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In this review, we highlight the role of intratumoral heterogeneity, focusing on the clinical and biological ramifications this phenomenon poses. 865-338-1377 Tugal Deis. J Mol Diagn 14(4):376–384, Ramon YCS, Segura MF, Hummer S (2019) Interplay between ncRNAs and cellular communication: a proposal for understanding cell-specific signaling pathways. These non-genetic influences shape the phenotypic states of cancer cells at the proteome level. Proc Natl Acad Sci U S A 112(1):118–123, Vogelstein B, Kinzler KW (2015) The path to cancer --three strikes and you’re out. Camillo: Why I started? You are a big name in the dance biz for years now and you were standing on many international stages as a dancer and a choreographer. Trends Cancer 5(1):1–5, Bedard PL, Hansen AR, Ratain MJ, Siu LL (2013) Tumour heterogeneity in the clinic. Cancer 107(8):1801–1811, Armengol G, Rojo F, Castellvi J, Iglesias C, Cuatrecasas M, Pons B, Baselga J, Ramon y Cajal S (2007) 4E-binding protein 1: a key molecular “funnel factor” in human cancer with clinical implications. It is a blessing to make people smile with something that makes you happy as well. Proc Natl Acad Sci U S A 115(13):E2970–E2979, Bychkov D, Linder N, Turkki R, Nordling S, Kovanen PE, Verrill C, Walliander M, Lundin M, Haglund C, Lundin J (2018) Deep learning based tissue analysis predicts outcome in colorectal cancer. Recently, the TRACERx consortium [7, 196] investigated tumor heterogeneity and evolution in early-stage NSCLC and showed the prognostic value of copy-number heterogeneity assessment in tumor biopsies and circulating tumor DNA detection in plasma. Camillo: You have to be flexible. Cancer 122(1):99–107, Martinez A, Sese M, Losa JH, Robichaud N, Sonenberg N, Aasen T, Ramon YCS (2015) Phosphorylation of eIF4E confers resistance to cellular stress and DNA-damaging agents through an interaction with 4E-T: a rationale for novel therapeutic approaches. Jovannah Lauricella. 865-338-9998 Dawsen Emard. Moreover, the deep learning tumor prediction heat map can be quite complementary to pathologists’ “workflow.” An algorithm can detect, for example, metastatic carcinoma in lymph nodes, or tumor budding in the colon or cervix, and help to recognize histologic patterns associated with higher malignant grades in gliomas [203], and moreover, can score the degree of malignancy in tumors such a prostate adenocarcinomas where quantification of the histological patterns are underway [197, 198]. Clin Cancer Res 21(6):1258–1266, PubMed  What fascinates you about being on stage? 7 Fred Camillo Town of Greenwich 8 Terrie Wood State of Connecticut 9 Jason Rojas Connecticut General Assembly 10 Josh Elliott CGA 11 Stephanie Thomas General Assembly 12 Heather Somers CGA 13 Justin Elicker City of New Haven 14 Rudy Marconi Town of Ridgefield 15 Maureen Nicholson 16 Richard Ives 17 Shari Cantor Town of West Hartford 18 Harry Arora Connecticut General Assembly 19 … Sci Rep 8(1):3395, Michaut M, Chin SF, Majewski I, Severson TM, Bismeijer T, de Koning L, Peeters JK, Schouten PC, Rueda OM, Bosma AJ et al (2016) Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer. 978-288-3989 Sarine Mabile. Genes (Basel) 5(3):497–507, Blanes A, Diaz-Cano SJ (2006) Complementary analysis of microsatellite tumor profile and mismatch repair defects in colorectal carcinomas. DanceAware: Camillo you travalled a lot during your career, also to THE MOST legendary dance studio in LA (Los Angeles) – the Millennium Dance Complex. 720-543-8540 Dariya Khouri. 