Community Research and Development Information Service - CORDIS

FP7

SYSBIODREZ Report Summary

Project reference: 626190
Funded under: FP7-PEOPLE

Final Report Summary - SYSBIODREZ (SYSTEMS BIOLOGY APPROACH TO PREDICTING OUTCOMES OF LUNG CANCER THERAPIES AND STRATEGIES TO OVERCOME DRUG RESISTANCE IN VITRO.)

Scientist in Charge: Paul Hofman (IRCAN, Inserm/CNRS), Researcher: Jeremie Roux (IRCAN, Inserm/CNRS), Scientific Partner: Jean-Luc Gouzé (BioCore, INRIA).

Summary

Single-cell technologies have changed the research dedicated to identifying predictive biomarkers of tumor sensitivity to anti-cancer therapies. New biomarkers have emerged, but there is still no comprehensive understanding that unifies the observed tumor cell type-specific behaviors, in particular the differential responses to anti-cancer drugs. The collective realization is that no single gene or protein expression measurement is predictive of therapeutic outcome. In addition, large-scale studies focusing on multiple genetic biomarkers only may be partially inadequate given the observed fractional killing of genetically identical clonal cell populations.

The objective of this proposal was to address this deficiency by coupling high-content analyses (dynamic live cell imaging, high-throughput assays) with theoretical and computational methods to provide a global understanding of the origins of tumor cell heterogeneity in response to anti-cancer drugs that target the apoptotic signaling pathway at the receptor level.

There is a series of outstanding achievements that have been made during the SysBioDRez project supported by a Marie Curie International Incoming Fellowship within the 7th European Community Framework Programme, regarding technology transfer, innovations and outreach, described in the following paragraphs. But it should also be emphasized that (1) all results and progresses toward the completion of the main objectives of this project have been well disseminated through three published articles, four conference presentations and two scientific events organized for the general public. (2) The "researcher" has obtained two additional research awards to carry on with the innovative findings from SysBioDRez. (3) At the completion of the SysBioDRez project, the "researcher" has been recruited by the CNRS on a tenured research position. (4) As SysBioDRez was carried out by a partnership between the Cancer Research laboratory in Nice (Institute of Research on Cancer and Aging in Nice, IRCAN) and the Applied Computer Science laboratory in Sophia-Antipolis (French Institute for Research in Computer Science and Automation, INRIA in Sophia-Antipolis), it initiated a very fruitful collaboration that is now set to continue and expand.

Technology transfer

We have successfully transferred a systems pharmacology workflow developed by the "researcher" (Jérémie Roux) during his postdoctoral fellowship that enables high-throughput analyses of living single cells, to study the dynamics of tumor cells responses to anti-cancer agents. We have applied it to make several type of predictions in lung cancer cell lines that we successfully validated experimentally, regarding receptor level biochemical mechanisms of drug resistance.
In the first term of the Marie Curie fellowship we were able to implement this workflow with the help of our partner lab (BioCore, INRIA). In addition to implementing image and data analyses framework as a whole, we revised the code so to analyze new cell lines (amelioration in cell segmentation and tracking algorithms). We have also added a number of features to store cell physiological parameters -such as cell position, size and shape that we have used in the second term of this proposal to ameliorate the predictive power of all our models (Article in preparation).
The host lab has been benefiting, as planned, of the "researcher's" expertise in image and data analysis, computational modelling and collection of reagents (cell lines, ligands) developed during his postdoctoral fellowship. He has also served as the link between the Inserm/CNRS and the INRIA to integrate computational methods: this effort has also proved to be useful to other members of the lab who collaborated with the department of mathematics at University of Nice-Sophia Antipolis.
In addition during this first year, the "researcher" has helped the microscopy core at IRCAN to setup the live cell microcopy system. This new setup has been used by a number of labs on site to expand on their analyses of signaling pathway using live cell imaging.

Innovation

This project’s innovations spanned the fields of quantitative biology and computational modeling of biological networks. There has been technological advances made in both.
Our primary biological innovation allowed to precisely quantify the relative importance of different TRAIL resistance mechanisms in cancer cells with diverse genotypes. This contrasted with a primary focus in the field on adding new proteins to a list of those involved in resistance. Our approach was also innovative in using single-cell methods to study the receptor activity; almost all studies of TRAIL resistance to date have involved bulk assays, despite the existence of dramatic cell-to-cell variability in response. Our automated approach can now produce almost 4 million data point per experiment, from which we extrapolate over 600,000 features of receptor dynamics after death-ligands stimulation. In our approach, key regulatory proteins are quantified; levels or activities manipulated genetically and the impact on cell fate determined by imaging. In addition, relationships between protein levels and phenotypes can be drawn at a single-cell level. Finally, our approach added the capacity in directly comparing natural ligands and multiple investigational drugs, and yielded new basic data on tumor cell sensitivities.
Three articles, including a study conducted during the period have been published as part of this SysBioDRez project (see Dissemination and Achievement records). Our findings propose an explanation for the failure of multiple death receptor therapeutic antibodies in clinical trials. Our data show an extraordinary lack of potency of apomab for example, when compared to the recombinant endogenous ligand for death receptors. We could confirm that this low potency was also observed in the great majority of other cell lines tested including lung, breast, ovarian, renal and colorectal cell lines. Using our workflow, combining experimental and computational approaches, we could predict and validate experimentally, that efficient cell killing by apomab in HeLa cells required a combination of clustering agent to increase the activation rate of the receptor complex and bortezomib (another chemotherapeutic agent in clinical trial) to increase the activity duration of this molecular complex. Rescuing death receptor agonists as a therapeutic class requires designing antibodies that can achieve these two features, which we can now measure thanks to our framework in place in the lab.

Outreach

As planned, we chose workshops as communication channel which has helped target all three types of audiences: students (aspiring scientists in biology, mathematics and informatics), scientists (in life sciences and in applied mathematics) and the general public. We have participated twice, with oral presentations, to the yearly meeting at the Cancéropôle PACA (single-cell biology) and the IRCAN retreat, gathering over a hundred scientists as well as the general public.
We have also participated to IRCAN CECAD and to three multidisciplinary workshops ("Physics of living matter series"), also gathering over a hundred students. Although we have not yet observed a impact on the number of undergraduate students enrolling classes in computational biology that are offered in Nice, we have noticed an increased momentum in the interactions between the graduate students with mixed training and the local labs with a complementary discipline (maths, informatics, and biology).
Lastly we have organized a booth at the 50th anniversary of the University of Nice-Sophia Antipolis, and we have joined the IRCAN in the organization of a Science Fair ("La Fete de la Science") which was held in October 7th-10th in Nice.

Future prospect

As noted above, during the course of the SysBioDRez project: scientific progress have been well disseminated through articles, conferences and public events, additional funding have been secured to purse the project innovative line of research and the "researcher" has been recruited on a CNRS tenured research position. With that, SysBioDRez is passing a unique opportunity to now concentrate the accumulated expertise of the host lab (IRCAN, CNRS), that has demonstrated over the last few years their driving interest and successful achievement in assays development, samples collection, maintaining a worldwide accessed lung tumor bank over the years, as well as with the partner lab (BioCore, INRIA), who are experts in mathematical modeling of biological systems, in order to challenge the promises of precision medicine.

Contact

DESCHAINTRES, SOPHIE (RESPONSABLE PARTENARIAT VALORISATION)
Tel.: +33 4 93954260
Fax: +33 4 92960339
E-mail

Subjects

Life Sciences
Record Number: 187640 / Last updated on: 2016-08-16