantifying MCMC Exploration of Phylogenetic Tree Space". Systematic Biology. 64 (3): 472–491. doi: 10.1093/sysbio/syv006 . PMC   4395846 . PMID   25631175.
  68. Köhn, Gordon (23 October 2023). Quantifying Markov Chain Monte Carlo Exploration of Tumour Progression Tree Spaces: Initialisation Strategies, Convergence Diagnostics & Multi-modalities. ETH Zürich Collection (Master Thesis). ETH Zurich. doi:10.3929/ethz-b-000642011.
  69. Kuipers, Jack (2017). "Advances in understanding tumour evolution through single-cell sequencing". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1867 (2): 127–138. doi:10.1016/j.bbcan.2017.02.001. PMC   5813714 . PMID   28193548.
  70. Schwartz, Russell (13 Feb 2017). "The evolution of tumour phylogenetics: principles and practice". Nature Reviews Genetics. 18 (4): 213–229. doi:10.1038/nrg.2016.170. PMC   5886015 . PMID   28190876.
  71. Farahani, Hossein; de Souza, Camila P. E.; Billings, Raewyn; Yap, Damian; Shumansky, Karey; Wan, Adrian; Lai, Daniel; Mes-Masson, Anne-Marie; Aparicio, Samuel; P. Shah, Sohrab (18 October 2017). "Engineered in-vitro cell line mixtures and robust evaluation of computational methods for clonal decomposition and longitudinal dynamics in cancer". Scientific Reports. 7 (1): 13467. Bibcode:2017NatSR...713467F. doi:10.1038/s41598-017-13338-8. PMC   5647443 . PMID   29044127.
  72. Zare, Habil (2014). "Inferring clonal composition from multiple sections of a breast cancer". PLOS Computational Biology. 10 (7): e1003703. Bibcode:2014PLSCB..10E3703Z. doi: 10.1371/journal.pcbi.1003703 . PMC   4091710 . PMID   25010360.
  73. Fischer, Andrej (2014). "High-definition reconstruction of clonal composition in cancer". Cell Reports. 7 (5): 1740–1752. doi:10.1016/j.celrep.2014.04.055. PMC   4062932 . PMID   24882004.
  74. Deshwar, Amit (2015). "Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns". Genome Biology. 16 (1): 35. doi: 10.1186/s13059-015-0602-8 . PMC   4359439 . PMID   25786235.
  75. Roth, Andrew (2014). "PyClone: statistical inference of clonal population structure in cancer". Nature Methods. 11 (4): 396–398. doi:10.1038/nmeth.2883. PMC   4864026 . PMID   24633410.
  76. Marass, Francesco (2015). "A phylogenetic latent feature model for clonal deconvolution". The Annals of Applied Statistics. 10 (4): 2377–2404. arXiv: 1604.01715 . doi:10.1214/16-AOAS986. S2CID   14986879.
  77. Matsui, Yusuke (2016). "phyC: Clustering cancer evolutionary trees". PLOS Computational Biology. 13 (5): e1005509. Bibcode:2017PLSCB..13E5509M. bioRxiv   10.1101/069302 . doi: 10.1371/journal.pcbi.1005509 . PMC   5432190 . PMID   28459850.
  78. Jiang, Yuchao; Qiu, Yu; Minn, Andy J.; Zhang, Nancy R. (29 August 2016). "Assessing intratumor heterogeneity and tracking longitudinal and spatial clonal evolutionary history by next-generation sequencing". Proceedings of the National Academy of Sciences. 113 (37): E5528–37. Bibcode:2016PNAS..113E5528J. doi: 10.1073/pnas.1522203113 . PMC   5027458 . PMID   27573852.
  79. Salehi, Sohrab (2017). "ddClone: joint statistical inference of clonal populations from single cell and bulk tumour sequencing data". Genome Biology. 18 (1): 44. doi: 10.1186/s13059-017-1169-3 . PMC   5333399 . PMID   28249593.
  80. Satas, Gryte (2017). "Tumor phylogeny inference using tree-constrained importance sampling". Bioinformatics. 33 (14): i152 –i160. doi:10.1093/bioinformatics/btx270. PMC   5870673 . PMID   28882002.
  81. Geng, Yu (2017). "Identifying Heterogeneity Patterns of Allelic Imbalance on Germline Variants to Infer Clonal Architecture". Intelligent Computing Theories and Application. Lecture Notes in Computer Science. Vol. 10362. pp. 286–297. doi:10.1007/978-3-319-63312-1_26. ISBN   978-3-319-63311-4.{{cite book}}: |journal= ignored (help)
  82. Ramazzotti, Daniele; Graudenzi, Alex; Sano, Luca De; Antoniotti, Marco; Caravagna, Giulio (4 September 2017). "Learning mutational graphs of individual tumor evolution from multi-sample sequencing data". bioRxiv   10.1101/132183 .
