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MICa 8004

Biology of Cancer

Spring Semester, 2018
9:05-9:55am M,W,Th,F

Room: TBA

Kaylee Schwertfeger (Course Co-Director), 6-9419, (, 3-132 CCRB
Timothy Hallstrom (Course Co-Director), 6-2905, (, 660D MCRB
David Largaespada (
Anindya Bagchi (
Martina Bazzaro (
Scott Dehm (
Ameeta Kelekar (
Carol Lange (
Louis Mansky (
Jim McCarthy (
Deepali Sachdev (
Timothy Starr (
Douglas Yee (
Christopher Pennell (


The Biology of Cancer. 2nd Edition. Robert A. Weinberg, Garland Publishing, New York, 2013.


Course materials are available through a Moodle course site through


We will be using the ChimeIn system for taking attendance and for class participation during the lectures. ChimeIn is similar to iClickers, except it is free and it is maintained by the University of Minnesota. To indicate your attendance and to participate in class polls you will need to have either a cell phone (smart or regular), iPad, tablet, or laptop during class. You will need to register for the class at the ChimeIn website:

There is a short Chimein tutorial video on the website that you should watch.

Course Format

The course will be divided into 15 blocks consisting of 4 meetings per block. Within each block, the first two meetings will be lectures with assigned textbook chapters and/or journal articles.
These lectures will cover key concepts that you will be expected to know for the final exam. Students should expect to spend time outside of class to learn techniques relevant to the assigned reading material. Course materials will be available through a Moodle course site.

The third meeting will be a journal club-style discussion of a paper that is related to the topic of the block. Students are expected to read the entire assigned paper before class and be ready to discuss it in detail. Students will be separated into groups and each group will be expected to present part of the paper to the class. The section your group will present will not be assigned until the day of class that you present, therefore, be prepared to discuss any part of the paper. You will have 10 minutes with your group at the beginning of class to prepare your presentation. Presentations will be approximately 5 minutes long. These assigned groups will change three times during the course. Your group assignments will be handed out the first day of class.

The instructor will e-mail a problem-solving quiz to each student shortly after the third meeting. Students will e-mail their answers back to the instructor before the beginning of the fourth meeting, after which the instructor will present acceptable answers and lead a discussion of alternative answers and their weaknesses. A summary of the key concepts, further review of the journal article, or directed problem solving will also occur at the fourth meeting.


The exams will include 15 problem-solving quizzes, one per block, and a fact-based short answer format final exam. The quiz may be one essay question or multiple questions. The quizzes will be e-mailed as MS Word documents by the block instructor to the students shortly after the third meeting of each block. The completed quizzes must be e-mailed by the students back to the block instructor by the beginning of the fourth meeting. Answers must be limited to 1 page, 12pt Times New Roman font, 1-inch margins, single spacing. Answers longer than 1 page will be given a score of 0. Any material available in the scientific literature may be used to answer the questions. However, students are expected to answer their own quiz independently. None of the quiz questions may be discussed with other members of the class until after the quiz. According to criteria discussed during the fourth session, the instructor will grade each quiz, and the graded quiz will be returned to students via e-mail upon completion of Moodle Feedback.

The final exam will be 1 hour in length, closed book, short answer format, and focused on the Key Concepts from each block.

Course Points

Exams - 10 points will be given for each take home quiz for a total of 150 points and 75 points will be given for the final exam.

Attendance - 5 points will be given for participation during each block for a total of 75 points. Attendance points will be based on attending all classes in each block. Attendance of all meetings is expected, with an exception for one excused absence during the course (NOT one excused absence per block). Excused absences MUST be for legitimate reasons and are to be requested from the course directors, Kaylee Schwertfeger and Timothy Hallstrom, when possible, before the missed meeting or immediately following.

