Difference between revisions of "Team:ETH Zurich/Project Description"

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{{ETH_Zurich}}
 
{{ETH_Zurich}}
 
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<h2> The light at the end of the tunnel...</h2>
 
<h2> The light at the end of the tunnel...</h2>
  
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<p>Overall, the integration of two general markers allows for the detection of various types of cancers with high reliability and a low false positive rate, while control of signal expression by the bacteria should result in a considerable increase in the signal to noise ratio compared to assay kit-based tests. The direct binding of our MicroBeacons to cancer cells allow for the detection of lactate and AHL in a very controlled microenvironment with minimal crosstalk from other cells in the sample or unbound MicroBeacons. Finally, the use of a fluorescent signal as our output signal will allow for easy measurement from the microfluidic chip through microscopy.</p>
 
<p>Overall, the integration of two general markers allows for the detection of various types of cancers with high reliability and a low false positive rate, while control of signal expression by the bacteria should result in a considerable increase in the signal to noise ratio compared to assay kit-based tests. The direct binding of our MicroBeacons to cancer cells allow for the detection of lactate and AHL in a very controlled microenvironment with minimal crosstalk from other cells in the sample or unbound MicroBeacons. Finally, the use of a fluorescent signal as our output signal will allow for easy measurement from the microfluidic chip through microscopy.</p>
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<text transform="matrix(1 0 0 1 416.965 302.2761)" class="st5 st6">MicroBeacon </text>
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<text transform="matrix(1 0 0 1 509.6614 302.2758)" class="st17 st6">coli</text>
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<text transform="matrix(1 0 0 1 787.4497 106.1319)" class="st5 st6">1. Apoptosis is induced only in cancer cells</text>
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<text transform="matrix(1 0 0 1 787.4497 124.8819)" class="st5 st6">by sTRAIL and causes phosphotadylserine (PS)</text>
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<text transform="matrix(1 0 0 1 787.4497 143.6319)" class="st5 st6">to flip to the outer membrane.</text>
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<text transform="matrix(1 0 0 1 731.4907 304.1405)" class="st5 st6">2. Mammalian cells and MicroBeacons are sent</text>
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<text transform="matrix(1 0 0 1 731.4907 322.8905)" class="st5 st6">through the microfluidic chip.</text>
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<text transform="matrix(1 0 0 1 916.2844 421.2782)" class="st5 st6">3. MicroBeacons with membrane-</text>
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<text transform="matrix(1 0 0 1 916.2844 440.0282)" class="st5 st6">expressed annexin V bind to exposed</text>
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<text transform="matrix(1 0 0 1 916.2844 458.7782)" class="st5 st6">PS on apoptotic cancer cells and not to</text>
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<text transform="matrix(1 0 0 1 916.2844 477.5282)" class="st5 st6">normal cells.</text>
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<text transform="matrix(1 0 0 1 187.8096 629.2689)" class="st5 st6">4. Higher lactate production rates in the</text>
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<text transform="matrix(1 0 0 1 187.8096 648.0189)" class="st5 st6">apoptotic cancer cell initiates quorum </text>
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<text transform="matrix(1 0 0 1 187.8096 666.7689)" class="st5 st6">sensing between the MicroBeacons to </text>
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<text transform="matrix(1 0 0 1 187.8096 685.5189)" class="st5 st6">amplify the signal.</text>
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<text transform="matrix(1 0 0 1 911.0817 638.6911)" class="st5 st6">5. A green fluorescent signal is</text>
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<text transform="matrix(1 0 0 1 911.0817 657.4411)" class="st5 st6">produced by MicroBeacons that have</text>
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<text transform="matrix(1 0 0 1 911.0817 676.1911)" class="st5 st6">detected the quorum sensing signals.</text>
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<h3> References </h3>
 
<h3> References </h3>

Revision as of 14:12, 15 July 2015

"What I cannot create I do not understand."
- Richard Feynmann

The light at the end of the tunnel...

Cancer diagnosis is one of modern medicine's major and challenging problems1. Thus, designing a novel method to test for cancer cells quickly caught our attention as a potential project idea. After researching current testing methods and brainstorming how a test could be implemented in a genetically-modified organism, we came up with a system for the assessment of metastasis risk in cancer patients and high-risk groups using a genetically-engineered strain of Escherichia coli which we call MicroBeacon E. coli.

Circulating tumour cells (CTCs) can be used as an indicator of the initial stages of metastasis2. In our project we aim to develop a novel method that is fast, economical, and reliable for the identification of CTCs by using MicroBeacons to detect two general cancer markers and indicate this through fluorescence. By design, this makes our system applicable to many types of cancer. To facilitate handling the cells, our detection system will be embedded in a microfluidic chip built especially for this purpose. In contrast to existing methods which rely on detection of very specific cancer markers3,4,5, a single general test would be more economical if it can be mass produced and deployed in a cost-effective manner.

