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MICa 8004

Biology of Cancer - MICA 8004


Spring Semester, 2020
9:05-9:55am M,W,Th,F

Room: 2-118 Moos Tower

Instructors:
Kaylee Schwertfeger (Course Co-Director), 6-9419, (schwe251@umn.edu), 3-132 CCRB
Timothy Hallstrom (Course Co-Director), 6-2905, (halls026@umn.edu), 660D MCRB
Martina Bazzaro (mbazzaro@umn.edu)
Scott Dehm (dehm@umn.edu)
Ameeta Kelekar (ameeta@umn.edu)
Carol Lange (lange047@umn.edu)

David Largaespada (larga002@umn.edu)
Louis Mansky (mansky@umn.edu)
Branden Moriarity (mori0164@umn.edu)
Deepali Sachdev (sachd003@umn.edu)
Timothy Starr (star0044@umn.edu)
Douglas Yee (yeexx006@umn.edu)
Christopher Pennell (penne001@umn.edu)

DOWNLOAD THE PDF HERE

Textbook

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

Technology

Course materials are available through a Canvas course site through umn.instructure.com

ChimeIn:

Some instructors use the ChimeIn system 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: https://chimein.cla.umn.edu/

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

Course Format

The course will be divided into 14 blocks consisting of 4 meetings per block. Within each block, the first three 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 the Canvas course site.

The fourth 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 fourth meeting. Students will e-mail their answers back to the instructor before the beginning of the next module (Wednesday @ 9:05).

Exams

The exams will include 14 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 fourth meeting of each block. The completed quizzes will be e-mailed by the students following grading. 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.

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 140 points and 70 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. 1 point will be assigned for the W/Th/F meetings and 2 points will be assigned for the journal club discussion on Mondays. 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 (14 at 10 pts each) – 140 points
Attendance Points (14 at 5 pts each block) – 70 points
Final Exam – 75 points
Total Points Available – 285

 

Block

Topic

Lecturer

Group Assignment 

Book Chapters

Dates (W, Th, F, M)

1

Introduction to the Course/Cancer Pathology/The TCGA

Starr

A Groups

1-2

Jan. 22, 23, 24, 27

2

Cancer Genetics: Cancer Viruses and Experimental Genetics

Mansky

A Groups

3-4

Jan 29, 30, 31, Feb 3


3

Cell Signaling I: The cytoplasm (GF receptors, G-protein coupled receptors), RAS, SRC, P13K, SHH, WNT, TGF

Lange

A Groups

5

Feb. 5, 6, 7, 10

4

RB/ Cell cycle/ P53

Hallstrom

A Groups

8-9

Feb. 12, 13, 14, 17

5

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

Dehm

A Groups 

1, 6

Feb 19, 20, 21, 24

6

Tumor suppressor genes; Genome Instability

Moriarity

B Groups

7, 12

Feb 26, 27, 28, March 2

7/8

Apoptosis Autophagy/Metabolism

Kelekar

B Groups

9

March 4, 5, 6, 16, 18, 19, 20, 23

9

Cellular Immortalization, Stem Cells, and Cancer Stem Cells

Largaespada

B Groups

10-11

March 25, 26, 27, 30

10

Angiogenesis

Bazzaro

B Groups

13

April 1, 2, 3, 6

11

Human Cancer and Microbes: Bacteria and Viruses

Largaespada

C Groups

11

April 8, 9, 10, 13

12

Tumor Microenvironment, Invasion and Metastasis

Schwertfeger

C Groups

14

April 15, 16, 17, 20

13

Cancer Therapy I: Tumor Immunology & Immune Therapies

Pennell

C Groups

15

April 22, 23, 24, 27

14

Cancer Therapy II: Small molecules and Targeted Therapy

Sachdev/Yee

C Groups

16

April 29, 30, May 1, 4

 

Spring break March 9-13

MICA 8004 Reading List - Spring Semester 2020

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

Block 1: Cancer Pathology and The Cancer Genome Atlas

Jan. 22 – 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) Homework assignment – finish before the first day of class and email me your response.