Take Home Quizzes (15 at 10 pts each) – 150 points Attendance Points (15 at 5 pts each block) – 75 points Final Exam – 75 points          


Block Topic Lecturer Group Dates (W,Th,F.M)
1 Introduction to the Course/Cancer Pathology/The TCGA Starr A Groups Jan. 18,19.20,23
2 Cancer Genetics: Cancer Viruses and Experimental Genetics Largaespada A Groups Jan. 25,26,27,30
3 Cell Signaling I: Transmitting the signal from surface receptors to the cytoplasm – Tyr Kinase Growth Factor Receptors (EGFR family), RAS, SRC, MAPKs, PI3K… Lange A Groups Feb. 1,2,3,6
4 Cell Signaling II:  The nucleus (steroid hormone receptors, Fos/Jun, JAK- STAT) beta Dehm A Groups Feb. 8,9,10,13
5 Tumor suppressor genes; Genome Instability Bagchi A Groups Feb. 15,16,17,20
6 RB/ Cell Cycle/P53 Hallstrom B Groups Feb. 22,23,24,27
7 Cellular Immortalization; Cancer Stem Cells Largaespada B Groups March 1,2,3,6
8/9 Apoptosis Autophagy/Metabolism Kelekar B Groups March 8,9,10,20,22,23,24,27
10 Angiogenesis Bazzaro B Groups March 29,30,31,April 3
11 Human Cancer and Microbes; Bacteria and Viruses Mansky C Groups April
12 Invasion & Metastasis McCarthy C Groups April 12,13,14,17
13 Tumor Microenvironment Schwertfeger C Groups April 19,20,21,24
14 Cancer Therapy I: Tumor Immunology & Immune Therapies Pennell C Groups April 26,227,28, May 1
15 Cancer Therapy II: Small molecules and Targeted therapy Sachdev/Yee C Groups May 3,4,5


Spring break March 13-17

MICA 8004 Reading List - Spring Semester 2016

Please read the material listed for each date BEFORE coming to class.

Block 1: Cancer Pathology and The Cancer Genome Atlas 

Jan. 18th – 1) Skim the first chapter of the textbook (Weinberg Chapter 1, pgs. 1-29). Use the bold words throughout the chapter to judge whether or not you already have this knowledge. If you can read the bold words and could define them in an essay question on a test, then you don’t need to read the chapter thoroughly. Watch at least one of the movies on the CD that comes with the book. This chapter is a review of the fundamentals of genetics. You should already know most of what is in this chapter.

2) The Cancer Genome Atlas (TCGA) data mining assignment. Goal: Answer the following two questions regarding all the colon cancer patients that were analyzed for somatic mutations by TCGA:

How many somatic mutations were found in beta-catenin?
What percentage of patients had a somatic mutation in beta-catenin?

Helpful hints for completing this assignment: Go to The Cancer Genome Atlas homepage ( Explore the website a little. Click on the "Launch Data Portal" to access the NCI's Genomic Data Commons. Figure out how to download the "Annotated Somatic Mutation" data for all the colon adenocarcinoma (TCGA: COAD) samples analyzed by the TCGA. TCGA uses a
.maf file extension for their annotated somatic mutation data files. These files can be opened in a basic text editor program, but to do this analysis you will likely want to transfer the data to an excel file. One caveat to this assignment is that TCGA actually provides annotated mutation data using four different methods for detecting somatic mutations. The four programs/algorithms that they provide data results from are: "somaticsniper", "mutect", "varscan", and "muse". Just to keep this assignment reasonable, use the file generated by "somaticsniper" and ignore the other three.  Another warning, the files are fairly large (20 – 100 Mb) so you should use a fast connection when trying to download them.

Jan. 19 - 1) Read the Synopsis and prospects and Key concepts (pp. 66-69) in Weinberg, Chapter 2. If some of the key concepts are new to you, read that portion of the chapter. Spend some time on the first part of the chapter learning nomenclature used to describe cancer pathology.

2) Read Hanahan, D. and Weinberg, R.A. Hallmarks of Cancer: The Next Generation. 2011. Cell 144, 646-674.

Jan. 20 - Journal article: Be prepared to present Figures 1 thru 3, Tables 1 thru 3 and supplemental figure 2. Rucaparib in relapsed, platinum-sensitive high-grade

ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Swisher, et al., Lancet Oncology, 2016 Nov 28 online. Hint: Sections 3.1 and 3.2 in the "protocol" in the supplemental document provide some helpful background. Take home exam will be distributed at the end of the class.

Jan. 23 – (additional readings, not required): A good historical account of cancer research: "The Emperor of All Maladies: A Biography of Cancer" by Siddhartha Mukherjee. This is a 1,000 page epic, but it is good for skimming. (Or you can watch the Ken Burns 6-episode PBS documentary based on the book)

Block 2: Cancer Genetics: Cancer Viruses and Experimental Genetics

Jan. 25th - Weinberg Chapter 3, read the Synopsis, Prospects, & Key Concepts pp. 86-90. Skim the chapter and read the bolded words/terms. Make sure you understand key concepts and bolded word/terms.

