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Intersecting hallmarks of cancer: mechanisms of and interplay between invasion and angiogenesis, guiding new strategies for cancer therapy

Objective

Acquisition of the hallmark capability for invasion and in turn metastasis is for most human cancers the defining event in progression to life threatening disease. Its determinants are remarkably complex. Genetically engineered mice can model human cancers, with tumors arising in specific organs, reflecting onco-genomic and histopathological features of particular tumor types. This project will use four mouse models to characterize newly implicated determinants of invasive tumor growth. We have observed that genetic polymorphisms can govern predisposition to invasive cancer. Additionally, therapeutic targeting of another hallmark capability – tumor angiogenesis – has revealed adaptive resistance, whereby late-stage tumors, faced with the inability to grow en masse supported by angiogenesis, switch instead to grow diffusively, by invading adjacent tissue; this phenomenon may underlay the limited benefit seen with anti-angiogenic therapies in the clinic. There are three interconnected goals:
(1) Polymorphic regulation of tumor invasion. We will investigate the mechanisms and functional importance of candidate genes resident within a genetic modifier locus on mouse Chr 17 that can alternatively suppress or facilitate invasive tumor growth dependent on constitutional genetic background.
(2) Adaptive induction of invasion. We will elucidate the determinants of the invasive growth capability that is induced in response to potent inhibition of angiogenesis.
(3) Testing mechanism-based therapeutic co-targeting of the capabilities for invasion and angiogenesis.
We will use functional genetic, genomic profiling, and pharmacological approaches to assess these two new modes of regulating invasive growth, and then apply the knowledge in preclinical trials aiming to lay the groundwork for future clinical trials in which these intersecting hallmark capabilities are coordinately disrupted, with promise for more enduring therapeutic responses and benefit to cancer patients.

Field of science

  • /medical and health sciences/clinical medicine/oncology/cancer

Call for proposal

ERC-2012-ADG_20120314
See other projects for this call

Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Address
Batiment Ce 3316 Station 1
1015 Lausanne
Switzerland
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 2 500 000
Principal investigator
Douglas Hanahan (Prof.)
Administrative Contact
Caroline Vandevyver (Dr.)

Beneficiaries (1)

ECOLE POLYTECHNIQUE FEDERALE DE LAUSANNE
Switzerland
EU contribution
€ 2 500 000
Address
Batiment Ce 3316 Station 1
1015 Lausanne
Activity type
Higher or Secondary Education Establishments
Principal investigator
Douglas Hanahan (Prof.)
Administrative Contact
Caroline Vandevyver (Dr.)