MICaB Course Information

MICa 8004 - Biology of Cancer

Syllabus for MICa 8004 (4 credits)
Spring Semester 2010
MWThF, 9:05-9:55 am
2-120 MCB

Course Coordinator, James McCarthy
2-184 Moos Tower
625-7454
mccar001@tc.umn.edu

The structure of the course is as follows: It is split into distinct topic areas that will be taught by experts in each area. There are 10 subject areas each consisting of 5-7 lecture periods. The lecture periods will include
overviews that are didactic in nature and come from either the required textbook (Weinberg, Cancer Biology), or a recommended text (Bunz, Principles of Cancer Genetics, Springer, copyright 2008 ISBN
978-1-4020-6783-9), or appropriate reviews. The classes will also include a discussion of original research papers that the students in which the students will actively participate..
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The overall objective is to familiarize students with current concepts of cancer initiation, progression, metastasis and therapy.

The course has several specific objectives which include more detailed discussions of:
a. Genetics of cancer
b. Regulation of tumor progression by translational and transcriptional mechanisms
c. Dysregulation of signal transduction pathways important for growth and survival
d. Mechanisms of hormonal control in hormonally dependent tumors
e. Importance of the tumor microenvironment in tumor formation and progression
f. Mechanisms of tumor cell survival that facilitate therapeutic resistance
g. Concepts in tumor immunology that are currently being considered in therapy
h. Identification and use of tumor biomarkers
i . Emerging therapies in cancer

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The required text is Weinberg, Cancer Biology. We decided it might be considered a financial burden to require too many texts for the course, but I strongly recommend you consider purchasing the Principles of Cancer Genetics book. It is available from the following link: It is available from Amazon.com with free 2 day shipping and no tax for approximately $79.00. This is a 20% discount over the list price.

http://www.amazon.com/s?ie=UTF8&search-type=ss&index=books&field-author=Fred%20Bunz&page=1


You will find this text is an excellent source not only for Cancer Biology, but it also covers basics for genetics in general to put the Genetics of Cancer into the appropriate context.
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Examinations in the course will be as follows:
1. There will be an in class quiz administered by each instructor that will cover some of the basic concepts of the topic. The quiz will be short answer in nature and worth a total of 20 possible points.
2. There will also be a take home question given by each instructor handed out at the end of each section. This will be worth 50 points. This question will be designed to give you an opportunity to synthesize
information presented during the discussions and/or design experiments to address specific problems.
Therefore, the point total for the course, will be a possible 700 points. There will be no midterm or final exam.
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The exams are handled electronically. The instructors will send out a take home question by e-mail on the last day of their section and you will send it back to the appropriate instructor by e-mail. You will have one week to complete the take home exam from each instructor.Their e-mail addresses are as follows:

David Largaespada (larga002@umn.edu)
Timothy Starr (star0044@umn.edu)
Simona Ognjanovic (ognja001@umn.edu)
Peter Bitterman (bitte001@umn.edu)
Vitaly Polunovsky (polun001@umn.edu)
Amy P.N. Skubitz (skubi002@umn.edu)
Scott Dehm (dehm@umn.edu)
James McCarthy (mccar001@umn.edu)
Carol Lange (lange047@umn.edu)
Haojie Huang (huang253@umn.edu)
Ameeta Kelekar (ameeta@umn.edu)
Chris Pennell (penne001@umn.edu)
Deepali Sachdev (sachd003@umn.edu)
Doug Yee (yeexx006@umn.edu)

Exams will be turned in to each investigator by using their specific e-mail address.

The class will also have a list serve that will include the registered students, me (mccar001@umn.edu), Louise Shand (shand@umn.edu; MICaB Executive Assistant) and the entire faculty teaching the course.

Faculty will use this e-mail address (mica8004-list@lists.umn.edu) to contact the entire class, and students can ask specific questions via this list serve on concepts discussed, questions about exams, etc.The list serve will be used by faculty to answer these questions so that everyone may benefit from the discussion/questions.
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January 20, 21, 22, 25, 27, 28
Section 1: David Largaespada: Genetics of Cancer

Weds., Jan. 20th. Lecture 1: Nature of Cancer, Genetic Theory of Cancer

Dr. Timothy Starr, Ph.D., starr0044@umn.edu
Assigned Reading:
Review Weinberg Chapters 1 and 2

Thurs., Jan. 21st. Lecture 2: Methods Used to Study Cancer - including Mouse Genetics in Cancer Research
Dr. David Largaespada, Ph.D., larga002@umn.edu
Assigned Reading:
• Weinberg Chapter 4 (pp 91-108) and 11
• Olive KP, Tuveson DA. The use of targeted mouse models for preclinical testing of novel cancer therapeutics. Clin Cancer Res. 2006 Sep 15;12(18):5277-87.
• Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, Madhu B, Goldgraben MA, Caldwell ME, Allard D, Frese KK, Denicola G, Feig C, Combs C, Winter SP, Ireland-Zecchini H, Reichelt S, Howat WJ, Chang A, Dhara M, Wang L, Rückert F, Grützmann R, Pilarsky C, Izeradjene K, Hingorani SR, Huang P, Davies SE, Plunkett W, Egorin M, Hruban RH, Whitebread N, McGovern K, Adams J, Iacobuzio-Donahue C, Griffiths J, Tuveson DA. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009 Jun 12;324(5933):1457-61..