Use the website CbioPortal (http://www.cbioportal.org/index.do) to answer the following questions:

A) Do breast cancer patients with BRCA1 and/or BRCA2 mutations survive longer than breast cancer patients without mutations in BRCA1 or BRCA2?

B) Do breast cancer patients with BRCA1 mutations survive longer than breast cancer patients with BRCA2 mutations?

Download one or more figures from the CbioPortal website to support your answer and send the figures to me by email before the first day of class (star0044@umn.edu).


Jan. 23
- 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. 24 - Journal articles:
1) Tripathy, D., Bardia, A. & Sellers, W. R. Ribociclib (LEE011): Mechanism of Action and Clinical Impact of This Selective Cyclin-Dependent Kinase 4/6 Inhibitor in Various Solid Tumors. Clin Cancer Res 23, 3251-3262, doi:10.1158/1078-0432.CCR-16-3157 (2017)

Read this quickly to understand the Phase III clinical trial, which is the 2nd article
2) Tripathy, D. et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol 19, 904-915, doi:10.1016/S1470-2045(18)30292-4 (2018).

Be prepared to present all figures and tables in the second article article and Figure 1-1 (p. 40) in the supplemental appendix. Skim the supplemental appendix. I will expect you to have a basic understanding of all the assays, experimental procedures, and terminology in the article. If there are concepts and terminology you don't understand, consult Google and Wikipedia.

Jan. 27 – (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. Alternatively, you can watch the Ken Burns 6-episode PBS documentary based on the book

Block 2: Cancer Genetics: Cancer Viruses and Experimental Genetics

Jan. 29 - 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. 30 - 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. 31 - One paper

Stehelin, D., H. E. Varmus, J. M. Bishop and P. K. Vogt (1976). "DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA." Nature 260(5547): 170-173.

Feb 3 – (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), SRC, RAS, MAPKs, PI3K, AKT, mTOR…

*Please use the textbook as a general point of reference for background to signaling. Please make sure you have reviewed this material and understand the concepts 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 the MAPKs and PI3K/Akt pathways). The context for this section is the function of these pathways and the role (i.e. following mutation or dysregulation) of these key regulatory molecules in cancer biology – the endpoint of signal transduction often being altered gene regulation (i.e. the cancer transcriptome) and the related “cell decisions” as consequences for aspects of cancer biology or cancer cell fate, behavior/phenotypes and responses to therapies.

Feb 5 – READ/SKIM Weinberg Chapter 5* –Tyrosine Kinase Growth Factor Receptors/Ras - Signal Transduction overview (what are the elements of signaling pathways?)

Feb 6 – READ/SKIM Weinberg Chapter 5 cont.* – Signal transduction downstream of PTKs - Protein Kinases (why are kinase cascades conserved?)

READ: Papke B1, Der CJ2. Drugging RAS: Know the enemy. Science. 2017 Mar 17;355(6330):1158-1163. doi: 10.1126/science.aam7622. Epub 2017 Mar 16.

Feb 7 – Signaling and specific cancer cell adaptations…
What cancer cell decisions are influenced by activated signaling pathways?
READ: Gomes AP, Blenis J. A nexus for cellular homeostasis: the interplay between metabolic and signal transduction pathways. Curr Opin Biotechnol. 2015 Aug;34:110-7. doi: 10.1016/j.copbio.2014.12.007. Epub 2015 Jan 3. Review. PMID: 25562138

READ - Schild T, Low V, Blenis J, Gomes AP. Unique Metabolic Adaptations Dictate Distal Organ-Specific Metastatic Colonization. Cancer Cell. 2018 Mar 12;33(3):347-354. doi: 10.1016/j.ccell.2018.02.001. Review. PMID: 29533780

Feb 10 – Read and be prepared to discuss in class - Wright KL1, Adams JR1, Liu JC2, Loch AJ3, Wong RG3, Jo CE3, Beck LA3, Santhanam DR3, Weiss L3, Mei X3, Lane TF4, Koralov SB5, Done SJ6, Woodgett JR7, Zacksenhaus E2, Hu P8, Egan SE9. Ras Signaling Is a Key Determinant for Metastatic Dissemination and Poor Survival of Luminal Breast Cancer Patients. Cancer Res. 2015 Nov 15;75(22):4960-72. doi: 10.1158/0008-5472. CAN-14-2992. Epub 2015 Sep 23.