Temin HM and H Rubin. 1958. Characteristics of an assay for Rous sarcoma virus and Rous sarcoma cells in tissue culture. Virology. 6:669-688.

Stehelin D, HE Varmus, JM Bishop, and PK Vogt. 1976. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature. 260:170-173.

Jan. 26th - Weinberg Chapter 4, read the Synopsis, Prospects, & Key Concepts pp. 112-
116. Skim the chapter and read the bolded words/terms. Make sure you understand key concepts and bolded word/terms.

Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008 Sep 26; 321 (5897):1807-12.

Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE, O'Rourke DM, Berger SL, Chan TA, Levine RL, Mellinghoff IK, IDH mutation impairs histone demethylation and results in a block to cell differentiation. Thompson CB. Nature. 2012 Feb 15; 483n (7390):474-8.

Jan. 27th  - One paper

Nik-Zanail, S. et al., 2016.  Landscape of somatic mutations in 560 breast cancer whole genome sequences.  Nature.  May 2; 534(7605): 47–54.

Jan. 30th – (additional readings, not required)

Read "The Emperor of All Maladies: A Biography of Cancer" by Siddhartha Mukherjee.

Block 3: Cell Signaling I: Transmitting the signal from surface receptors to the cytoplasm – Tyr Kinase Growth Factor Receptors (EGFR family), RAS, SRC, MAPKs, PI3K…

*Please use the textbook as a general point of reference for background to signaling. THUS READ THIS PRIOR TO CLASS - Topics of interest include mechanisms of growth factor tyrosine kinase receptor (EGFR family members) signaling and regulation of downstream protein kinase cascades (focus primarily on MAPKs and PI3K/Akt). The context for this section is the role of mutation or dysregulation of these key regulatory molecules in cancer biology – the endpoint of signal transduction being altered gene regulation and aspects of cancer biology or cancer cell behavior/phenotypes.

Feb 1st – Weinberg Chapter 5* –Tyrosine Kinase Growth Factor Receptors/Ras

Feb 2nd – Weinberg Chapter 5 cont.* – Signal transduction downstream of PTKs

Required reading: Translational choices from the breast cancer literature…  Moasser MM and Krop IE. The Evolving Landscape of HER2 Targeting in Breast Cancer. JAMA Oncol. 2015 Nov;1(8):1154-61. doi: 10.1001/jamaoncol.2015.2286.

80048004aEndocr Relat Cancer. 2016 Dec;23(12):T243-T257. Epub 2016 Oct 7.  Elizalde PV1, Cordo Russo RI2, Chervo MF2, Schillaci R2. ErbB-2 nuclear function in breast cancer growth, metastasis and resistance to therapy. Endocr  Relat Cancer. 2016 Dec;23(12):T243-T257. Epub 2016 Oct 7.

Feb 3rd – Research Article for Group Discussion (assignment released)

Required Reading: Mechanism of early dissemination and metastasis in Her2+ mammary cancer. KL Harper et. al 2016 Nature 540, 588–592 (22 December
2016) doi:10.1038/nature 20609

Suggested further reading: Early dissemination seeds metastasis in breast  cancer. Hosseini H, Obradović MM, Hoffmann M, Harper KL, Sosa MS, Werner-Klein M, Nanduri LK, Werno C, Ehrl C, Maneck M, Patwary N,
Haunschild G, Gužvić M, Reimelt C, Grauvogl M, Eichner N, Weber F, Hartkopf

AD, Taran FA, Brucker SY, Fehm T, Rack B, Buchholz S, Spang R, Meister G, Aguirre-Ghiso JA, Klein CA. Nature. 2016 Dec 14. doi: 10.1038/nature20785. [Epub ahead of print] PMID: 27974799

Feb 6th – Review / Discussion of Key Concepts (assignment review)

Block 4: Cell Signaling II: The Nucleus (Steroid Hormone Receptors, Fos/Jun, JAK-STAT) Feb. 8th - Weinberg Chapter 1.6, 1.7, 1.8, and Weinberg Chapter 6.1, 6.5, 6.6, 6.8, 6.10,
6.12 (these should already have been read in preparation for previous Blocks)

Dawson MA and Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell.  150: 12-27, 2012.

