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Breast Cancer Metastasis Studying Tool
During the metastatic process, breast cancer cells must come into contact with the extra-cellular matrix (ECM) at every step. The ECM provides both structural support and biochemical cues, and cell–ECM interactions can lead to changes in drug response. Here, we used fibroblast-derived ECM (FDM) to perform high throughput drug screening of 4T1 breast cancer cells on metastatic organ ECM (lung), and we see that drug response differs from treatment on plastic. The FDMs that we can produce from different organs are abundant in and contains a complex mixture of ECM proteins. We also show differences in ECM composition between the primary site and secondary organ sites. Furthermore, we show that global kinase signalling of 4T1 cells on the ECM is relatively unchanged between organs, while changes in signalling compared to plastic are significant. Our study highlights the importance of context when testing drug response in vitro, showing that consideration of the ECM is critically important.
2. Current Analysis on Cancer–ECM interactions
ECM produced by fibroblasts from different murine organs (to which breast cancer metastasise) is complex, abundant in ECM constituents, and differ in composition between organs.
FDMs can be used to assess global kinase signalling of 4T1 and 67NR breast cancer cells in vitro. Inter-organ kinase activation differs to a smaller degree compared to cancer cells on plastic.
FDMs can be used to perform high-throughput screening of kinase inhibitors on 4T1 cells. Inhibition of 4T1 proliferation on ECM differs from 4T1 cells screened on plastic.
Network analysis performed proposes targets to inhibit proliferation of 4T1 cells in the lung by combining lung ECM changes with kinase activation profiles, and inferring protein–protein interaction pathways.
The entry is from 10.3390/cancers13133331
- Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell 2000, 100, 57–70.
- Dillekås, H.; Rogers, M.S.; Straume, O. Are 90% of deaths from cancer caused by metastases? Cancer Med. 2019, 8, 5574–5576.
- Cox, T.R.; Erler, J.T. Remodeling and homeostasis of the extracellular matrix: Implications for fibrotic diseases and cancer. Dis. Models Mech. 2011, 4, 165–178.
- Cox, T.R. The matrix in cancer. Nat. Rev. Cancer 2021, 21, 217–238.
- Langley, R.R.; Fidler, I.J. The seed and soil hypothesis revisited—The role of tumor-stroma interactions in metastasis to different organs. Int. J. Cancer 2011, 128, 2527–2535.
- Kalluri, R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 2016, 16, 582–598.
- Sahai, E.; Astsaturov, I.; Cukierman, E.; DeNardo, D.G.; Egeblad, M.; Evans, R.M.; Fearon, D.; Greten, F.R.; Hingorani, S.R.; Hunter, T.; et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 2020, 20, 174–186.
- Burgstaller, G.; Oehrle, B.; Gerckens, M.; White, E.S.; Schiller, H.B.; Eickelberg, O. The instructive extracellular matrix of the lung: Basic composition and alterations in chronic lung disease. Eur. Respir. J. 2017, 50, 1601805.
- Lee, J.Y.; Chang, J.K.; Dominguez, A.A.; Lee, H.P.; Nam, S.; Chang, J.; Varma, S.; Qi, L.S.; West, R.B.; Chaudhuri, O. YAP-independent mechanotransduction drives breast cancer progression. Nat. Commun. 2019, 10, 1848.
- Brett, E.; Sauter, M.; Timmins, É.; Azimzadeh, O.; Rosemann, M.; Merl-Pham, J.; Hauck, S.M.; Nelson, P.J.; Becker, K.F.; Schunn, I.; et al. Oncogenic Linear Collagen VI of Invasive Breast Cancer Is Induced by CCL5. J. Clin. Med. 2020, 9, 991.
- Park, D.; Sahai, E.; Rullan, A. SnapShot: Cancer-Associated Fibroblasts. Cell 2020, 181, 486–486.e1.
- Naba, A.; Clauser, K.R.; Hoersch, S.; Liu, H.; Carr, S.A.; Hynes, R.O. The matrisome: In silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices. Mol. Cell. Proteom. 2012, 11, M111.014647.
- Kaukonen, R.; Jacquemet, G.; Hamidi, H.; Ivaska, J. Cell-derived matrices for studying cell proliferation and directional migration in a complex 3D microenvironment. Nat. Protoc. 2017, 12, 2376–2390.
- Qi, L.; Zhang, Y.; Song, F.; Han, Y.; Ding, Y. A newly identified small molecular compound acts as a protein kinase inhibitor to suppress metastasis of colorectal cancer. Bioorg. Chem. 2021, 107, 104625.
- Manning, G.; Whyte, D.B.; Martinez, R.; Hunter, T.; Sudarsanam, S. The protein kinase complement of the human genome. Science 2002, 298, 1912–1934.
- Tan, H.-Y.; Wang, N.; Lam, W.; Guo, W.; Feng, Y.; Cheng, Y.-C. Targeting tumour microenvironment by tyrosine kinase inhibitor. Mol. Cancer 2018, 17, 43.
- Du, Z.; Lovly, C.M. Mechanisms of receptor tyrosine kinase activation in cancer. Mol. Cancer 2018, 17, 58.
- Heldin, C.H. Targeting the PDGF signaling pathway in tumor treatment. Cell Commun. Signal. 2013, 11, 97.