Fri, Jan 22nd. Lecture 3: Inherited Cancer Predispostion: Li-Fraumeni Syndrome
Dr. Simona Ognjanovic, Ph.D., ognja001@umn.edu
Assigned Reading:
• Weinberg Chapter 9, pp 307-333
• Palmero EI, Achatz MI, Ashton-Prolla P, Olivier M, Hainaut P. Tumor protein 53 mutations and inherited cancer: beyond Li-Fraumeni syndrome. Curr Opin Oncol. 2010 Jan;22(1):64-9.
• Tinat J, Bougeard G, Baert-Desurmont S, Vasseur S, Martin C, Bouvignies E, Caron O, Bressac-de Paillerets B, Berthet P, Dugast C, Bonaïti-Pellié C, Stoppa-Lyonnet D, Frébourg T. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol. 2009 Sep 10;27(26):e108-9. PMID: 19652052 [PubMed - indexed for MED
• Bougeard G, Sesboüé R, Baert-Desurmont S, Vasseur S, Martin C, Tinat J, Brugières L, Chompret A, de Paillerets BB, Stoppa-Lyonnet D, Bonaïti-Pellié C, Frébourg T; French LFS working group.Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet. 2008 Aug;45(8):535-8. PMID: 18511570

Mon., Jan. 25th. Lecture 4: Telomeres, Immortality, and Chromosome Instability
Dr. David Largaespada, Ph.D., larga002@umn.edu
Assigned Reading:
• Weinberg Chapter 10
• Artandi SE, Chang S, Lee SL, Alson S, Gottlieb GJ, Chin L, DePinho RA. “Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice.” Nature. 406:641-5. 2000

Weds., Jan 27th. Lecture 5: The PI3K - mTor pathway and cancer chemotherapy resistance
Dr. David Largaespada, Ph.D., larga002@umn.edu
• Weinberg Chapter 6.6, pp 176-184
• Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S, Cordon-Cardo C, Pelletier J, Lowe SW. “Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy.” Nature. 2004. 428:332-7.

Thurs., Jan 28th. Lecture 6: The Human Cancer Genome Project, In Class Quiz and Take Home Exam
Dr. David Largaespada, Ph.D., larga002@umn.edu
Assigned Reading
• Weinberg Chapter 11 (review it)
• Hanahan D and Weinberg RA. The hallmarks of cancer. Cell 100:57-70. (2000).
• Futreal et al., A census of human cancer genes. Nature Reviews Cancer 4:177-183 (2004)
• Wood LD, Parsons DW, Jones S, et al. The genomic landscapes of human breast and colorectal cancers. Science, 318(5853):1108-13. (2007).
• Ley TJ, Mardis ER, Ding L, Fulton B, McLellan MD, Chen K, Dooling D, Dunford-Shore BH, McGrath S, Hickenbotham M, Cook L, Abbott R, Larson DE, Koboldt DC, Pohl C, Smith S, Hawkins A, Abbott S, Locke D, Hillier LW, Miner T, Fulton L, Magrini V, Wylie T, Glasscock J, Conyers J, Sander N, Shi X, Osborne JR, Minx P, Gordon D, Chinwalla A, Zhao Y, Ries RE, Payton JE, Westervelt P, Tomasson MH, Watson M, Baty J, Ivanovich J, Heath S, Shannon WD, Nagarajan R, Walter MJ, Link DC, Graubert TA, DiPersio JF, Wilson RK. DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome. Nature. 2008 Nov 6;456(7218):66-72. PMID: 18987736

Plus In Class Quiz Today (20 points) and distribution of first take home exam (50 points)

January 29, February 1, 3, 4, 5, 8
Section 2: Vitaly Polunovsky/Peter Bitterman: Translational Control of Tumor Growth


Fri Jan 29 – Didactic - Everything you ever wanted to know about cancer in 50 minutes or less…
- assigned reading: Weinberg: chapters 4 and 7
Bitterman lecture 1