709-648-2014 Rowly Pagliuca. Cell 152(4):714–726, Zhang J, Fujimoto J, Wedge DC, Song X, Seth S, Chow CW, Cao Y, Gumbs C, Gold KA, Kalhor N et al (2014) Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing. We must establish more rational and ambitious organizational models and strategies, with real networks and professional, well-trained teams. In this context, some caution should be taken for the evaluation of early epithelial neoplasms. Nat Commun 6:6605, Dagogo-Jack I, Shaw AT (2018) Tumour heterogeneity and resistance to cancer therapies. PubMed Google Scholar. Cancer Discov. Another important advantage (although under certain situations it may be a disadvantage) is that it tends to reflect an aggregate of the output (ctDNA/CTC etc.) 709-648-6693 Yancey Kerstiens. Semin Cell Dev Biol 64:18–25, Bhawal UK, Tsukinoki K, Sasahira T, Sato F, Mori Y, Muto N, Sugiyama M, Kuniyasu H (2007) Methylation and intratumoural heterogeneity of 14-3-3 sigma in oral cancer. In these situations it is crucial to stay calm. Genome Res 22(2):271–282, Lobo J, Barros-Silva D, Henrique R, Jeronimo C (2018) The emerging role of Epitranscriptomics in Cancer: focus on urological tumors. Artificial intelligence. Importantly, there are many nonspecific genetic alterations in human tumors. The field of radiogenomics, which correlates genomic data with the radiological features of the tumors, must also be taken into account [139, 140]. 709-648-4831 Izaya Felgenhauer. These studies, nowadays, can be expensive and tedious in time as well as in their interpretation, but are already showing results of high clinical interest; for example, the identification of heterogeneity of mutations of the PIK3CA gene in breast cancer with HER2 amplification where the authors describe that PIK13A and HER2 are not always present in the same cells and that chemotherapy selected the cells with mutant PIK3CA [111]. The size of the sample is another critical issue [130,131,132], and signal-to-noise ratios need to be balanced. Cancer Res 75(6):1102–1112, Musa J, Orth MF, Dallmayer M, Baldauf M, Pardo C, Rotblat B, Kirchner T, Leprivier G, Grunewald TG (2016) Eukaryotic initiation factor 4E-binding protein 1 (4E-BP1): a master regulator of mRNA translation involved in tumorigenesis. Int J Cancer 60(2):235–243, Sanchez-Prieto R, Quintanilla M, Cano A, Leonart ML, Martin P, Anaya A, Ramon y Cajal S (1996) Carcinoma cell lines become sensitive to DNA-damaging agents by the expression of the adenovirus E1A gene. Hier findet ihr die aktuellsten News, Dates, Clips & Pics. In this regard, the concept of cancer as a consortium of clones and local factors has been proposed [101]. Camillo: What really lacks the german dance scene are the opportunities you have in the USA. Clinical implications of intratumor heterogeneity: challenges and opportunities, https://doi.org/10.1016/j.molonc.2015.12.001, https://doi.org/10.1158/2159-8290.CD-15-1483, https://doi.org/10.1007/s00109-020-01874-2. was just incredible and definitely a big boost for both of us. Tumor heterogeneity has presented a considerable challenge to matching patients with the right treatment at the right time; therefore, it poses a challenge to accomplish the goals of precision medicine [8, 9]. Cancer Res 67(16):7551–7555, Pons B, Peg V, Vazquez-Sanchez MA, Lopez-Vicente L, Argelaguet E, Coch L, Martinez A, Hernandez-Losa J, Armengol G, Ramon YCS (2011) The effect of p-4E-BP1 and p-eIF4E on cell proliferation in a breast cancer model. 720-543-4275 Zay Ferdman. As Horning recently said [204], “science and technology are at an inflection point with convergence—the integration of life sciences, physical sciences, mathematics, engineering, and information technology—poised to make significant progress”. Lancet Oncol 16(8):937–948, Malladi S, Macalinao DG, Jin X, He L, Basnet H, Zou Y, de Stanchina E, Massague J (2016) Metastatic latency and immune evasion through autocrine inhibition of WNT. Despite claims in recent models that only three driver mutations are required for the development of various forms of advanced cancer [66, 67], the number of molecular changes necessary to enable the emergence of a clinically relevant tumor has, for some time, been assumed to be higher than previously thought, given standard mutation rates in any cell type. Light-emitting electrospun nanofibers of poly[(9,9-dioctylfluorenyl-2,7-diyl)-co-(N,N′-diphenyl)-N,N′-di(p-butyl-oxy-phenyl)-1,4-diaminobenzene)] (PFO–PBAB) are produced