Block 4: RB/Cell Cycle/P53

Feb 12 - Weinberg Chapter 8

Feb 13
Keith W. Orford & 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.

Feb 14 – Weinberg Chapter 9.1-9.12

Feb 17 – A Code of Mono-phosphorylation Modulates the Function of RB. Molecular Cell. 2019. 73:1-16.

Block 5: Cell Signaling II: The Nucleus (Steroid Hormone Receptors, Fos/Jun, JAK-STAT)

Feb. 19 - 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)

Additional Reading (not required but will enhance understanding)
Kim TK and Shiekhattar R. Architectural and Functional Commonalities between Enhancers and Promoters. Cell. 162: 948-59, 2015.

See YX, Wang BZ, and Fullwood MJ. Chromatin Interactions and Regulatory Elements in Cancer: From Bench to Bedside. Trends in Genetics. 35:145-158, 2019.

Transcription Factors and 3D Genome Conformation in Cell-Fate Decisions. Nature. 569:345-354, 2019.

Feb. 20 - Dawson MA and Kouzarides T. Cancer epigenetics: from mechanism to therapy. Cell. 150: 12-27, 2012.
Additional Reading (not required but will enhance understanding)

Brien GL, Stegmaier K, and Armstrong SA. Targeting Chromatin Complexes in Fusion Protein-Driven Malignancies. Nature Reviews Cancer. 19:255-269, 2019.

Feb. 21 - Jozwik KM, Carroll JS. Pioneer factors in hormone-dependent cancers. Nature Reviews Cancer. 12:381-385, 2012.

Feb. 24 – Journal Club Discussion: Parolia A et al., Distinct Structural Classes of Activating FOXA1 Alterations in Advanced Prostate Cancer. Nature 571:413-418, 2019.

Additional Reading (not required but will enhance understanding)
Adams EJ et al., FOXA1 Mutations Alter Pioneering Activity, Differentiation and Prostate Cancer Phenotypes. Nature. 571:408-412, 2019.

Block 6: Tumor Suppressor Genes, Genome Instability

Feb. 26 - Weinberg Chapter 7, pgs. 209-254

Feb. 27 - Weinberg Chapter 12, pgs. 463-526

Feb. 28 - Leveraging DNA repair for genome engineering
Programmable editing of a target base in genomic DNA without double-stranded DNA  cleavage.Nature. 2016 May 19;533(7603):420-4. doi: 10.1038/nature17946. Epub 2016 Apr 20. 
Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage.Nature. 2017 Nov 23;551(7681):464-471. doi: 10.1038/nature24644. Epub 2017 Oct 25.
Chromosomal translocations in human cells are generated by canonical nonhomologous end-joining.Mol Cell. 2014 Sep 18;55(6):829-842. doi: 10.1016/j.molcel.2014.08.002. Epub 2014 Sep 4.
March 2 – Emerging landscape of oncogenic signatures across human cancers. Nat Genet.2013 Oct;45(10):1127-33. doi: 10.1038/ng.2762.

Block 7/8: Apoptosis/Autophagy/Metabolism

March 4 and 5 – Apoptosis & the Bcl-2 Family (didactic)
Weinberg Chapter 9 pages 361-381

Additional Reading (recommended) –
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-

H. Kalkavan and D. R. Green. MOMP, cell suicide as a BCL-2 family business. Cell Death and Diff, 2018. 25:45–55

Optional- Kale, J. E.J. Osterlund and D. Andrews. BCL-2 family proteins: changing partners in the dance towards death. Cell Death and Diff, 2018. 25:65–80

March 5 and 6 – Autophagy (didactic)
Recommended Reading
Liu J. and Debnath J. The Evolving, Multifaceted Roles of Autophagy in Cancer. Adv Cancer Res. 2016. 130: p.1-53.

Rybstein, M. D., J. M.l Bravo-San Pedro, G. Kroemer and L. Galluzzi. The autophagic network and cancer. Nature Cell Biology, 2018. 20:243–251

March 16 - Review Apoptosis and Autophagy in second half of class.

