Role of fibroblastic focal adhesion kinase (fak) in pancreatic adenocarcinoma
The relatively recent appreciation of the importance of microenvironment modifications in tumor progression has revolutionized the field and raises many innovative questions: Could a better understanding of the role of the tumor microenvironment allow 1- the identification of new therapeutic targets for patients with pancreatic adenocarcinoma (PDAC)? 2- to diagnosis the disease earlier? 3- to propose personalized medicine to patients based on the analysis of their tumor microenvironment?
Our research aims at answering these questions and focuses on two key events of PDAC tumor progression: activation of fibroblasts into CAF and remodeling of the extracellular matrix (ECM) (Belhabib et al., Cancers 2021). Our research projects have identified mechanotransduction as a key regulator of CAF activation and acquisition of pro-tumor functions.
Thus, we identified that the kinase activity of Focal Adhesion Kinase (FAK), a key mechanosensor (Sulzmaier et al., Nat Rev Cancer, 2014), is strongly increased in CAFs from PDAC tumors compared to its activity in fibroblasts from healthy pancreas. The level of fibroblastic FAK activity is a prognostic marker for PDAC patient survival. In vivo, pharmacological or genetic inactivation of FAK in fibroblasts modifies the ECM, reduces the number of immunosuppressive cells in primary tumors and ultimately inhibits tumor spread and metastasis. Thus, FAK activity within CAFs appears as an independent PDAC prognostic marker and a promising therapeutic target against PDAC (Zaghdoudi et al., EMM 2020). Evaluating FAK activity within CAFs should allow to identify patients with high risk of early relapse and patients that may benefit from a personalized protocol using FAK inhibitor treatment, currently used in clinical trials.
Fibroblastic FAK inactivation in vivo drastically modifies the tumor ECM; we will seek to identify precisely quantitative (Matrisome) and qualitative (stiffness, organization…) changes induced and their implications in tumor progression and chemoresistance. Thus, we will follow two main tracks:
- The potential involvement of fibroblast FAK activity in the establishment of a cross-talk with blood vessels promoting chemoresistance,
- The potential involvement of the activation of mechanotransduction pathways in the generation of physical forces that would contribute to tumor progression.
Funding: Cancer Plan, Ligue Nationale Contre le Cancer.
Members: Ismahane Belhabib (Thesis, LNCC) and Claire Lac (Thesis, ministerial grant).
- Belhabib I, Zaghdoudi S, Lac C, Bousquet C, Jean C. Extracellular Matrices and Cancer-Associated Fibroblasts: Targets for Cancer Diagnosis and Therapy? Cancers (Basel). 2021 Jul 11;13(14):3466. doi: 10.3390/cancers13143466. PMID:34298680; PMCID: PMC8303391.
- Zaghdoudi S, Decaup E, Belhabib I, Samain R, Cassant-Sourdy S, Rochotte J, Brunel A, Schlaepfer D, Cros J, Neuzillet C, Strehaiano M, Alard A, Tomasini R, Rajeeve V, Perraud A, Mathonnet M, Pearce OM, Martineau Y, Pyronnet S, Bousquet C, Jean C. FAK activity in cancer-associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer. EMBO Mol Med. 2020 Nov 6;12(11):e12010. doi: 10.15252/emmm.202012010. Epub 2020 Oct 7. PMID: 33025708; PMCID: PMC7645544.
- Sulzmaier FJ, Jean C, Schlaepfer DD. FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer. 2014 Sep;14(9):598-610. doi:10.1038/nrc3792. Epub 2014 Aug 7. PMID: 25098269; PMCID: PMC4365862.