- Normanno, N.; De Luca, A.; Bianco, C.; Strizzi, L.; Mancino, M.; Maiello, M.R.; Carotenuto, A.; De Feo, G.; Caponigro, F.; Salomon, D.S. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006, 366, 2–16.
- Roskoski, R., Jr. Properties of FDA-approved small molecule protein kinase inhibitors: A 2020 update. Pharmacol. Res. 2020, 152, 104609.
- Ediriweera, M.K.; Tennekoon, K.H.; Samarakoon, S.R. In vitro assays and techniques utilized in anticancer drug discovery. J. Appl. Toxicol. 2019, 39, 38–71.
- Driehuis, E.; Kretzschmar, K.; Clevers, H. Establishment of patient-derived cancer organoids for drug-screening applications. Nat. Protoc. 2020, 15, 3380–3409.
- Kitaeva, K.V.; Rutland, C.S.; Rizvanov, A.A.; Solovyeva, V.V. Cell Culture Based in vitro Test Systems for Anticancer Drug Screening. Front. Bioeng. Biotechnol. 2020, 8, 322.
- Press, D.J.; Miller, M.E.; Liederbach, E.; Yao, K.; Huo, D. De novo metastasis in breast cancer: Occurrence and overall survival stratified by molecular subtype. Clin. Exp. Metastasis 2017, 34, 457–465.
- Liu, J.; Pandya, P.; Afshar, S. Therapeutic Advances in Oncology. Int. J. Mol. Sci. 2021, 22, 2008.
- Waks, A.G.; Winer, E.P. Breast Cancer Treatment: A Review. JAMA 2019, 321, 288–300.
- Aslakson, C.J.; Miller, F.R. Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res. 1992, 52, 1399–1405.
- Pulaski, B.A.; Ostrand-Rosenberg, S. Mouse 4T1 breast tumor model. Curr. Protoc. Immunol. 2001, 39, 20.2.1–20.2.16.
- Franco-Barraza, J.; Beacham, D.A.; Amatangelo, M.D.; Cukierman, E. Preparation of Extracellular Matrices Produced by Cultured and Primary Fibroblasts. Curr. Protoc. Cell Biol. 2016, 71, 10.9.1–10.9.34.
- Fidler, I.J. The pathogenesis of cancer metastasis: The ‘seed and soil’ hypothesis revisited. Nat. Rev. Cancer 2003, 3, 453–458.
- Rafaeva, M.; Erler, J.T. Framing cancer progression: Influence of the organ- and tumour-specific matrisome. FEBS J. 2020, 287, 1454–1477.
- Shinsato, Y.; Doyle, A.D.; Li, W.; Yamada, K.M. Direct comparison of five different 3D extracellular matrix model systems for characterization of cancer cell migration. Cancer Rep. 2020, 3, e1257.
- Hutchinson, L.; Kirk, R. High drug attrition rates—where are we going wrong? Nat. Rev. Clin. Oncol. 2011, 8, 189–190.
- Yemanyi, F.; Vranka, J.; Raghunathan, V. Chapter 12—Generating cell-derived matrices from human trabecular meshwork cell cultures for mechanistic studies. In Methods in Cell Biology; Caballero, D., Kundu, S.C., Reis, R.L., Eds.; Academic Press: Cambridge, MA, USA, 2020; Volume 156, pp. 271–307.
- Walker, C.; Mojares, E.; Del Río Hernández, A. Role of Extracellular Matrix in Development and Cancer Progression. Int. J. Mol. Sci. 2018, 19, 3028.
- Pickup, M.W.; Laklai, H.; Acerbi, I.; Owens, P.; Gorska, A.E.; Chytil, A.; Aakre, M.; Weaver, V.M.; Moses, H.L. Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas. Cancer Res. 2013, 73, 5336–5346.
- Kutys, M.L.; Doyle, A.D.; Yamada, K.M. Regulation of cell adhesion and migration by cell-derived matrices. Exp. Cell Res. 2013, 319, 2434–2439.
- Petrie, R.J.; Gavara, N.; Chadwick, R.S.; Yamada, K.M. Nonpolarized signaling reveals two distinct modes of 3D cell migration. J. Cell Biol. 2012, 197, 439–455.
- Mazhar, S.; Taylor, S.E.; Sangodkar, J.; Narla, G. Targeting PP2A in cancer: Combination therapies. Biochim. Biophys. Acta Mol. Cell Res. 2019, 1866, 51–63.
- Kim, J.; Koo, B.-K.; Knoblich, J.A. Human organoids: Model systems for human biology and medicine. Nat. Rev. Mol. Cell Biol. 2020, 21, 571–584.
- Maru, Y.; Tanaka, N.; Itami, M.; Hippo, Y. Efficient use of patient-derived organoids as a preclinical model for gynecologic tumors. Gynecol. Oncol. 2019, 154, 189–198.
- Li, Z.; Dranoff, J.A.; Chan, E.P.; Uemura, M.; Sévigny, J.; Wells, R.G. Transforming growth factor-beta and substrate stiffness regulate portal fibroblast activation in culture. Hepatology 2007, 46, 1246–1256.
- Hoshiba, T.; Tanaka, M. Decellularized matrices as in vitro models of extracellular matrix in tumor tissues at different malignant levels: Mechanism of 5-fluorouracil resistance in colorectal tumor cells. Biochim. Biophys. Acta BBA Mol. Cell Res. 2016, 1863, 2749–2757.