March 16 and 18– Cancer Metabolism (didactic)
Recommended Reading
Cantor, J.R. and D.M. Sabatini, Cancer cell metabolism: one hallmark, many faces. Cancer Discovery, 2012. 2(10): p. 881-898
Vander Heiden, M. G. and R. DeBerardinis. Understanding the Intersections between Metabolism and Cancer Biology. Cell 2017. 168: 657-669

Additional Reading (optional) –
Liberti, M. M. and Locasale, J. W. The Warburg Effect: How Does it Benefit Cancer Cells? Trends in Biochemical Sciences 2016. 41:211-217

March 19 – Paper for discussion
La Belle Flynn, A., B.C. Calhoun, A. Sharma, et al., Autophagy inhibition elicits emergence from metastatic dormancy by inducing and stabilizing Pfkfb3 expression. Nat Commun, 2019. 10(1): p. 3668.

March 20 – Paper for discussion
Garcia-Bermudez, J., L. Baudrier, K. La, et al. Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours. 2018. Nature Cell Biology, 2018. 20:775–781

March 23 – Paper for discussion
Labuschagne, C.F., E.C. Cheung, J. Blagih, et al., Cell Clustering Promotes a Metabolic Switch that Supports Metastatic Colonization. Cell Metab, 2019. 30(4): p. 720-734 e5.

Block 9: Cellular Immortalization, Stem Cells, and Cancer Stem Cells

March 25- Weinberg Chapter 10, pgs. 357-398
Liu, T., X. Yuan and D. Xu (2016). "Cancer-Specific Telomerase Reverse Transcriptase (TERT) Promoter Mutations: Biological and Clinical Implications." Genes (Basel) 7(7).

March 26 - Weinberg Chapter 11, pgs. 399-441

March 27 – Three papers:
Tomasetti, C. and B. Vogelstein (2015). "Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions." Science 347(6217): 78-81.

Wu, S., S. Powers, W. Zhu and Y. A. Hannun (2016). "Substantial contribution of extrinsic risk factors to cancer development." Nature 529(7584): 43-47.

Tomasetti, C., L. Li and B. Vogelstein (2017). "Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention." Science 355(6331): 1330-1334.

March 30 – Journal Club Paper:
Zhu, L., D. Finkelstein, C. Gao, L. Shi, Y. Wang, D. Lopez-Terrada, K. Wang, S. Utley, S. Pounds, G. Neale, D. Ellison, A. Onar-Thomas and R. J. Gilbertson (2016). "Multi-organ Mapping of Cancer Risk." Cell 166(5): 1132-1146 e1137.

Block 10: Angiogenesis

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

April 2 – 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

April 3 -

April 6– 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.

Block 11: Human Cancer and Microbes: Bacteria and Viruses

April 8 - Weinberg Chapter 11, pgs. 488-500 and one paper:
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 9 – One paper:
Rajagopala, S. V., S. Vashee, L. M. Oldfield, Y. Suzuki, J. C. Venter, A. Telenti and K. E. Nelson (2017). "The Human Microbiome and Cancer." Cancer Prev Res (Phila) 10(4): 226-234.

April 10 – One paper:
Bullman, S., C. S. Pedamallu, E. Sicinska, T. E. Clancy, X. Zhang, D. Cai, D. Neuberg, K. Huang, F. Guevara, T. Nelson, O. Chipashvili, T. Hagan, M. Walker, A. Ramachandran, B. Diosdado, G. Serna, N. Mulet, S. Landolfi, Y. C. S. Ramon, R. Fasani, A. J. Aguirre, K. Ng, E. Elez, S. Ogino, J. Tabernero, C. S. Fuchs, W. C. Hahn, P. Nuciforo and M. Meyerson (2017). "Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer." Science 358(6369): 1443-1448.

