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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Decoding tumor cell invasive switching

Alternative title: Dechiffrere de endringer som driver kreft celler til spredning (metastase).

Awarded: NOK 7.2 mill.

Carcinogenesis is a multistep process, during which the DNA of healthy cells acquires (genetic and epigenetic) changes that push normal cells towards a cancerous phenotype. This process includes triggering events that drive benign growing tumors to switch to more malignant behavior, in which cells escape the confines of the original tumor site, invade and migrate within neighbouring tissue. Such malignant cells can form metastasic tumours, spreading to distant sites in the body where they again must invade normal tissue and establish new tumour colonies, metastases. The final malignant invasive and metastatic stage is the ultimate cause of mortality in >90% of cancer patients. This complicated sequence of events requires that cancer cells make several behavioural adaptations to escape from, migrate to, and reintegrate within the host environment. Each adaptation, if understood, presents an opportunity for therapeutic intervention. Despite its importance, there is no clear understanding of what triggers a switch to malignancy, whether it is preventable, or even reversible, arguing a clear and urgent need for mechanistic insight that may facilitate disease prevention and management. This proposal puts in vivo genetic approaches (using the fruit fly, Drosophila melanogaster, due to its cutting edge genetic toolkit and the conservation of cancer-causing genes) to both define the abnormal rewired intracellular signaling that drives spreading/migration, and, investigate the influence on the growth/spread of cancer cells by signalling within the microenvironment, in particular from surrounding normal healthy cells. Understanding these steps in cancer metastasis progression will provide novel opportunities to develop new treatments capable of blocking metastasis.

Carcinogenesis is a multistep process, during which pre-neoplastic cells rewire signaling pathways to push normal cells towards a cancerous phenotype. This process includes triggering events that switch the behavior of benign growing tumors to malignant invasive and metastatic behavior. This final malignant invasive and metastatic stage is the ultimate cause of mortality for the majority of cancer patients. Despite its importance, there is no clear understanding of what triggers a switch to malignancy, whether it is preventable, or even reversible, arguing a clear and urgent need for mechanistic insight to facilitate disease prevention and management. This project presents an in vivo genetically amendable model of tumor cell switching to a malignant invasive phenotype. Unpublished results demonstrate that oncogenic Receptor Tyrosine Kinase, RTK, expression when coupled to TORC1 inhibition triggers an invasive switch. Moreover, it identifies a key component of the invasive switch, a transcription factor (GRH) downstream of the RTK, which when blocked reduces the spread of the invasive cells to control levels. The project proposes to use this system to decode the signaling pathways that enable this invasive switch, with focus on both the RTK signaling to the cytoskeletal machinery and the negative feedback signals from TORC1 that normally suppress oncogenic RTK induced cell migration. Additionally, the project proposes to elaborate upon the existing model, expanding its capabilities by introducing the ability to perform knockdown of gene function in tissue surrounding the oncogenic RTK expressing cells. This will enable screening the signaling pathways in the microenvironment that impact the growth and spread of tumor cells. This is in part motivated by the unpublished data finding that many of the GRH transcription factor target genes are secreted proteins (eg WNT pathway) and hence potentially modulate the response of the microenvironment to the invasion.

Funding scheme:

FRIMEDBIO-Fri prosj.st. med.,helse,biol

Funding Sources