Feb. 9th - Jozwik KM, Carroll JS.  Pioneer factors in hormone-dependent cancers.
Nature Reviews Cancer.  12:381-385, 2012.

Feb. 10th - Lovén J et al.  Selective inhibition of tumor oncogenes by disruption of super- enhancers. Cell. 153: 320, 2013.

Feb. 13th – (additional readings, not required)

Kim TK and Shiekhattar R. Architectural and Functional Commonalities between Enhancers and Promoters.  Cell.  162: 948-59, 2015.

Shi J, Vakoc CR.  The mechanisms behind the therapeutic activity of BET bromodomain inhibition.  Mol Cell. 54: 728-36, 2014.

Rathert P et al.  Transcriptional plasticity promotes primary and acquired resistance to BET inhibition.  Nature 525: 543-7, 2015.
ENCODE Project Consortium.  An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57-74, 2012.

Block 5: Tumor Suppressor Genes, Genome Instability Feb. 15th - Weinberg Chapter 7, pgs. 209-254  Feb. 16th - Weinberg Chapter 12, pgs. 463-526
Feb. 17th - The Landscape of Microsatellite Instability in Colorectal and Endometrial Cancer Genomes Cell, Volume 155, Issue 4, 7 November 2013, Pages 858–868

Feb. 20th – (additional readings, not required)


Block 6: RB/Cell Cycle/P53

Feb. 22nd - Weinberg Chapter 8
Feb. 23rd - Weinberg Chapter 9.1-9.12
Feb. 24th – KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis. Cell Reports. 2016 Sept 13;16(11):3016-27.

Feb. 27th – (additional readings, not required)

Keith W. Orford1 & David T. Scadden. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nature Reviews Genetics 9, 115-128 (February 2008) | doi:10.1038/nrg2269

Kastan M., Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004. Nov 18; 432(7015):316-23.

Block 7: Cellular Immortalization; Cancer Stem Cells March 1st - Weinberg Chapter 10, pgs. 357-398 March 2nd - Weinberg Chapter 11, pgs. 399-441 March 3rd One paper
Zhu L, Finkelstein D, Gao C, Shi L, Wang Y, López-Terrada D, Wang K, Utley S, Pounds S, Neale G, Ellison D, Onar-Thomas A, Gilbertson RJ. Multi-organ Mapping of Cancer Risk.  Cell. 2016 Aug 25;166(5):1132-1146.e7. doi: 10.1016/j.cell.2016.07.045. PMID: 27565343

March 6th – (additional readings, not required)

Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Tomasetti C, Vogelstein B. Science. 2015 Jan 2;347(6217):78-81. doi: 10.1126/science.1260825.

Block 8/9: Apoptosis Autophagy/Metabolism March 8th Weinberg Chapter 9 pages 361-381
Additional Reading (optional) - Ola, M.S., M. Nawaz, and H. Ahsan, Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem, 2011. 351(1-2): p. 41-

March 9th –  Mizushima, N. and M. Komatsu, Autophagy: renovation of cells and tissues. Cell, 2011. 147(4): p. 728-741

March 10th –  Green, D.R. and Levine, B. To Be or Not to Be?: How Selective Autophagy and Cell Death Govern Cell Fate, Cell 2014. 157 (1): p. 65-75

Review Apoptosis and Autophagy

March 20th Cantor, J.R. and D.M. Sabatini, Cancer cell metabolism: one hallmark, many faces. Cancer Discov, 2012. 2(10): p. 881-898

Liberti, M. M. and Locasale, J. W. The Warburg Effect: How Does it Benefit Cancer Cells? Trends in Biochemical Sciences 2016. 1211 (in press, available online)

March 22nd Review Cancer Metabolism
March 23rd Paper for discussion
Tan et al. A kinase independent role for EGF Receptor in Autophagy Initiation. Cell 2015. 160: 145-160

March 24th Paper for discussion
Vincent E. E. et al. Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth.
Molecular Cell2015. 60: 195-207

March 27th Discussion and review of assignments

Block 10: Angiogenesis

March 29th - Weinberg Chapter 13:1-13:6
Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Bergers Gabriele et al, Nature Cell Biology, 2000.