Mon Feb 1 - TUMOR SUPPRESSOR DISCOVERY
- assigned reading:
1. Harris, Miller, Klein, Worst, Tachibana. Suppression of Malignancy by Cell Fusion
Nature, Vol. 223, 1969, p363. pdf
2. Murphree AL and Benedict WF. Retinoblastoma: Clues to human oncogenesis. Science
Vol 223, 1984 p1028 pdf

Wed Feb 3 – RAS, THE ARCHTYPE ONCOGENE
- assigned reading: Chin L, Tam A, Pomerantz J, Wong M, Holash J, Bardeesy N, Shen Q,
O'Hagan R, Pantginis J, Zhou H, Horner JW 2nd, Cordon-Cardo C, Yancopoulos GD, DePinho
RA. Essential role for oncogenic Ras in tumour maintenance. Nature. 1999 Jul 29;
400(6743):468-72. pdf

Thurs Feb 4
– Didactic - TRANSLATIONAL CONTROL OF CANCER
- assigned reading:
- Jackson, RJ, Hellen C, Pestova T. The mechanism of eukaryotic translation initiation and
principles of its regulation. Moll Cell Biol. 2010 Feb; 10(2),113- 127
- Sonenberg N. eIF4E, the mRNA cap-binding protein: from basic discovery to translational
research. Biochem Cell Biol. 2008 Apr; 86 (2):178-83.
- Polunovsky VA and Bitterman PB. The cap-dependent translational apparatus integrates and
amplifies cancer pathways. RNA Biology 2006;3:10-17

Fri Feb 5
– TRANSLATIONAL CONTROL OF CANCER
- assigned reading: Avdulov S, Li S, Michalek V, Burrichter D, Peterson M, Perlman DM,
Manivel JC, Sonenberg N, Yee D, Bitterman PB, Polunovsky VA. Activation of translation
complex eIF4F is essential for the genesis and maintenance of the malignant phenotype in
human mammary epithelial cells. Cancer Cell. 2004 Jun; 5(6):553-63.

Mon Feb 8 – REPRESSORS OF THE TRANSLATION INITIATION MACHINERY AS COLLABORATORS WITH P53 IN TUMOR SUPPRESSION.
- assigned reading: Petroulakis E, Parsyan A, Dowling RJ, LeBacquer O, Martineau Y,
Bidinosti M, Larsson O, Alain T, Rong L, Mamane Y, Paquet M, Furic L, Topisirovic I,
Shahbazian D, Livingstone M, Costa-Mattioli M, Teodoro JG, Sonenberg N. p53-dependent
translational control of senescence and transformation via 4E-BPs. Cancer Cell. 2009 Nov
6;16(5):439-46. PubMed PMID: 19878875.

February 10- February 18
Section 3: Scott Dehm: Transcriptional Control of Tumor Growth

Feb 10,11,12,15,17,18, Scott Dehm
Wednesday, February 10:
This will be the first of two didactic lectures for this section, providing a broad overview of the mechanisms of eukaryotic transcriptional control. Key structure/function relationships of genes, chromatin, promoters, enhancers, transcription factors, coregulators, and components of the basal transcriptional apparatus will be discussed. The role of microRNAs in gene expression will also be covered. These concepts will lay the foundation for lectures 3-6, where we will discuss specific research articles that illustrate how these processes can go awry in cancer cells.
Required Reading:
1. Weinberg Chapters 1.7 & 1.8
2. Maston GA. Transcriptional Regulatory Elements in the Human Genome. Annu Rev. Genom. Human Genet. (2006) 7: 29-59. PMID 16719718
3. Chromatin Modifications and Their Function. Cell (2007) 128: 693-705. PMID 17320507
Recommended Reading:
1. Kadonaga JT. Regulation of RNA Polymerase II Transcription by Sequence-Specific DNA Binding Factors. Cell (2004) 116: 247-257. PMID 14744435.
2. Ruthenburg AJ. Multivalent Engagement of Chromatin Modifications by Linked Binding Modules. Nature Reviews Molecular Cell Biology (2007) 8: 983-994. PMID 18037899

Thursday, February 11:
This will be the second and final didactic lecture in this section. We will discuss molecular strategies and techniques for studying eukaryotic transcriptional regulation (and de-regulation) in normal and cancer cells. These concepts will facilitate and enhance comprehension of the research articles that will be discussed during lectures 3-6.
Required Reading:
1. Kim TH. Genome-Wide Analysis of Protein-DNA Interactions. Annu. Rev. Genom. Human Genet. (2006) 7: 81-102. PMID 16722805.
2. We will continue discussing both the required and recommended reading material for the February 10 lecture.
Friday, February 12:
This will be the first of four journal club-style discussions of the primary scientific literature. Students will be called upon to present specific figures and are expected to summarize approaches, rationale, findings, and significance of the data. In our first lecture, we will discuss an article that identifies a small-molecule inhibitor for the Ews-Fli1 translocation-generated transcription factor fusion. EWS-ETS fusions are the underlying cause of highly malignant Ewing family tumors, and this paper challenges the prevailing thought that such transcription factors are an “undruggable” class of oncogenes.
Required Reading:
Erkizan HV et al. A small molecule blocking oncogenic protein EWS-FLI interaction with RNA helicase A inhibits growth of Ewing’s sarcoma. Nature Medicine (2009) 15: 750-757. PMID 19584866
*please note that there is supplemental data for this paper. These supplemental figures and tables are recommended reading.

