VASCULAR ONCOLOGY

Principal Investigator

Federico Bussolino

Telephone: 011.993.3347

Email: federico.bussolino@ircc.it

Staff

Research topic

Tumor microenvironment (TME) includes immune and stromal cells, blood vessels, nerves and extracellular matrix.  The Lab is interested in analyzing the  circuits between cancer cells and TME orchestrated by the transcription factor EB (TFEB)  and understanding their roles in disease progression and therapeutic responses, with an emphasis on pancreatic ductal adenocarcinomas (PDAC) and melanomas.

Background

Tumor cells reshape cellular phenotypes  within their host tissues. The appearing TME is continuously evolving  and assumes pro- or anti-tumor activities.  The plastic features of TME rely on  gene regulatory networks based the interplay between transcription factors (TFs), coding and non-coding DNA and chromatin modifications.   In these last years we focused our scientific efforts on TFEB, a basic helix-loop-helix leucine zipper oncogenic TF that participates to cellular adaptation to stressing events, such as, in cancer, the response to therapies or the journey in blood circulation to metastatic dissemination.  TFEB can be expressed both by cancer cells and by TME cells.  Accordingly to these expression patterns, PDAC or melanoma behaviors might be different, opening the perspective of targeting this TF to improve the response to therapies or favorably condition the disease progression.

Research achievements

Our projects aim at exploring the mechanisms of tumor dependency on the features of TME and at understanding how such dependency might be modulated by the amount of TFEB expressed in 3 cellular compartments: cancer cells, stroma cells and endothelial cells lining blood capillaries.  We hypothesize that TFEB dosage   changes the structure of the chromatin and influences the role of enhancer thus making groups of genes active or silenced depending on the conditions and theus dynamically influencing cancer-TEM cross-talks

Our experimental platform entails the deployment of multi-dimensional data (transcriptional, chromatin and enhancer landscapes) obtained in genetic engineered mouse models and in 3D in vitro cellular models recapitulating the circuits between cancer cells and TME. By CRISPR-CAS genome editing, these models allow tunable amount of TFEB in the above mentioned cellular compartments. By this approach, we have demonstrated that: i)  overexpression of TFEB  in PDAC  stellate cells modifies  their differentiation in cancer-associated fibroblasts reducing the desmoplastic  potential of the tumor; ii) TFEB deletion deeply influence the response of vascular capillaries.

Conclusions and perspectives

For many years, TFs were considered undruggable. However,  the recent progresses in understanding their molecular features are allowing   the generation of specific inhibitors, with new therapeutic perspective.

Our studies provide a robust approach to evaluate the role of TFEB dosage in regulating the circuits between cancer and TME cells and to experience the effect of pharmacological TFEB manipulation in the control of cancer progression and response to chemotherapy or targeted therapies. 

Publications

At this link, you can find all the scientific publications of the Principal Investigator.