March 30th – Weinberg Chapter 13:7-13:11
The ever expanding role of HIF in tumor and stromal biology. LaGory Edward et al, Nature cell biology, 2016

March 31st - Normalized Tumor vessels by Tie2 activation and and2 inhibition enhances drug delivery and produces favorable tumor microenvironment. Park Jin-Sung et al, Cancer Cell 2016.

April 3rd – (additional readings, not required)


Block 11: Human Cancer and Microbes: Bacteria and Viruses April 5th - Weinberg Chapter 11, pgs. 488-500
April 6th - Schwabe RF and Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013 Nov;13(11):800-12. doi: 10.1038/nrc3610. Epub 2013 Oct 17.

April 7th - Feng H, Shuda M, Chang Y, Moore PS. Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science. 2008 Feb 22;319(5866):1096-100. doi: 10.1126/science.1152586. Epub 2008 Jan 17.

April 10th – (additional readings, not required)

Urisman et al., Identification of a Novel Gammaretrovirus in Prostate Tumors of Patients Homozygous for R462Q RNASEL Variant. PLoS Pathogens. 2006 Mar;2(3):e25. Epub 2006 Mar 31.

Block 12: Invasion and Metastasis April 12th & 13th –

Weinberg, pgs 577-603 Heterotypic Interactions in tumors review, tumor associated stroma composition and remodeling of ECM (synthesis, general discussion of impact of proteases and glycosidases) – wounds that do not heal

Weinberg, pgs 689-695 cell adhesion, motility and therapeutic resistance – structural and biochemical signals, ECM density and mechanosignal transduction.

Weinberg, pgs 657-685 regulation of EMT/Stem cell phenotype – formation and impact of myofibroblasts. General introduction to phenotypic heterogeneity dependent on location in tumor

Weinberg, pgs 641-656, 709-711 intravasation CTC, extravasation, colonization. General intro to premetastatic niche

April 14th Original Research Paper for Students to Discuss
Jiang, et al. 2016. Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy. Nature Medicine. 22: 851-860

April 17th Review and Discussion

Suggested Reading:

8004bShort, et al. 2000. Integrins Regulate the Linkage between Upstream and Downstream Events in G Protein-coupled Receptor Signaling to Mitogen- activated Protein Kinase. J. Biol. Chem. 275:12970-12977.

Schedin and Keely. 2011. Mammary Gland ECM Remodeling, Stiffness, and Mechanosignaling in Normal Development and Tumor Progression. . Cold Spring Harb Perspect Biol 2011;3:a003228.

Jung et al. 2015. Molecular Pathways: Linking Tumor Microenvironment to Epithelial–Mesenchymal Transition in Metastasis. Clin. Cancer. Res. 21: 962-968

Hoye and Erler. 2016. Structural ECM components in the premetastatic and metastatic niche. Am. J. Physiol. Cell Physiol. 310: C955-C967.

Block 13: Tumor Microenvironment

April 19th Weinberg text: pages 486-498 (review), 604-606
Coussens, L.M. and Werb, Z. “Inflammation and cancer” Nature 420(6917) 2002, 860-867. PMID 12490959

April 20th Weinberg text: pages 669-671, 685-689

April 21st Journal article discussion:
Kitamura et al., “CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages”, J Exp Med 212(7), 1043-1059, 2015. PMID 26056232

April 24th 

Suggested reading for additional background, not required:

de Visser, K.E. et al. “Paradoxical roles of the immune system during cancer development”, Nature Reviews Cancer 6, 2006, 24-37. PMID 16397525

DeNardo, D.G. et al. “CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages”
Cancer Cell. 2009 Aug 4;16(2):91-102.

Giraudo, E, Inoue, M, Hanahan, D. “An amino-bisphosphonate targets MMP-9- expressing macrophages and angiogenesis to impair cervical carcinogenesis” Journal of Clinical Investigation 114(5), 623-633, 2004.

de Visser, KE, Korets, LV and Coussens, LM. “De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent” Cancer Cell 7(5), 411-423, 2005.

Pardoll, D. “Metastasis-promoting immunity: when T cells turn to the dark side” Cancer Cell. 2009 Aug 4;16(2):81-2.

Balkwill, F., “The chemokine system and cancer” Journal of Pathology 226, 2012, 148-157.

Block 14: Cancer Therapy I: Tumor Immunology and Immune Therapies April 26th - Weinberg Chapter 15
April 27th - Weinberg Chapter 15
April 28th Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, Ambrose D, Grupp SA, Chew A, Zheng Z, Milone MC, Levine BL, Melenhorst JJ, June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015 Sep 2;7(303):303ra139.