by electrospinning under different experimental conditions. AJR Am J Roentgenol 199(3):654–663, Jamshidi N, Jonasch E, Zapala M, Korn RL, Brooks JD, Ljungberg B, Kuo MD (2016) The radiogenomic risk score stratifies outcomes in a renal cell cancer phase 2 clinical trial. Cancer Genet 216-217:37–51, Assenov Y, Brocks D, Gerhauser C (2018) Intratumor heterogeneity in epigenetic patterns. Nat Med 21(7):827, Newman AM, Lovejoy AF, Klass DM, Kurtz DM, Chabon JJ, Scherer F, Stehr H, Liu CL, Bratman SV, Say C et al (2016) Integrated digital error suppression for improved detection of circulating tumor DNA. Nevertheless, the puzzle and variability of cancer pathology are made tremendously complicated at the genomic level by the vast number of DNA changes, with thousands of known translocations and more than 1500 mutations, deletions, and amplifications reported to date [8, 26,27,28,29]. Although some molecular alterations are recurrent in some tumors, not all the tumors of the same type, and similar morphology, show the same genetic profile. Given that proteins are the final effectors of all cellular pathways, along with small metabolites, it seems reasonable to think that the “ideal” targets for therapy are those protein factors that have the most stable expression and activation in tumor cells. Cell 170(5):927–938 e920, Graff JR, Konicek BW, Carter JH, Marcusson EG (2008) Targeting the eukaryotic translation initiation factor 4E for cancer therapy. Simply, because I had a lot of fun dancing. Mol Ther Nucleic Acids 2:e109, Best MG, Sol N, Kooi I, Tannous J, Westerman BA, Rustenburg F, Schellen P, Verschueren H, Post E, Koster J et al (2015) RNA-Seq of tumor-educated platelets enables blood-based pan-cancer, multiclass, and molecular pathway cancer diagnostics. J Pathol 231(4):424–432, Reuben A, Spencer CN, Prieto PA, Gopalakrishnan V, Reddy SM, Miller JP, Mao X, De Macedo MP, Chen J, Song X et al (2017) Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma. Cell 153(1):38–55, Rastetter M, Schagdarsurengin U, Lahtz C, Fiedler E, Marsch W, Dammann R, Helmbold P (2007) Frequent intra-tumoural heterogeneity of promoter hypermethylation in malignant melanoma. Ramón y Cajal, S., Sesé, M., Capdevila, C. et al. This control is profoundly altered in cancer [56]. This is also true for non-small cell lung cancer and EGFR mutations [40]. Trends Genet 25(1):30–38, Ramon YCS, Capdevila C, Hernandez-Losa J, De Mattos-Arruda L, Ghosh A, Lorent J, Larsson O, Aasen T, Postovit LM, Topisirovic I (2017) Cancer as an ecomolecular disease and a neoplastic consortium. There are a lot of redundant genetic alterations in cellular and biological pathways. A summary of main molecular events related with intratumoral heterogeneity is shown in Table 1. Therefore, studies carried out from the perspective of systems biology [149], tailored towards the identification of hubs or other central factors in this complicated tangle of biochemical networks responsible for maintaining the tumorigenic state, will be fundamental in the identification of addictions and vulnerabilities in cancer that would otherwise be difficult to imagine [147, 164]. It is likely that combinations will be needed for most subtypes. 709-648-2163 Bassianus Herczeg. Every tumor is unique as a result of its interactions with the host and the genetic and epigenetic variability. See more ideas about choreography, dance choreography, dance. 720-543-3992 Volya Romack. PLoS One 8(8):e71189, Dotto GP (2014) Multifocal epithelial tumors and field cancerization: stroma as a primary determinant. If the genetic diversity of constitutive alterations in DNA is enormous, then at the level of the proteome, this diversity increases exponentially. Share. Importantly, molecular diagnosis based on small samples and genetic alterations can lead to a false negative diagnosis or treatment due to genetic and epigenetic changes present in a small subset of tumor cells. One mechanism by which different environmental stimuli drive such heterogeneity is by epigenetic modifications of the genome, which can persist over many cell divisions [61]. Nat Commun 6:8839, Murtaza M, Dawson SJ, Pogrebniak K, Rueda OM, Provenzano E, Grant J, Chin SF, Tsui DW, Marass F, Gale D et al (2015) Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer. The importance of such approach is highlighted by the observation of clustered populations within a tumor that differ in gene expression [133], as well as genetic composition [134]. 