Monday, February 15:
During our second of four journal club-style lectures, we will continue our discussion of the role of EWS-ETS fusions in the biology of Ewing family tumors. The article we will discuss identifies the histone methyltransferase EZH2 as a downstream transcriptional target of the EWS-Fli1 fusion. EZH2 is a key regulator of stem cell self-renewal and differentiation. In cancer cells, EZH2 is frequently overexpressed and is correlated with cancer aggressiveness.
Required Reading:
Richter GHS et al. EZH2 is a mediator of EWS/FLI1 driven tumor growth and metastasis blocking endothelial and neuro-ectodermal differentiation. PNAS (2009) 106: 5324-5329. PMID 19289832
*please note that there is supplemental data for this paper. These supplemental figures and tables are recommended reading.

Wednesday, February 17:
During our third of four journal club-style lectures, we will discuss an article that discovers a novel gene fusion involving the promoter region of the androgen-regulated TMPRSS2 gene and the coding region of ETS transcription factor family members. The authors demonstrate that TMPRSS2-ETS fusions are common and early events in prostate cancer.
Required Reading:
Tomlins SA et al. Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer. Science (2005) 310: 644-648. PMID: 16254181
*please note that there is supplemental data for this paper. These supplemental figures and tables are recommended reading.

Thursday, February 18:
During our fourth and final journal club-style lecture, we will discuss an article that identifies hCAS/CSE1L as a novel co-activator for a well-known transcription factor, the p53 tumor suppressor. This article further describes the mechanisms by which hCAS influences the p53 mediated decision of whether a cell with DNA damage will undergo growth arrest or apoptosis.
Required Reading:
Tanaka T et al. hCAS/CSE1L Associates with Chromatin and Regulates Expression of Select p53 Target Genes. Cell (2007) 130: 638-650. PMID: 17719542.
*please note that there is supplemental data for this paper. These supplemental figures and tables are recommended reading.
**there is a nice minireview of this article in the Leading Edge section of this Cell issue that details the significance of these findings (Aylon Y and Oren M. Living with p53, Dying of p53. Cell (2007) 130: 597-600. PMID: 17719538)

Information on Examinations:
A short (10 minute) in-class quiz, worth a total of 20 points, will be administered at thebeginning of class on Monday, February 15. This quiz will encompass material covered during lectures 1 and 2. There will be no access to notes, textbooks, or any other material during this quiz.

A take home exam, worth a total of 50 points, will be sent to students via e-mail by Friday, February 19. Exams must be returned to Scott Dehm via e-mail (dehm@umn.edu) by Friday, February 26.

February 19- March 1
Section 4: Haojie Huang: Hormone Action and Cancer Growth

19,22,24,25,26 Mar 1, Haojie Huang

In-class quiz (20 points)
The exact date for in-class quiz has not been decided yet.

Take home exam (50 points)
Home exam will be sent out by email after the March 1 class. Answers must be returned to Haojie Huang by email (huang253@umn.edu) no later than 5 pm March 8, 2010.

Friday, February 19 – Lecture
Androgens, estrogens and the basic function of their receptors
Additional reading:
1. Weinberg Chapter 2: The nature of cancer.
2. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70.
3. Glass CK, Rosenfeld MG. The coregulator exchange in transcriptional functionsof nuclear receptors. Genes Dev. 2000 Jan 15;14(2):121-41.
4. Heemers HV, Tindall DJ. Androgen receptor coregulators: a diversity of functions converging on and regulating the androgen receptor transcriptional complex. Endocr Rev. 28: 778-808, 2007.

Monday, February 22 – Lecture
Therapy/endocrine resistance in breast and prostate cancer
Additional reading:
1. Feldman BJ and Feldman D. The development of androgen-independent prostate cancer. Nature Rev Cancer, 1: 34-45, 2001.
2. Denmeade SR, Isaacs JT. A history of prostate cancer treatment. Nat Rev Cancer. 2:3 89-96, 2002.
3. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. 23: 8253-61, 2005.
4. Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009 Sep;9(9):631-43.
5. Risbridger GP, Davis ID, Birrell SN, Tilley WD. Breast and prostate cancer: more
similar than different. Nat Rev Cancer. 2010 Feb 11.