May 1st – (additional readings, not required)

Barrett DM, Grupp SA, June CH. Chimeric Antigen Receptor-and TCR-Modified T Cells Enter Main Street and Wall Street. J Immunol. 2015 Aug 1;195(3):755- 61.

Block 15: Cancer Therapy II: Small Molecules and Targeted Therapy May 3rd Weinberg Chapter 16 pgs. 797-815
May 4th  - Weinberg Chapter 16 pgs. 815-818; 825-833; 844-860
May 5th  - Goel et al.  Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell. 29: 255-269, 2016.

Final Exam


May 10th 10:30-12:30pm, 2-580 MoosT

MICA 8004 – Biology of Cancer Key Concepts

Block 1: Cancer Pathology and the TCGA

  • Use and understand terminology describing pathological and molecular processes in cancer development and progression

  • Enumerate and provide an overview of the hallmarks of cancer and their significance to diagnosis and therapy
  • Discuss changes in the dynamics of cancer incidence and prevalence in the past 3-5 decades (i.e., answer the question, “is there a cancer epidemic?”)
  • Describe the histological origins of cancer and their relationship to processes of developmental biology
  • Evaluate the usefulness of The Cancer Genome Atlas

Block 2: Cancer Genetics: Cancer Viruses, Experimental Genetics

  • Know how Rous sarcoma virus helped to confirm that viruses could cause cancer
  • Know the basic properties of transformed cells
  • Describe the basic genetic approaches to engineering mice for the study of cancer
  • Describe the histological origins of cancer and their relationship to processes of developmental biology
  • Know the basic properties of retrovirus structure and replication
  • Describe how Rous sarcoma virus (RSV) and acute transforming retroviruses cause cancer
  • Describe how the study of RSV lead to the identification of cellular oncogenes
  • Know how slowly transforming retroviruses cause cancer and how to identify cancer causing insertions in chromosomal DNA
  • Describe how DNA viruses (e.g., SV40) cause cancer
  • Describe the basic methods used in the TCGA and some important information learned (mutation load, mutation signatures).


Block 3: Cell Signaling I: Transmitting the signal from surface receptors to the cytoplasm – Tyr Kinase Growth Factor Receptors (EGFR family), RAS, SRC, MAPKs, PI3K…

  • How growth factors and growth factor receptors facilitate cell-to-cell communications.
  • The mechanism of kinases and their importance for signal transduction.
  • The structure and function of receptor tyrosine kinases.
  • Basics of other receptors in cell-to-cell signaling.
  • How the above (1-4) can be altered in the context of cancer and what that means for the development of cancer therapy.

Block 4: Cell Signaling II: The Nucleus (Steroid Hormone Receptors, Fos/Jun, JAK-STAT)

  • Define what is meant by signal transduction
  • Be able to name/explain the function of the key components of signaling pathways and their conserved motifs that allow for protein-protein interaction and signal propagation.
  • Understand the role of signal transduction with regard to gene expression.
  • Be able to discuss mechanisms of signaling specificity (i.e. complexity) in normal and cancer cell biology.
  • Be able to related these concepts (1-4) to discussions of cancer treatments that use targeted (i.e. to signaling molecules) therapies (what strategies are being employed and what are the major challenges?).


Block 5: Tumor Suppressor Genes: Genome Instability

  • Mechanisms for loss of heterozygoisity (LOH) during tumorigenesis

  • DNA repair mechanisms are tumor suppressive
  • Base excision repair
  • Mismatch repair
  • Homologous recombination

Block 6: RB/Cell Cycle/P53

  • The cell cycle, cyclins and their catalytic CDK binding partners
  • Timing and signals of cell fate, such as growth, quiescence, apoptosis, differentiation or senescence
  • E2F transcription factors associated with promoters of genes that control cell cycle, DNA replication and mitosis.
  • Hypophosphorylated pRb and hyperphosphorylated pRb
  • Loss of pRb function
  • Inactive pRb and activation of pro-apoptotic or senescence programs.