April 13 – Journal Club Paper
Liu, L., F. K. Tabung, X. Zhang, J. A. Nowak, Z. R. Qian, T. Hamada, D. Nevo, S. Bullman, K. Mima, K. Kosumi, A. da Silva, M. Song, Y. Cao, T. S. Twombly, Y. Shi, H. Liu, M. Gu, H. Koh, W. Li, C. Du, Y. Chen, C. Li, W. Li, R. S. Mehta, K. Wu, M. Wang, A. D. Kostic, M. Giannakis, W. S. Garrett, C. Hutthenhower, A. T. Chan, C. S. Fuchs, R. Nishihara, S. Ogino and E. L. Giovannucci (2018). "Diets That Promote Colon Inflammation Associate With Risk of Colorectal Carcinomas That Contain Fusobacterium nucleatum." Clin Gastroenterol Hepatol 16(10): 1622-1631 e1623.

Block 12: Tumor microenvironment, invasion and metastasis

April 15
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.

April 16
Weinberg, pgs 657-685 mechanisms of invasion, EMT, MMPs, contribution of stromal cells to tumor cell invasion

April 17
Weinberg, pgs 641-656, 709-711 mechanisms of metastasis, chemokines, metastatic tropism

April 20 Journal club discussion
TBD

Block 13: Cancer Therapy I: Tumor Immunology and Immune Therapies

April 22 – No class due to Masonic Cancer Center Annual Symposium
Students are strongly encouraged to attend the keynote seminar
9:30-10:30, TCF Stadium
Dr. Laura Esserman, MD, MBA
Title TBD

April 23 - Weinberg Chapter 15

April 24
– Please read this review article for a discussion about immune checkpoint inhibitors. Park, Y.-J., Kuen, D.-S., Chung, Y. 2018. Future prospects of immune checkpoint blockade in cancer: from response prediction to overcoming resistance. Exp Mol. Medicine 50:109. DOI 10.1038/s12276-018-0130-1

April 27 – Come to class prepared to present and discuss: Ruella, M., et al. 2018. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nature Medicine 24(10):1499-1503. DOI: 10.1038/s41591-018-0201-9

Block 14: Cancer Therapy II: Small Molecules and Targeted Therapy

April 29 – Weinberg Chapter 16 pgs. 797-815

April 30 - Weinberg Chapter 16 pgs. 815-818; 825-833; 844-860

May 1 - Goel et al. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell. 29: 255-269, 2016.

May 4

 

MICA 8004 – Biology of Cancer
Key Concepts

Block 1: Cancer Pathology and the TCGA
1. Use and understand terminology describing pathological and molecular processes in cancer development and progression
2. Enumerate and provide an overview of the hallmarks of cancer and their significance to diagnosis and therapy
3. 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?”)
4. Describe the histological origins of cancer and their relationship to processes of developmental biology
5. Evaluate the usefulness of The Cancer Genome Atlas

Block 2: Cancer Genetics: Cancer Viruses, Experimental Genetics
1. Know how Rous sarcoma virus helped to confirm that viruses could cause cancer
2. Know the basic properties of transformed cells
3. Describe the basic genetic approaches to engineering mice for the study of cancer
4. Describe the histological origins of cancer and their relationship to processes of developmental biology
5. Know the basic properties of retrovirus structure and replication
6. Describe how Rous sarcoma virus (RSV) and acute transforming retroviruses cause cancer
7. Describe how the study of RSV lead to the identification of cellular oncogenes
8. Know how slowly transforming retroviruses cause cancer and how to identify cancer causing insertions in chromosomal DNA
9. Describe how DNA viruses (e.g., SV40) cause cancer
10. 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…
1. How growth factors and growth factor receptors facilitate cell-to-cell communications.
2. The mechanism of kinases and their importance for signal transduction.
3. The structure and function of receptor tyrosine kinases.
4. Basics of other receptors in cell-to-cell signaling.
5. How the above (1-4) can be altered in the context of cancer and what that means for tumor progression and the development of cancer therapies that target one vs. multiple hallmarks of cancer (or cancer plasticity).