Wednesday, February 24 - Paper discussion
Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, Sawyers CL. Molecular determinants of resistance to antiandrogen therapy. Nature Medicine 10: 33-9, 2004.

Thursday, February 25 - Paper discussion
Xin L, Teitell MA, Lawson DA, Kwon A, Mellinghoff IK, Witte ON. Progression of prostate cancer by synergy of AKT with genotropic and nongenotropic actions of the androgen receptor. Proc Natl Acad Sci U S A. 2006 May 16;103(20):7789-94.

Friday, February 26 - Paper discussion
Hurtado A, Holmes KA, Geistlinger TR, Hutcheson IR, Nicholson RI, Brown M, Jiang J, Howat WJ, Ali S, Carroll JS. Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. Nature. 2008 Dec 4;456(7222):663-6.

Monday, March 1 -Paper discussion
Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs. Science.
2002 Mar 29;295(5564):2465-8.

March 3-March 11
Section 5: Carol Lang: Signal Transduction in Tumors

Mar 3,4,5,8,10,11, Carol Lange

LANGE Lectures/ Required Reading:

*Please use the textbook as a general point of reference for background to signaling. Topics of interest include mechanisms of growth factor tyrosine kinase receptor (EGFR family members) signaling and regulation of downstream protein kinase cascades (MAPKs and PI3K/Akt). The context for this section is the role of these regulatory molecules in cancer biology.

There will be a Quiz (March 4, 5, 8, 10, or 11)

MARCH 3rd: Lecture: MAPK pathway and signaling specificity

1. Ferrell JE Jr. What do scaffold proteins really do? Sci STKE. 2000 Oct 3;2000 (52):PE1. Review.

2. Ubersax JA and Ferrell JE Jr. Mechanisms of specificity in protein phosphorylation. Nature Reviews 530-541 (2007).

3. Anjum R and Blenis J. The RSK family of kinases: emerging roles in cellular signaling. Nature Reviews Molecular Cell Biology 9 747-758 (2008).

MARCH 4th: (Ras signaling specificity in cancer biology)
(Discuss Gupta paper (item #5) in class.)

4. AR Ramjaun and J Downward. Ras and Phosphoinositide 3-Kinase: Partners in Development and Tumorigenesis. Cell Cycle 6:23, 2902-2905, 2007

5. S Gupta et. al (Julian Downward lab). Binding of Ras to PI3K p110a is required for Ras-driven tumorigenesis in mice. Cell 129: 957-968, 2007.

MARCH 5th:  Translating the strength and duration (i.e. specificity) of the signal into changes in cell biology.
(Discuss Blenis Lab research papers (#7 & 8) in good detail in Class)

6. L. Murphy, J. Blenis. MAPK signal specificity: the right place at the right time. Trends in Biochemical Sciences, Volume 31, Issue 5, Pages 268-275 (2006).

7. Leon O. Murphy, Sallie Smith, Rey-Huei Chen, Diane C. Fingar & John Blenis. Molecular interpretation of ERK signal duration by immediate early gene products Nature Cell Biology  4, 556 - 564 (2002)

8. Murphy LO, MacKeigan JP, Blenis J. A network of immediate early gene products propagates subtle differences in mitogen-activated protein kinase signal amplitude and duration. Mol Cell Biol. 2004 Jan;24(1):144-53.

MARCH 8th: Lecture: Signaling Kinetics: What can a 3-kinase cascade do?

(MAP Kinase primary literature on kinetic modeling of a 3-kinase cascade)
9. Huang CY, Ferrell JE Jr. Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10078-83.

MARCH 10th: Nucleo-cytoplasmic transport in signaling (yet another mechanism of signaling specificity…)
(Discuss Yoon et. al paper (item #12) in class)

10. James E. Ferrell, Jr. How regulated protein translocation can produce switch-like responses. TIBS 23: 461-465, 1998.

11. Chahine MN, Pierce GN. Therapeutic targeting of nuclear protein import in pathological cell conditions. Pharmacol Rev. 2009 Sep;61(3):358-72. Review. (Good background and relevance to cancer therapy)

12. Yoon S-O et. al (Blenis lab). Ran-binding protein 3 phosphorylation links the Ras and PI3-Kinase pathways to nucleocytoplasmic transport. Mol Cell 29: 362-375 (2008).

MARCH 11th: Outside the Dog(ma) House: Nuclear Actions of Membrane Receptors?
(Discuss both papers 13 & 14 in class)
Wrap Up – General Questions

13. S-C Wang and M-C Hung. Nuclear Translocation of the Epidermal Growth Factor Receptor Family Membrane Tyrosine Kinase Receptors. Clinical Cancer Research 15(21):6484-9 (2009 Review).