709-648-4543 Aden Straatmann. This heterogeneity poses a problem when trying to standardize a therapy in a specific tumor type, requiring a personalized approach based on the particular genetic alterations of the tumor, to improve the response rates to the treatment. N Engl J Med 373(20):1895–1898, Sehgal R, Sheahan K, O’Connell PR, Hanly AM, Martin ST, Winter DC (2014) Lynch syndrome: an updated review. Cell 144(5):646–674, Maddipati R, Stanger BZ (2015) Pancreatic cancer metastases harbor evidence of polyclonality. Sci Transl Med 7(283):283ra254, McGranahan N, Swanton C (2017) Clonal heterogeneity and tumor evolution: past, present, and the future. At present, approaches such as multispectral imaging of multiple proteins from a common signaling pathway allow the accessible, multiplexed elucidation of proteomic heterogeneity at the level of signal transduction [84]. Clin Cancer Res 23(2):387–398, Louis DN, Perry A, Burger P, Ellison DW, Reifenberger G, von Deimling A, Aldape K, Brat D, Collins VP, Eberhart C et al (2014) International society of neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading. Thus, targeted therapies in heterogeneous neoplasms lead to transient tumor regression and subsequent selective outgrowth of existing resistant populations, leading to recurrence in the long run. Inflammatory cytokines are another example, released by stromal or immune cells, which can alter DNA methylation and other epigenetic markers. The development of artificial intelligence algorithms with automatic learning (“deep learning”) is already shaping the field. 978-288-2326 Clean Takeshita. Share. potentially from both primary and various metastatic sites. This results in important differences between tumors from different individuals, named as intertumoral heterogeneity. Cancer Cell 21(5):655–667, Brocks D, Assenov Y, Minner S, Bogatyrova O, Simon R, Koop C, Oakes C, Zucknick M, Lipka DB, Weischenfeldt J et al (2014) Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. PLoS One 10(4):e0123352, Gerdes MJ, Sood A, Sevinsky C, Pris AD, Zavodszky MI, Ginty F (2014) Emerging understanding of multiscale tumor heterogeneity. 978-288-0701 Dillyn In. 720-543-9839 Zeke Jax. BMC Cancer 12:260, Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, Sevillano M, Palomo-Ponce S, Tauriello DV, Byrom D et al (2015) Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. One of the most characteristic examples is EGFR-driven lung adenocarcinoma in non small-cell lung cancer (NSCLC), as there have been cases of resistance associated with conversion to small-cell lung cancer (SCLC) phenotype after long-term treatment with EGFR tyrosine kinase inhibitors [22]. Intratumoral heterogeneity arises through complex genetic, epigenetic, and protein modifications that drive phenotypic selection in response to environmental pressures. Moreover, initial studies have shown that a characteristic morphological pattern could be due to specific oncogenic changes and that malignancy is dependent on the immune response [43]. Intertumor heterogeneity (also known as interlesion heterogeneity) refers to the differences found between tumors in different patients. Because cancer is a heterogeneous dynamic target, individual patients, lesions, and cell populations should be thoroughly characterized at varying times. Cancer Discov 6(3):286–299, Lohr JG, Adalsteinsson VA, Cibulskis K, Choudhury AD, Rosenberg M, Cruz-Gordillo P, Francis JM, Zhang CZ, Shalek AK, Satija R et al (2014) Whole-exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer.