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Paul Mischel

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Paul S. Mischel (born July 13, 1962) is an American physician-scientist whose laboratory has made pioneering discoveries in the pathogenesis of human cancer. He is currently a Professor and Vice Chair of Research for the Department of Pathology and Institute Scholar of ChEM-H, Stanford University.[1][2][3] Mischel was elected into the American Society for Clinical Investigation (ASCI),[4] serving as ASCI president in 2010/11. He was inducted into the Association of American Physicians, and was elected as a fellow of the American Association for the Advancement of Science.[5][6]

Career

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Mischel was born on July 13, 1962. After losing his father to cancer, he became committed to a career in cancer research. He attended the University of Pennsylvania and received his M.D. from Cornell University Medical College in 1991,[7] graduating Alpha Omega Alpha. Mischel completed residency training in Anatomic Pathology and Neuropathology at UCLA,[8] followed by post-doctoral research training with Louis Reichardt at HHMI-UCSF. Mischel joined the faculty of UCLA in 1998. In August 2012, he was recruited to the Ludwig Institute for Cancer Research, San Diego and UCSD. In 2021, he joined Stanford University School of Medicine, where he currently serves as a Professor and Vice Chair of Research for the Department of Pathology and Institute Scholar of ChEM-H.

Research

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Mischel’s work bridges cancer genetics, signal transduction and cellular metabolism in the pathogenesis of human cancer.[9]

Extrachromosomal oncogene amplification

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Mischel found that tumors can dynamically change in response to changing environments at a rate that cannot be explained by classical genetics. Prior to 2017, extrachromosomal DNA was thought to be a rare, but interesting event in cancer (1.4% of tumors),[10] of unclear biological significance. Mischel and colleagues integrated whole genome sequencing, cytogenetics and structural modeling to accurately and globally quantify extrachromosomal oncogene amplification, measure its diversity, map its contents, and study its biochemical regulation. They demonstrated widespread extrachromosomal oncogene amplification across many cancer types, showed that it potently drives tumor evolution and drug resistance, and identified specific signaling, biochemical and metabolic mechanisms that control its copy number and activity in response to changing environmental conditions.[11][12][13][14][15] This ground-breaking work challenges existing chromosomal maps of cancer, provides new insights into the mechanisms controlling the level, location and activity of amplified oncogenes, and yields new paradigms in the genotype-environment interactions that promote cancer progression and drug resistance.[16][17][18][19][20]

Metabolic co-dependency pathways in cancer

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Integrating mechanistic studies with analyses of tumor tissue from patients treated in clinical trials, Mischel and colleagues discovered signaling, transcriptional, and metabolic co-dependencies that are downstream consequences of oncogene amplification, including alterations in glucose and lipid metabolism that drive tumor growth, progression and drug resistance.[21][22][23][24][25][26][27] These studies, focused primarily on the highly lethal brain cancer, glioblastoma, resulted in new understandings of the fundamental metabolic processes by which oncogene amplification drives cancer progression and drug resistance, demonstrating a central role for EGFR and its downstream effector mTORC2, in cancer pathogenesis through metabolic reprogramming.[28][29][30][31]

Awards and honors

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Alpha Omega Alpha, Cornell University Medical College, 1991

Pfizer New Faculty Award (one in Neuroscience in United States), 1996

The Johnny Mercer Foundation Research Award, 2004

America’s Top Doctors for Cancer (Castle Connolly and U.S. News & World Report), 2006–present[7]

Farber Award (top brain tumor research award given jointly by the American Association of Neurological Surgeons and the Society for NeuroOncology), 2007[32]

American Society for Clinical Investigation, 2007[4]

Profiled by Journal of Cell Biology in the “People and Ideas” section, 2008[33]

President, American Society for Clinical Investigation, 2010–2011

Association of American Physicians, 2012

Elected Fellow, American Association for the Advancement of Science, 2015[5][6]

Personal life

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Mischel lives in La Jolla, California with his wife, Deborah Kado, a Professor of Medicine at UCSD, and his daughters Anna and Sarah.