14. S-C Wang et. al. Binding at and transactivation of the COX-2 promoter by nuclear tyrosine kinase receptor ErbB-2. Cancer Cell. Vol 6(3): 251-261 (2004).

March 12-29
Section 6: Jim McCarthy: Tumor microenvironment
March 12, 22,24,25,26,29

March 12
Weinberg:
Chapter 13 Dialogue Replaces Monologue: Heterotypic Interactions and the Biology of Angiogenesis. Pp. 527-586
 
Chapter 14: Moving Out: Invasion and Metastasis. Pp. 587-654.

March 22 - 29: The articles in bold: Each group is to present in detail. The other articles are for your use if need be.

3/22 Group 1 Embyronic Properties of Microenvironment

Topczewska, J. M., L. M. Postovit, N. V. Margaryan, A. Sam, A. R. Hess, W. W. Wheaton, B. J. Nickoloff, J. Topczewski and M. J. Hendrix (2006). "Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness." Nat Med 12(8): 925-32.
Pierce, G. B., C. G. Pantazis, J. E. Caldwell and R. S. Wells (1982). "Specificity of the control of tumor formation by the blastocyst." Cancer Res 42(3): 1082-7.
Mintz, B. and K. Illmensee (1975). "Normal genetically mosaic mice produced from malignant teratocarcinoma cells." Proc Natl Acad Sci U S A 72(9): 3585-9.

3/24 Group 2 Tumor Promoting Properties of Tumor Reactive Stroma

Ao, M., O. E. Franco, D. Park, D. Raman, K. Williams and S. W. Hayward (2007). "Cross-talk between paracrine-acting cytokine and chemokine pathways promotes malignancy in benign human prostatic epithelium." Cancer Res 67(9): 4244-53.
Hayward, S. W., Y. Wang, M. Cao, Y. K. Hom, B. Zhang, G. D. Grossfeld, D. Sudilovsky and G. R. Cunha (2001). "Malignant transformation in a nontumorigenic human prostatic epithelial cell line." Cancer Res 61(22): 8135-42.

3/25 Group 3 Hyaluronan in Tumor Reactive Stroma and Tumor Progression

Bharadwaj, A. G., J. L. Kovar, E. Loughman, C. Elowsky, G. G. Oakley and M. A. Simpson (2009). "Spontaneous metastasis of prostate cancer is promoted by excess hyaluronan synthesis and processing." Am J Pathol 174(3): 1027-36.
Tuxhorn, J. A., G. E. Ayala, M. J. Smith, V. C. Smith, T. D. Dang and D. R. Rowley (2002). "Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling." Clin Cancer Res 8(9): 2912-23.
Posey, J. T., M. S. Soloway, S. Ekici, M. Sofer, F. Civantos, R. C. Duncan and V. B. Lokeshwar (2003). "Evaluation of the prognostic potential of hyaluronic acid and hyaluronidase (HYAL1) for prostate cancer." Cancer Res 63(10): 2638-44.

3/26 Group 4 Source of Tumor Reactive Stromal Cells

Mishra, P. J., R. Humeniuk, D. J. Medina, G. Alexe, J. P. Mesirov, S. Ganesan, J. W. Glod and D. Banerjee (2008). "Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells." Cancer Res 68(11): 4331-9.
Tuxhorn, J. A., G. E. Ayala, M. J. Smith, V. C. Smith, T. D. Dang and D. R. Rowley (2002). "Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling." Clin Cancer Res 8(9): 2912-23.

3/29 Group 5 The Pre-Metastatic Niche – Specialized Microenvironment for Metastasis?

Kaplan, R. N., R. D. Riba, S. Zacharoulis, A. H. Bramley, L. Vincent, C. Costa, D. D. MacDonald, D. K. Jin, K. Shido, S. A. Kerns, Z. Zhu, D. Hicklin, Y. Wu, J. L. Port, N. Altorki, E. R. Port, D. Ruggero, S. V. Shmelkov, K. K. Jensen, S. Rafii and D. Lyden (2005). "VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche." Nature 438(7069): 820-7.
Geiger, T. R. and D. S. Peeper (2009). "Metastasis mechanisms." Biochim Biophys Acta 1796(2): 293-308.

March 31-April 8
Section 7: Ameeta Keleka: Apoptosis and Autophagy in Tumors

Mar 31 Apr 1,2,4,7,8 Ameeta Kelekar

Apoptosis (Didactic Lectures) March 31, April 1
Required Reading
1. Chipuk, J.E., T. Moldoveanu, F. Llambi, M.J. Parsons, and D.R. Green, The BCL-2 family reunion. Mol Cell. 37(3): p. 299-310.