Block 4: RB/Cell Cycle/P53
1. Understand how cyclins and their catalytic CDK binding partners control cell cycle
2. How do hypo- and hyper-phosphorylated pRb control cell cycle, differentiation and cancer and how does this pathway differ in stem cells
3. The E2F transcription factors associate with promoters of genes that control cell cycle, DNA replication, mitosis, DNA repair, apoptosis and cancer cell proliferation.
4. Timing and signals that control distinct cell fates, such as cell cycle, quiescence, apoptosis, differentiation or senescence
5. How does the loss of pRb function activate pro-apoptotic or senescence programs and how does p53 fit in this pathway
6. How does DNA damage interface with the cell cycle to minimize the risk of cancer, and how do Rb and p53 control this

Block 5: Cell Signaling II: The Nucleus (Steroid Hormone Receptors, Fos/Jun, JAK-STAT)
1. Transcription and deregulation in cancer
2. Myc, Fos/Jun, STATs and oncogenic signal transduction pathways
3. Hormone receptors and the development and progression of prostate and breast cancers.
4. Androgen and estrogen signaling pathways, “molecularly targeted therapies” and resistance
5. Therapeutic targeting of epigenetic deregulation in cancer

Block 6: Tumor Suppressor Genes: Genome Instability
1. Mechanisms for loss of heterozygoisity (LOH) during tumorigenesis
2. DNA repair mechanisms are tumor suppressive
3. Base excision repair
4. Mismatch repair
5. Homologous recombination

Block 7/8: Apoptosis /Autophagy/Metabolism
1. Programmed Cell Death and Apoptotic pathways in normal cells and their aberrant regulation in cancer, with special emphasis on the Bcl-2 protein family
2. Autophagy as a Stress Response in normal cells, and the contradictory and contextual roles for deregulated Autophagy in tumor suppression and tumor progression
3. The Warburg Hypothesis and Metabolic Reprogramming in actively proliferating normal cells and cancer cells
4. Crosstalk between Apoptosis, Autophagy and Metabolism, overlap and shared regulators

Block 9: Cellular Immortalization; Cancer Stem Cells
1. 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
2. A long succession of growth-and-division cycles occur as they evolve toward the neoplastic growth state
3. 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)
4. 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
5. Normal cells evolve into cells with increasingly neoplastic phenotypes through a process termed tumor progression
6. 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
7. 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 10: Angiogenesis
1. Tumors and intercommunication between various cell types
2. The recruitment of macrophages, fibroblasts and fibroblast and their key roles during tumor-associated angiogenesis
3. The “Angiogenic switch” and tumor-associated angiogenesis as a critical determinant of tumor growth.
4. 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
1. Viruses and bacteria can cause human cancer. Roughly 20% of human cancer has a viral etiology.
2. Roughly 20% of human cancer cases have a viral etiology.
3. Microbes are incomplete carcinogens, often cause chronic inflammation leading to cancer.
4. Viral proteins designed to enhance replication can contribute to cancer development.
5. Criteria for establishing causation differs from Koch’s postulates

Block 12: Tumor microenvironment, invasion and metastasis
1. Tumor growth and metastasis require intercommunication between various cell types
2. Importance of heterotypic interactions in primary tumors and metastasis. Tumors as wounds in a perpetual state of healing. Paracrine vs. Autocrine interactions in progression Transcriptional Regulation of EMT/stem cell properties.
3. 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.
4. Tumor reactive stroma and therapeutic resistance. Impact of stromal organization and composition on clinical response in cancer.
5. EMT and invasion are important for tumor cell invasion and metastasis.

Block 13: Cancer Therapy I: Tumor Immunology and Immune Therapies
1. Immune surveillance constantly eliminates nascent tumors and, by definition, cancer has escaped immune surveillance. 
2. The characteristics of the immune system that make it attractive for cancer therapy include specificity, potency, memory, and plasticity.
3. Immune therapeutics for cancer include monoclonal antibodies, adoptively transferred cells (some of which are genetically manipulated), vaccines, and immune stimulants.
4. The major hurdles for cancer immunotherapeutics include: a) identifying a suitable target antigen to minimize reactivity with healthy tissues; b) getting the immunotherapeutic to the tumor site; and c) overcoming tumor-mediated immune suppression in the tumor microenvironment.

Block 14: Cancer Therapy II: Small Molecules and Targeted Therapy
1. Understand the role of systemic therapy in reducing breast cancer deaths.
2. Identifying prognostic factors and their roles as targets for cancer therapy.
3. Describe the role for targeted therapies and mechanism of action.
4. Resistance to targeted therapies is frequently seen and can be either de novo or acquired. Understand that targeting multiple pathways may be critical