References

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  1. ^ "Team". Paul Mischel Lab. Retrieved 2021-04-15.
  2. ^ "Paul Salomon Mischel's Profile | Stanford Profiles". profiles.stanford.edu. Retrieved 2021-04-15.
  3. ^ "Paul Mischel | ChEM-H". chemh.stanford.edu. Retrieved 2021-04-15.
  4. ^ a b "The American Society for Clinical Investigation". Retrieved 2019-01-31.
  5. ^ a b "Ludwig San Diego's Paul Mischel elected AAAS Fellow". EurekAlert!. Retrieved 2019-01-29.
  6. ^ a b "2015 AAAS Fellows Recognized for Contributions to Advancing Science". American Association for the Advancement of Science. Retrieved 2019-01-29.
  7. ^ a b "Dr. Paul Mischel, Pathologist in La Jolla, CA | US News Doctors".
  8. ^ "Faculty Database Production Server | David Geffen School of Medicine at UCLA". people.healthsciences.ucla.edu. Retrieved 2019-01-30.
  9. ^ "Paul Mischel Lab - University of California, San Diego". Paul Mischel Lab. Retrieved 2019-06-13.
  10. ^ "Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer". cgap.nci.nih.gov. Retrieved 2018-11-27.
  11. ^ Nathanson, David A.; Gini, Beatrice; Mottahedeh, Jack; Visnyei, Koppany; Koga, Tomoyuki; Gomez, German; Eskin, Ascia; Hwang, Kiwook; Mischel, Paul S. (2014-01-03). "Targeted Therapy Resistance Mediated by Dynamic Regulation of Extrachromosomal Mutant EGFR DNA". Science. 343 (6166): 72–76. Bibcode:2014Sci...343...72N. doi:10.1126/science.1241328. ISSN 0036-8075. PMC 4049335. PMID 24310612.
  12. ^ Turner, Kristen M.; Deshpande, Viraj; Beyter, Doruk; Koga, Tomoyuki; Rusert, Jessica; Lee, Catherine; Li, Bin; Arden, Karen; Mischel, Paul S. (2017-02-08). "Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity". Nature. 543 (7643): 122–125. Bibcode:2017Natur.543..122T. doi:10.1038/nature21356. ISSN 0028-0836. PMC 5334176. PMID 28178237.
  13. ^ Fikes, Bradley J. (9 February 2017). "Cancer genes hide outside chromosomes". sandiegouniontribune.com. Retrieved 2019-01-31.
  14. ^ "Non-Chromosomal DNA Drives Tumor Evolution". The Scientist Magazine®. Retrieved 2019-02-01.
  15. ^ Wu, Sihan; Turner, Kristen M.; Nguyen, Nam; Raviram, Ramya; Erb, Marcella; Santini, Jennifer; Luebeck, Jens; Rajkumar, Utkrisht; Diao, Yarui; Li, Bin; Zhang, Wenjing (November 2019). "Circular ecDNA promotes accessible chromatin and high oncogene expression". Nature. 575 (7784): 699–703. Bibcode:2019Natur.575..699W. doi:10.1038/s41586-019-1763-5. ISSN 0028-0836. PMC 7094777. PMID 31748743.
  16. ^ Furnari, Frank B.; Cloughesy, Timothy F.; Cavenee, Webster K.; Mischel, Paul S. (2015-04-09). "Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma". Nature Reviews Cancer. 15 (5): 302–310. doi:10.1038/nrc3918. ISSN 1474-175X. PMC 4875778. PMID 25855404.
  17. ^ Verhaak, Roel G. W.; Bafna, Vineet; Mischel, Paul S. (May 2019). "Extrachromosomal oncogene amplification in tumour pathogenesis and evolution". Nature Reviews Cancer. 19 (5): 283–288. doi:10.1038/s41568-019-0128-6. ISSN 1474-175X. PMC 7168519. PMID 30872802.
  18. ^ Pennisi, Elizabeth (2017-06-09). "Circular DNA throws biologists for a loop". Science. 356 (6342): 996. Bibcode:2017Sci...356..996P. doi:10.1126/science.356.6342.996. ISSN 0036-8075. PMID 28596318.
  19. ^ Aranda, Victoria (2014-01-07). "Cancer: Extrachromosomal resistance". Nature Medicine. 20: 28. doi:10.1038/nm.3452. ISSN 1546-170X. S2CID 45444065.
  20. ^ Zimmer, Carl (2019-11-20). "Scientists Are Just Beginning to Understand Mysterious DNA Circles Common in Cancer Cells". The New York Times. ISSN 0362-4331. Retrieved 2020-02-05.
  21. ^ Masui, Kenta; Tanaka, Kazuhiro; Akhavan, David; Babic, Ivan; Gini, Beatrice; Matsutani, Tomoo; Iwanami, Akio; Liu, Feng; Mischel, Paul S. (2013-11-05). "mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc". Cell Metabolism. 18 (5): 726–739. doi:10.1016/j.cmet.2013.09.013. ISSN 1932-7420. PMC 3840163. PMID 24140020.