2. Youle, R.J. and A. Strasser, The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol, 2008. 9(1): p. 47-59.

3. Guicciardi, M.E. and G.J. Gores, Life and death by death receptors. Faseb J, 2009. 23(6): p. 1625-1637.

Optional Reading - Weinberg Chapter 9, Pages 325 -356
Article for Discussion, Friday, April 2

Kolluri, S.K., X. Zhu, X. Zhou, B. Lin, Y. Chen, K. Sun, X. Tian, J. Town, X. Cao, F. Lin, D. Zhai, S. Kitada, F. Luciano, E. O'Donnell, Y. Cao, F. He, J. Lin, J.C. Reed, A.C. Satterthwait, and X.K. Zhang, A short Nur77-derived peptide converts Bcl-2 from a protector to a killer. Cancer Cell, 2008. 14(4): p. 285-298.


Autophagy (Didactic Lecture), Monday, April 5
Required Reading
1. Levine, B. and G. Kroemer, Autophagy in the pathogenesis of disease. Cell, 2008. 132(1): p. 27-42.

2. Maiuri, M.C., E. Tasdemir, A. Criollo, E. Morselli, J.M. Vicencio, R. Carnuccio, and G. Kroemer, Control of autophagy by oncogenes and tumor suppressor genes. Cell Death Differ, 2009. 16(1): p. 87-93.


QUIZ IN LAST 10 MINUTES OF CLASS


Article for Discussion, Wednesday, April 7

Mathew, R., C.M. Karp, B. Beaudoin, N. Vuong, G. Chen, H.Y. Chen, K. Bray, A. Reddy, G. Bhanot, C. Gelinas, R.S. Dipaola, V. Karantza-Wadsworth, and E. White, Autophagy suppresses tumorigenesis through elimination of p62. Cell, 2009. 137(6): p. 1062-1075.
Article for Discussion, Thursday, April 8

Colell, A., J.E. Ricci, S. Tait, S. Milasta, U. Maurer, L. Bouchier-Hayes, P. Fitzgerald, A. Guio-Carrion, N.J. Waterhouse, C.W. Li, B. Mari, P. Barbry, D.D. Newmeyer, H.M. Beere, and D.R. Green, GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation. Cell, 2007. 129(5): p. 983-997.

April 9-April 19
Section 8: Chris Pennell: Tumor Immunolog
y
Apr 9,12,14,15,16,19, Chris Pennell
Chris Pennell (penne001@umn.edu; Office: 760B MCRB, 625-7138)

Didactic lecture requirements:  Read the assignments and come prepared to answer questions related to them.

Journal club requirements:   Read the assignments. We’ll follow the approach Dr. Lange took. I will place you into one of several groups and assign your group a figure to discuss. Your group will have 5-10 minutes to share insights and choose a spokesperson to lead the class discussion regarding that figure.

Friday, April 9 Didactic lecture

Immunosurveillance
1. Weinburg’s The Biology of Cancer: Chapter 15
(students with a strong background in immunology or those taking MICA 8003 may skip sections 15.1-15.7)
2.
Zitvogel L, Tesniera A and Kroemer G. 2006. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nature Rev Immunol 6:715.

Monday, April 12 Journal club
Immunosurveillance
Background reading
1.
Rakoff-Nahoum S and Medzhitov R. 2009. Toll-like receptors and cancer. Nature Rev Cancer 9:57.
Discussion article
2. Swann JB, Vesely MD, Silva A, Sharkey J, Akira S, Schreiber RD and Smyth MJ. 2008. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc Natl Acad Sci USA 105(2):652

Wednesday, April 14 Didactic lecture
Humoral anti-tumor immunity
1. Reichert JM and Valge-Archer VE. 2007. Development trends for monoclonal antibody cancer therapeutics. Nature Rev Drug Discovery 6:349.

Thursday, April 15 Journal club
Humoral anti-tumor immunity
1. Stagg J, Sharkey J, Pommey S, Young R, Takeda K, Yagita H, Johnstone RW and Smyth MJ. 2008. Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response. Proc. Natl. Acad. Sci. USA 105(42):16254.

Friday, April 16 Didactic lecture
Cellular anti-tumor immunity
1. Rosenberg SA and Dudley ME. 2009. Adoptive cell therapy for the treatment of patients with metastatic melanoma. Curr Opin Immunol 21:233

Monday, April 19 Journal club
Cellular anti-tumor immunity
1. Hinrichs CS et al. 2009. Adoptively transferred effector cells derived from naïve rather than central memory CD8 T cells mediate superior antitumor immunity. Proc Natl Acad Sci USA 106(41):17469.

April 21-April 28
Section 9: Amy Skubitz: Biomarker Discovery/Validation in Tumors


Wednesday’s class (April 21st)
will be a general overview of biomarkers.  Since there are few chapters (or even pages) that deal with this subject in the class textbook (only pages 727-732), I am recommending the following article as background reading for Wednesday's class.

