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]

Contents

Career

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

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

Extrachromosomal oncogene amplification

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

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

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

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

Related Research Articles

<span class="mw-page-title-main">Tumor hypoxia</span> Situation where tumor cells have been deprived of oxygen

Tumor hypoxia is the situation where tumor cells have been deprived of oxygen. As a tumor grows, it rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Hypoxic microenvironements in solid tumors are a result of available oxygen being consumed within 70 to 150 μm of tumour vasculature by rapidly proliferating tumor cells thus limiting the amount of oxygen available to diffuse further into the tumor tissue. In order to support continuous growth and proliferation in challenging hypoxic environments, cancer cells are found to alter their metabolism. Furthermore, hypoxia is known to change cell behavior and is associated with extracellular matrix remodeling and increased migratory and metastatic behavior.

<span class="mw-page-title-main">Glioblastoma</span> Aggressive type of brain cancer

Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke. Symptoms often worsen rapidly and may progress to unconsciousness.

In oncology, the Warburg effect is the observation that most cancer cells release energy predominantly not through the 'usual' citric acid cycle and oxidative phosphorylation in the mitochondria as observed in normal cells, but through a less efficient process of 'aerobic glycolysis' consisting of a high level of glucose uptake and glycolysis followed by lactic acid fermentation taking place in the cytosol, not the mitochondria, even in the presence of abundant oxygen. This observation was first published by Otto Heinrich Warburg, who was awarded the 1931 Nobel Prize in Physiology for his "discovery of the nature and mode of action of the respiratory enzyme". The precise mechanism and therapeutic implications of the Warburg effect, however, remain unclear.

<span class="mw-page-title-main">Epidermal growth factor receptor</span> Transmembrane protein

The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.

Double minutes are small fragments of extrachromosomal DNA, which have been observed in a large number of human tumors including breast, lung, ovary, colon, and most notably, neuroblastoma. They are a manifestation of gene amplification as a result of chromothripsis, during the development of tumors, which give the cells selective advantages for growth and survival. This selective advantage is as a result of double minutes frequently harboring amplified oncogenes and genes involved in drug resistance. DMs, like actual chromosomes, are composed of chromatin and replicate in the nucleus of the cell during cell division. Unlike typical chromosomes, they are composed of circular fragments of DNA, up to only a few million base pairs in size, and contain no centromere or telomere. Further to this, they often lack key regulatory elements, allowing genes to be constitutively expressed. The term ecDNA may be used to refer to DMs in a more general manner.

<span class="mw-page-title-main">HER2</span> Mammalian protein found in humans

Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 or CD340.

<span class="mw-page-title-main">Targeted therapy</span> Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

Extrachromosomal DNA is any DNA that is found off the chromosomes, either inside or outside the nucleus of a cell. Most DNA in an individual genome is found in chromosomes contained in the nucleus. Multiple forms of extrachromosomal DNA exist, and, while some of these serve important biological functions, they can also play a role in diseases such as cancer.

<span class="mw-page-title-main">Tumor metabolome</span>

The study of the tumor metabolism, also known as tumor metabolome describes the different characteristic metabolic changes in tumor cells. The characteristic attributes of the tumor metabolome are high glycolytic enzyme activities, the expression of the pyruvate kinase isoenzyme type M2, increased channeling of glucose carbons into synthetic processes, such as nucleic acid, amino acid and phospholipid synthesis, a high rate of pyrimidine and purine de novo synthesis, a low ratio of Adenosine triphosphate and Guanosine triphosphate to Cytidine triphosphate and Uridine triphosphate, low Adenosine monophosphate levels, high glutaminolytic capacities, release of immunosuppressive substances and dependency on methionine.

<span class="mw-page-title-main">Warburg hypothesis</span> Hypothesis explaining cancer

The Warburg hypothesis, sometimes known as the Warburg theory of cancer, postulates that the driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria. The term Warburg effect in oncology describes the observation that cancer cells, and many cells grown in vitro, exhibit glucose fermentation even when enough oxygen is present to properly respire. In other words, instead of fully respiring in the presence of adequate oxygen, cancer cells ferment. The Warburg hypothesis was that the Warburg effect was the root cause of cancer. The current popular opinion is that cancer cells ferment glucose while keeping up the same level of respiration that was present before the process of carcinogenesis, and thus the Warburg effect would be defined as the observation that cancer cells exhibit glycolysis with lactate production and mitochondrial respiration even in the presence of oxygen.

<span class="mw-page-title-main">KRAS</span> Protein-coding gene in humans

KRAS is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). It is called KRAS because it was first identified as a viral oncogene in the KirstenRAt Sarcoma virus. The oncogene identified was derived from a cellular genome, so KRAS, when found in a cellular genome, is called a proto-oncogene.

The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

<span class="mw-page-title-main">ERBB3</span> Protein found in humans

Receptor tyrosine-protein kinase erbB-3, also known as HER3, is a membrane bound protein that in humans is encoded by the ERBB3 gene.

<span class="mw-page-title-main">ROS1</span> Protein-coding gene in the species Homo sapiens

Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 gene.

<span class="mw-page-title-main">RICTOR</span> Protein-coding gene in the species Homo sapiens

Rapamycin-insensitive companion of mammalian target of rapamycin (RICTOR) is a protein that in humans is encoded by the RICTOR gene.

<span class="mw-page-title-main">LAPTM4B</span> Protein-coding gene in the species Homo sapiens

Lysosomal-associated transmembrane protein 4B is a protein that in humans is encoded by the LAPTM4B gene.

<span class="mw-page-title-main">Neratinib</span> Chemical compound

Neratinib (INN), sold under the brand name Nerlynx, is a tyrosine kinase inhibitor anti-cancer medication used for the treatment of breast cancer.

mTOR Complex 2 (mTORC2) is an acutely rapamycin-insensitive protein complex formed by serine/threonine kinase mTOR that regulates cell proliferation and survival, cell migration and cytoskeletal remodeling. The complex itself is rather large, consisting of seven protein subunits. The catalytic mTOR subunit, DEP domain containing mTOR-interacting protein (DEPTOR), mammalian lethal with sec-13 protein 8, and TTI1/TEL2 complex are shared by both mTORC2 and mTORC1. Rapamycin-insensitive companion of mTOR (RICTOR), mammalian stress-activated protein kinase interacting protein 1 (mSIN1), and protein observed with rictor 1 and 2 (Protor1/2) can only be found in mTORC2. Rictor has been shown to be the scaffold protein for substrate binding to mTORC2.

Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies. In some cases, cancers can evolve resistance to multiple drugs, called multiple drug resistance.

Extrachromosomal circular DNA (eccDNA) is a type of double-stranded circular DNA structure that was first discovered in 1964 by Alix Bassel and Yasuo Hotta. In contrast to previously identified circular DNA structures, eccDNA are circular DNA found in the eukaryotic nuclei of plant and animal cells. Extrachromosomal circular DNA is derived from chromosomal DNA, can range in size from 50 base pairs to several mega-base pairs in length, and can encode regulatory elements and full-length genes. eccDNA has been observed in various eukaryotic species and it is proposed to be a byproduct of programmed DNA recombination events, such as V(D)J recombination.

References

  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. 1 2 "The American Society for Clinical Investigation" . Retrieved 2019-01-31.
  5. 1 2 "Ludwig San Diego's Paul Mischel elected AAAS Fellow". EurekAlert!. Retrieved 2019-01-29.
  6. 1 2 "2015 AAAS Fellows Recognized for Contributions to Advancing Science". American Association for the Advancement of Science. Retrieved 2019-01-29.
  7. 1 2 "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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