  83. Roman, Theodore; Xie, Lu; Schwartz, Russell; Raphael, Benjamin J. (23 October 2017). "Automated deconvolution of structured mixtures from heterogeneous tumor genomic data". PLOS Computational Biology. 13 (10): e1005815. arXiv: 1604.02487 . Bibcode:2017PLSCB..13E5815R. doi: 10.1371/journal.pcbi.1005815 . PMC   5695636 . PMID   29059177.
  84. Malikic, Salem (2017). "Integrative inference of subclonal tumour evolution from single-cell and bulk sequencing data". bioRxiv   10.1101/234914 .
  85. Oesper, Layla; Mahmoody, Ahmad; Raphael, Benjamin J. (29 July 2013). "THetA: inferring intra-tumor heterogeneity from high-throughput DNA sequencing data". Genome Biology. 14 (7): R80. doi: 10.1186/gb-2013-14-7-r80 . ISSN   1474-760X. PMC   4054893 . PMID   23895164.
  86. Zeng, By (2018). "Phylogeny-based tumor subclone identification using a Bayesian feature allocation model". arXiv: 1803.06393 [stat.AP].
  87. Cun, Yupeng; Yang, Tsun-Po; Achter, Viktor; Lang, Ulrich; Peifer, Martin (24 May 2018). "Copy-number analysis and inference of subclonal populations in cancer genomes using Sclust". Nature Protocols. 13 (6): 1488–1501. doi:10.1038/nprot.2018.033. ISSN   1754-2189. PMID   29844525. S2CID   44070107.
  88. Wang, Xiaodong; Ogundijo, Oyetunji E. (2019-12-01). "SeqClone: sequential Monte Carlo based inference of tumor subclones". BMC Bioinformatics. 20 (1): 6. doi: 10.1186/s12859-018-2562-y . ISSN   1471-2105. PMC   6320595 . PMID   30611189.
  89. Raphael, Benjamin J.; Satas, Gryte; Myers, Matthew A. (22 January 2019). "Inferring tumor evolution from longitudinal samples". bioRxiv: 526814. doi: 10.1101/526814 .
  90. Toosi, Hosein; Moeini, Ali; Hajirasouliha, Iman (6 June 2019). "BAMSE: Bayesian model selection for tumor phylogeny inference among multiple samples". BMC Bioinformatics. 20 (11): 282. doi: 10.1186/s12859-019-2824-3 . ISSN   1471-2105. PMC   6551234 . PMID   31167637.
  91. Ricketts, Camir; Seidman, Daniel; Popic, Victoria; Hormozdiari, Fereydoun; Batzoglou, Serafim; Hajirasouliha, Iman (4 October 2019). "Meltos: Multi-Sample Tumor Phylogeny Reconstruction for Structural Variants". Bioinformatics. 36 (4): 1082–1090. doi:10.1093/bioinformatics/btz737. PMC   8215921 . PMID   31584621.
  92. Sundermann, Linda (2021). "Reconstructing tumor evolutionary histories and clone trees in polynomial-time with SubMARine" (PDF). PLOS Computational Biology. 17 (1): e1008400. Bibcode:2021PLSCB..17E8400S. doi: 10.1371/journal.pcbi.1008400 . PMC   7845980 . PMID   33465079 . Retrieved 22 June 2020.
  93. Zhou, Tianjian (2020). "RNDClone: Tumor subclone reconstruction based on integrating DNA and RNA sequence data". The Annals of Applied Statistics. 14 (4). doi:10.1214/20-aoas1368. S2CID   220632005.
  94. Baghaarabani, Leila; Goliaei, Sama; Foroughmand-Araabi, Mohammad-Hadi; Shariatpanahi, Seyed Peyman; Goliaei, Bahram (1 March 2021). "Conifer: Clonal Tree Inference for Tumor Heterogeneity With Single-cell and Bulk Sequencing Data". BMC Bioinformatics. 22 (1): 416. doi: 10.1186/s12859-021-04338-7 . PMC   8404257 . PMID   34461827.
  95. Andersson, Natalie; Chattopadhyay, Subhayan; Valind, Anders; Karlsson, Jenny; Gisselsson, David (20 September 2021). "DEVOLUTION—A method for phylogenetic reconstruction of aneuploid cancers based on multiregional genotyping data". Communications Biology. 4 (1): 1103. doi: 10.1038/s42003-021-02637-6 . ISSN   2399-3642. PMC   8452746 . PMID   34545199.
  96. Xia, Jie; Wang, Lequn; Zhang, Guijun; Zuo, Chunman; Chen, Luonan (December 2021). "RDAClone: Deciphering Tumor Heterozygosity through Single-Cell Genomics Data Analysis with Robust Deep Autoencoder". Genes. 12 (12): 1847. doi: 10.3390/genes12121847 . PMC   8701080 . PMID   34946794.