Journal of Proteome Research 2005, 4, 1053-1059, "So, you want to look for biomarkers" by Joshua LaBaer.

Thursday's class (April 22nd ) will deal with gene expression and the recommended reading for background is:

Journal of Pathology 2001, 195:41-52, "Towards a novel classification of human malignancies based on gene expression patterns" by A.A. Alizadeh, D.T. Ross, C.M. Perou, and M. van de Rijn.

 American Journal of Pathology, 2004, 165:397-414, "Differential gene expression in ovarian carcinoma:  Identification of potential biomarkers"  by K. Hibbs et al.

Friday’s class (April 23rd) will be a lecture on proteomic techniques for biomarker discovery and the recommended reading for background is:

Molecular & Cellular Proteomics, 5:1772-1786, 2006. "Proteomics of breast cancer:  Principles and potential clinical applications" by F. Bertucci, D. Birnbaum, and A. Goncalves,

Cancer Research 64:5882-5890, August 15, 2004, "Three biomarkers identified from serum proteomic analysis for the detection of early stage ovarian cancer" Zhen Zheng, Robert C. Bast, Jr., Yinhua Yu, et al.

Monday's class (April 26th) will be a journal club format with class participation.  We will go over the following article (Required reading):

PLOS Medicine December 2008, Volume 5, Issue 12, e232, “Ovarian carcinoma subtypes are different diseases:  Implications for biomarker studies” by M. Kobel, S.E. Kalloger, N. Boyd, et al.

Wednesday’s class (April 28th) will start off with a 10-minute quiz (no notes/books), followed by a journal club format with class participation.  We will go over the following article (Required reading):

Cancer Research, 69:66944, 2009, “Identification of Nectin-4 Oncoprotein as a Diagnostic and Therapeutic Target for Lung Cancer” A. Takano,  N. Ishikawa, R. Nishino, et al.


April 29- May 7
Section 10: Deepali Sachdev/Doug Yee: Emerging Therapies for Cancer Treatment

April 29, 30 May 3,5,6,7 Doug Yee/Deepali Sachde

Lectures and Reading List

The first and third sessions will be didactic lectures.  The remaining sessions will be interactive discussions of papers listed below.  Students are expected to participate in these discussions.

Assigned reading for this module includes Weinberg Chapter 16 pp. 725-737; 748-755; and the required papers listed below:

Thursday, April 29
Introductory lecture on targeted therapies for cancer by Doug Yee

Friday, April 30
Discussion of the paper by Fong et al
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009 Jul 9;361(2):123-34.

Hannah Farmer1,2*, Nuala McCabe1,2*, Christopher J. Lord2*, Andrew N. J. Tutt2,3, Damian A. Johnson2, Tobias B. Richardson2, Manuela Santarosa2†, Krystyna J. Dillon4, Ian Hickson4, Charlotte Knights4, Niall M. B. Martin4, Stephen P. Jackson4,5, Graeme C. M. Smith4 & Alan Ashworth1,2. 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy, Nature 434:917-921.

Monday, May 3

Lecture on the development of IGF-1R inhibitors for cancer therapy by Deepali Sachdev

Suggested Reading:
Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 2008 Dec;8(12):915-28. Review. Erratum in: Nat Rev Cancer.  

Wednesday, May 5

We will discuss the paper by Olive et al.
Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Tuveson DA et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009 Jun 12;324(5933):1457-61.

Thursday, May 6

Discussion of the paper Novosyadlyy by  et al.
Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y, Carboni JM, Gottardis MM, Pennisi PA, Molinolo AA, Kurshan N, Mejia W, Santopietro S, Yakar S, Wood TL, LeRoith D. Insulin-mediated acceleration of breast cancer development and progression in a nonobese model of type 2 diabetes. Cancer Res. 2010 Jan 15;70(2):741-51.

Friday, May 7

Discussion of the paper by Pàez-Ribes et al.

Required reading:
Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, Casanovas O. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009 Mar 3;15(3):220-31.

Recommended reading:
Loges S, Mazzone M, Hohensinner P, Carmeliet P. Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell. 2009 Mar 3;15(3):167-70.

The article by Loges et al. is a minireview that discusses how VEGF inhibitors can induce divergent effects on primary tumor growth and metastasis which is the topic of the paper to be discussed in class.

Be prepared to discuss the paper by Pàez-Ribes et al. in class.   

Quiz and take home exam

A 15 minute in-class quiz worth 20 points will be given at the end of the class on Thursday, May 6 or at the beginning of class on Friday, May 7.

A take home exam will be sent via e-mail by 5 pm on Friday, May 8.