Block 7: Cellular Immortalization; Cancer Stem Cells

  • Cancer cells acquire and display distinct neoplastic traits (e.g. via activation of oncogenes and loss of tumor suppressor genes) that usually require several decades’ time to develop
  • A long succession of growth-and-division cycles occur as they evolve toward the neoplastic growth state
  • Cancer risk in various organs may be related to the regenerative capacity of that tissue (i.e. number of resident tissue stem cells and the number of cell divisions such cells undergo)
  • Incipient cancer cells must breach the barrier that normally limits their proliferative potential (and thus become immortal so that they can successfully complete the multiple steps of tumor development
  • Normal cells evolve into cells with increasingly neoplastic phenotypes through a process termed tumor progression
  • This is driven by a sequence of randomly occurring mutations and epigenetic alterations

of DNA that affect the genes controlling

    • Cell proliferation
    • Survival
    • Other traits associated with the malignant cell phenotype
  • A subset of cells within a tumor mass actually are required for long term propagation of the tumor, are targets for mutations that cause tumor progression, and may be the source of metastatic disease and recurrent disease after treatment

Block 8/9: Apoptosis /Autophagy/Metabolism

  • Programmed Cell Death and Apoptotic pathways in normal cells and their aberrant regulation in cancer, with special emphasis on the involvement of the Bcl-2 family of proteins
  • Autophagy as a Stress Response in normal cells, and the contradictory and contextual roles for deregulated Autophagy in tumor suppression and tumor progression
  • The Warburg Hypothesis and Metabolic Reprogramming in actively proliferating normal cells and cancer cells

  • Apoptosis, Autophagy and Metabolism are closely linked – understanding the crosstalk, the overlap and the shared regulators


Block 10: Angiogenesis

  • Tumors and intercommunication between various cell types
  • The recruitment of macrophages, fibroblasts and fibroblast and their key roles during tumor-associated angiogenesis
  • The “Angiogenic switch” and tumor-associated angiogenesis as a critical determinant of tumor growth.
  • Neo-angiogenesis as target for development of novel anticancer agents as angiogenesis inhibitors are designed to “cut off cancer’s supplies”

Block 11: Human Cancer and Microbes: Bacteria and Viruses

  • Viruses and bacteria can cause human cancer. Roughly 20% of human cancer has a viral etiology.
  • Roughly 20% of human cancer cases have a viral etiology.
  • Microbes are incomplete carcinogens, often cause chronic inflammation leading to cancer.
  • Viral proteins designed to enhance replication can contribute to cancer development.
  • Criteria for establishing causation differs from Koch’s postulates


Block 12: Invasion and Metastasis

  • Importance of heterotypic interactions in primary tumors and metastasis. Tumors as wounds in a perpetual state of healing. Paracrine vs. Autocrine interactios in progression Transcriptional Regulation of EMT/stem cell properties
  • ECM remodeling in primary tumors and impact on malignant progression. Changes in ECM composition, cellular content. Mechano-signal transduction in tumor reactive stroma and tumor progression
  • Tumor reactive stroma and therapeutic resistance. Impact of stromal organization and composition on clinical response in cancer

Block 13: Tumor Microenvironment

  • Inflammation, which can be caused by both extrinsic and intrinsic factors, can contribute to tumor growth and progression.
  • Cells associated with the inflammatory response, including both innate and adaptive immune cells, contribute to tumor formation and progression.
  • Innate immune cells within the tumor microenvironment produce soluble pro- tumorigenic factors that act on both tumor and stromal cells to alter the microenvironment and promote tumor growth.
  • Targeting the pro-tumorigenic inflammatory response represents a viable therapeutic option for cancer therapy.


Block 14: Cancer Therapy I: Tumor Immunology and Immune Therapies

  • Immune surveillance constantly eliminates nascent tumors and, by definition, cancer has escaped immune surveillance.

  • The characteristics of the immune system that make it attractive for cancer therapy include specificity, potency, and memory.
  • Immune therapeutics for cancer include monoclonal antibodies, adoptively transferred cells, and vaccines.
  • Overcoming cancer-mediated immune suppression is critical for the success of cell-based immune therapies.

Block 15: Cancer Therapy II: Small Molecules and Targeted Therapy

    • Understand the role of systemic therapy in reducing breast cancer deaths.
    • Identifying prognostic factors and their roles as targets for cancer therapy.
    • Describe the role for targeted therapies and mechanism of action.
    • Resistance to targeted therapies is frequently seen and can be either de novo or acquired. Understand that targeting multiple pathways may be critical