The first marker we are planning to detect is the increased production rate of lactate by cancer cells due to the Warburg effect, a metabolic shift occurring in tumor cells that is characterized by a much higher glycolysis rate and subsequent lactic acid fermentation6,7. The constitutive expression of LldR, a repressor of the lldPRD operon in E. coli, is an important part of our method. Binding of lactate to LldR causes a conformational change inhibiting its ability to bind to its target operators and activating the operon8. Due to the accumulation of lactate over time in the environment, we designed our sensor to detect fold-changes instead of a concentration threshold using a gene expression system with an incoherent feedforward loop topology9. Overall, a newly designed lldR-lacO fusion promoter acts as a filter which will only allow the production of quorum sensing molecules (AHL) if an elevated lactate production rate is detected. This is where the second cancer marker comes into play.

For the second signal, apoptosis is induced only in cancer cells by incubating the sample in a solution containing soluble TNF-related apoptosis-inducing ligand (sTRAIL) prior to the introduction of MicroBeacons to the environment10. The initiation of apoptosis can then be detected by the strong binding of Annexin V to phosphatidylserine (PS) that appears on the outer membrane of the target CTCs11. Although it is normally an intracellular protein12, we plan to engineer it to be expressed on the surface of our MicroBeacons, allowing them to bind to the target CTCs. Co-localisation of several MicroBeacons on the surface of an apoptotic CTC will be detected via quorum sensing signals which are only initiated upon detection of elevated lactate levels. The final output of the system is the expression of reporter green fluorescent protein (GFP) coupled to this quorum sensing system, which should only be significantly expressed near a target if it is a cancer cell.

Overall, the integration of two general markers allows for the detection of various types of cancers with high reliability and a low false positive rate, while control of signal expression by the bacteria should result in a considerable increase in the signal to noise ratio compared to assay kit-based tests. The direct binding of our MicroBeacons to cancer cells allow for the detection of lactate and AHL in a very controlled microenvironment with minimal crosstalk from other cells in the sample or unbound MicroBeacons. Finally, the use of a fluorescent signal as our output signal will allow for easy measurement from the microfluidic chip through microscopy.

  • sTRAIL cancer cell normal cell MicroBeacon coli 1. Apoptosis is induced only in cancer cells by sTRAIL and causes phosphotadylserine (PS) to flip to the outer membrane. 2. Mammalian cells and MicroBeacons are sent through the microfluidic chip. 3. MicroBeacons with membrane- expressed annexin V bind to exposed PS on apoptotic cancer cells and not to normal cells. 4. Higher lactate production rates in the apoptotic cancer cell initiates quorum sensing between the MicroBeacons to amplify the signal. 5. A green fluorescent signal is produced by MicroBeacons that have detected the quorum sensing signals. lactate AHL

References

  1. International Agency for Research on Cancer. (2014). World cancer report 2014. Geneva: WHO.
  2. Sleijfer, S., Gratama, J. W., Sieuwerts, A. M., Kraan, J., Martens, J. W., & Foekens, J. A. (2007). Circulating tumour cell detection on its way to routine diagnostic implementation?. European Journal of Cancer, 43(18), 2645-2650.
  3. Cooke, T., Reeves, J., Lanigan, A., & Stanton, P. (2001). HER2 as a prognostic and predictive marker for breast cancer. Annals of oncology, 12(suppl 1), S23-S28.
  4. Garcea, G., Neal, C. P., Pattenden, C. J., Steward, W. P., & Berry, D. P. (2005). Molecular prognostic markers in pancreatic cancer: a systematic review. European Journal of Cancer, 41(15), 2213-2236.
  5. Singhal, S., Vachani, A., Antin-Ozerkis, D., Kaiser, L. R., & Albelda, S. M. (2005). Prognostic implications of cell cycle, apoptosis, and angiogenesis biomarkers in non–small cell lung cancer: a review. Clinical Cancer Research,11(11), 3974-3986.
  6. Chen, Z., Lu, W., Garcia-Prieto, C., & Huang, P. (2007). The Warburg effect and its cancer therapeutic implications. Journal of bioenergetics and biomembranes, 39(3), 267-274.
  7. Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 324(5930), 1029-1033.
  8. Aguilera, L., Campos, E., Giménez, R., Badía, J., Aguilar, J., & Baldoma, L. (2008). Dual role of LldR in regulation of the lldPRD operon, involved in L-lactate metabolism in Escherichia coli. Journal of bacteriology, 190(8), 2997-3005.
  9. Goentoro, L., Shoval, O., Kirschner, M. W., & Alon, U. (2009). The incoherent feedforward loop can provide fold-change detection in gene regulation. Molecular cell, 36(5), 894-899.
  10. Srivastava, R. K. (2001). TRAIL/Apo-2L: mechanisms and clinical applications in cancer. Neoplasia, 3(6), 535-546.
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