The Seeds and the Soil: Roles of Tumor Heterogeneity and the Tumor Microenvironment in Cancer Metastasis

Readings

week #	topics	readings
1	Introduction See the Lecture Summary	No Readings
2	Epithelial-Mesenchymal Transition and Dissemination from the Primary Tumor See the Lecture Summary	Yang, J., Mani, S. A., Donaher, J. L., et al. (2004) Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis (PDF). Cell 117, 927-939. Janda, E., Lehmann, K., Killisch, I., et al. (2002) Ras and TGFβ cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. The Journal of Cell Biology 156, 299–314.
3	Cancer in Transit: Dynamics and Behaviors of Circulating Tumor Cells (CTCs) See the Lecture Summary	Yu, M., Bardia, A., Wittner, B. S., et al. (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339, 580–584. Cheung, K. J., Padmanaban, V., Silvestri, V., et al. (2016) Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters. Proc Natl Acad Sci U S A 113, E854–863.
4	Stromal Support of Dissemination See the Lecture Summary	Lin, E. Y., Nguyen, A. V., Russell, R. G., and Pollard, J. W. (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193, 727–740. Labelle, M., Begum, S., and Hynes, R. O. (2011) Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell 20, 576–590.
5	EMT Plasticity and Metastatic Colonization See the Lecture Summary	Ocana, O. H., Corcoles, R., Fabra, A., et al. (2012) Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22, 709–724. Pastushenko, I., Brisebarre, A., Sifrim, A., et al. (2018) Identification of the tumour transition states occurring during EMT. Nature 556, 463–468.
6	Cancer Stem Cells See the Lecture Summary	de Sousa e Melo, F., Kurtova, A. V., Harnoss, J. M., et al. (2017) A distinct role for Lgr5(+) stem cells in primary and metastatic colon cancer (PDF - 4.9MB). Nature 543, 676–680. Fumagalli, A., Oost, K.C., Kester, L., et al. (2020) Plasticity of Lgr5-negative cancer cells drives metastasis in colorectal cancer. Cell Stem Cell 26, 569–578.e7.
7	Genetic Heterogeneity and Evolution of Metastatic Disease See the Lecture Summary	Turajlic, S., Xu, H., Litchfield, K., et al. (2018) Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal. Cell 173, 581–594 e12. Reiter, J. G., Makohon-Moore, A. P., Gerold, J. M., et al. (2018) Minimal functional driver gene heterogeneity among untreated metastases. Science 361, 1033–1037.
8	Field Trip See the Lecture Summary	Dang, L., White, D. W., Gross, S., et al. (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462, 739–744.
9	Determinants of Metastatic Tropism See the Lecture Summary	Valiente, M., Obenauf, A. C., Jin, X., et al. (2014) Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156, 1002–1016. Reichert, M., Bakir, B., Moreira, L., et al. (2018) Regulation of epithelial plasticity determines metastatic organotropism in pancreatic cancer. Dev Cell. 45, 696–711.e8.
10	The Metastatic Niche See the Lecture Summary	Shiozawa, Y., Pedersen, E. A., Havens, A. M., et al. (2011) Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest 121, 1298–1312. Malanchi, I., Santamaria-Martinez, A., Susanto, E., et al. (2011) Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85–89.
11	Systemic Effects and the Pre-metastatic Niche See the Lecture Summary	Costa-Silva, B., Aiello, N. M., Ocean, A. J., et al. (2015) Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 17, 816–826. Elkabets, M., Gifford, A. M., Scheel, C., et al. (2011) Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice. J. Clin. Invest. 121, 784–799.
12	Interactions Between Dormant DTCs and the Immune System See the Lecture Summary	Malladi, S., Macalinao, D. G., Jin, X., et al. (2016) Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell 165, 45–60. Pommier, A., Anaparthy, N., Memos, N., et al. (2018) Unresolved endoplasmic reticulum stress engenders immune-resistant, latent pancreatic cancer metastases. Science 360, eaao4908.
13	Oral Presentations and Closing Remarks See the Lecture Summary	No Readings