  22. ^ Masui, Kenta; Tanaka, Kazuhiro; Ikegami, Shiro; Villa, Genaro R.; Yang, Huijun; Yong, William H.; Cloughesy, Timothy F.; Yamagata, Kanato; Mischel, Paul S. (2015-07-28). "Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance". Proceedings of the National Academy of Sciences. 112 (30): 9406–9411. Bibcode:2015PNAS..112.9406M. doi:10.1073/pnas.1511759112. ISSN 0027-8424. PMC 4522814. PMID 26170313.
  23. ^ Babic, Ivan; Anderson, Erik S.; Tanaka, Kazuhiro; Guo, Deliang; Masui, Kenta; Li, Bing; Zhu, Shaojun; Gu, Yuchao; Mishcel, Paul S. (2013-06-04). "EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer". Cell Metabolism. 17 (6): 1000–1008. doi:10.1016/j.cmet.2013.04.013. ISSN 1932-7420. PMC 3679227. PMID 23707073.
  24. ^ Gu, Yuchao; Albuquerque, Claudio P.; Braas, Daniel; Zhang, Wei; Villa, Genaro R.; Bi, Junfeng; Ikegami, Shiro; Masui, Kenta; Mischel, Paul S. (2017-07-06). "mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT". Molecular Cell. 67 (1): 128–138.e7. doi:10.1016/j.molcel.2017.05.030. ISSN 1097-4164. PMC 5521991. PMID 28648777.
  25. ^ Guo, Deliang; Reinitz, Felicia; Youssef, Mary; Hong, Cynthia; Nathanson, David; Akhavan, David; Kuga, Daisuke; Amzajerdi, Ali Nael; Mischel, Paul S. (2011-10-01). "An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR–Dependent Pathway". Cancer Discovery. 1 (5): 442–456. doi:10.1158/2159-8290.CD-11-0102. ISSN 2159-8274. PMC 3207317. PMID 22059152.
  26. ^ Chowdhry, Sudhir; Zanca, Ciro; Rajkumar, Utkrisht; Koga, Tomoyuki; Diao, Yarui; Raviram, Ramya; Liu, Feng; Turner, Kristen; Yang, Huijun; Brunk, Elizabeth; Bi, Junfeng (May 2019). "NAD metabolic dependency in cancer is shaped by gene amplification and enhancer remodelling". Nature. 569 (7757): 570–575. Bibcode:2019Natur.569..570C. doi:10.1038/s41586-019-1150-2. ISSN 0028-0836. PMC 7138021. PMID 31019297.
  27. ^ Bi, Junfeng; Ichu, Taka-Aki; Zanca, Ciro; Yang, Huijun; Zhang, Wei; Gu, Yuchao; Chowdhry, Sudhir; Reed, Alex; Ikegami, Shiro; Turner, Kristen M.; Zhang, Wenjing (September 2019). "Oncogene Amplification in Growth Factor Signaling Pathways Renders Cancers Dependent on Membrane Lipid Remodeling". Cell Metabolism. 30 (3): 525–538.e8. doi:10.1016/j.cmet.2019.06.014. PMC 6742496. PMID 31303424.
  28. ^ Masui, Kenta; Cavenee, Webster K.; Mischel, Paul S. (2014-07-25). "mTORC2 in the center of cancer metabolic reprogramming". Trends in Endocrinology and Metabolism. 25 (7): 364–373. doi:10.1016/j.tem.2014.04.002. ISSN 1879-3061. PMC 4077930. PMID 24856037.
  29. ^ Wu, Si-Han; Bi, Jun-Feng; Cloughesy, Timothy; Cavenee, Webster K.; Mischel, Paul S. (2014). "Emerging function of mTORC2 as a core regulator in glioblastoma: metabolic reprogramming and drug resistance". Cancer Biology & Medicine. 11 (4): 255–263. doi:10.7497/j.issn.2095-3941.2014.04.004. ISSN 2095-3941. PMC 4296088. PMID 25610711.
  30. ^ Bi, Junfeng; Wu, Sihan; Zhang, Wenjing; Mischel, Paul S. (2018-05-23). "Targeting cancer's metabolic co-dependencies: A landscape shaped by genotype and tissue context". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1870 (1): 76–87. doi:10.1016/j.bbcan.2018.05.002. ISSN 1879-2561. PMC 6193564. PMID 29775654.
  31. ^ Bi, Junfeng; Chowdhry, Sudhir; Wu, Sihan; Zhang, Wenjing; Masui, Kenta; Mischel, Paul S. (January 2020). "Altered cellular metabolism in gliomas — an emerging landscape of actionable co-dependency targets". Nature Reviews Cancer. 20 (1): 57–70. doi:10.1038/s41568-019-0226-5. ISSN 1474-1768. PMID 31806884. S2CID 208768689.
  32. ^ "SNO Awards". www.soc-neuro-onc.org. Retrieved 2019-01-31.
  33. ^ Williams, Ruth (2008-06-30). "Paul Mischel: All about brains". The Journal of Cell Biology. 181 (7): 1044–1045. doi:10.1083/jcb.1817pi. ISSN 0021-9525. PMC 2442209. PMID 18591424.
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