At the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2024, Phase II data for the Fibroblast Activation Protein (FAP)-targeted Radioligand Therapy ¹⁷⁷Lu-FAP-2286 (NovoFib) were presented. This therapy demonstrated favorable tolerability and encouraging antitumor activity in various advanced solid tumors (e.g., pancreatic cancer, breast cancer), particularly showing partial responses in the highly treatment-resistant sarcomatoid carcinoma and chemotherapy-refractory patients, bringing new hope for FAP-targeted therapies.As a core molecule in tumor stroma regulation, the unique expression and multifaceted functions of the FAP target within the tumor microenvironment are becoming a research hotspot. Let's explore further.

 

Fibroblast Activation Protein (FAP) is a type II transmembrane serine protease, almost exclusively expressed by Cancer-Associated Fibroblasts (CAFs) which are abundant in the tumor stroma. In normal adult tissues, FAP expression is extremely low, but it is significantly upregulated in CAFs of over 90% of epithelial-derived malignancies, including pancreatic, colorectal, breast, and lung cancers.

Comprising 760 amino acids, FAP can be divided into three main domains: a short intracellular domain, a transmembrane domain, and a functional extracellular domain. The extracellular domain contains two key functional subunits: a seven-bladed β-propeller domain and an α/β hydrolase domain. The β-propeller domain, formed by seven blades surrounding a central channel, acts as a "molecular filter," selectively regulating substrate entry. The α/β hydrolase domain houses the catalytic active center. This three-dimensional conformation enables FAP to possess both dipeptidyl peptidase and endopeptidase activities and to play a crucial role in interacting with molecules like integrins and forming homo/heterodimers.

Image placeholder: The role of fibroblast activation protein in health and malignancy

 

FAP promotes tumor progression by regulating multiple biological processes including the extracellular matrix, intracellular signal transduction, the tumor immune microenvironment, and angiogenesis.
 

I) Promoting Tumor Invasion and Metastasis
 

FAP significantly enhances tumor cell invasion and metastasis through both enzyme activity-dependent and -independent mechanisms. The endopeptidase activity of its extracellular domain specifically cleaves denatured type I and III collagen, effectively degrading the Extracellular Matrix (ECM) and creating physical channels for tumor cell migration. Through its β-propeller domain, FAP interacts with cell surface receptors like integrins (e.g., α3β1), forming complexes that activate intracellular small GTPase Rac1 signaling, directly driving actin cytoskeleton reorganization and enhancing cell motility. Furthermore, FAP-expressing CAFs remodel the topological structure and mechanical properties of the ECM, providing a pro-invasive "microenvironmental niche" for tumor cells.
 

II) Driving Immune Suppression and Treatment Resistance
 

FAP-positive CAFs are key mediators shaping the immunosuppressive tumor microenvironment, primarily inducing immune tolerance via physical exclusion and active suppression. On one hand, these cells are a major source of the chemokine CXCL12, forming a chemical gradient barrier at the tumor-stroma interface that hinders the infiltration of Cytotoxic T Lymphocytes (CTLs) into the tumor bed, leading to an "immune-excluded" phenotype. On the other hand, FAP+ CAFs secrete CCL2, recruiting large numbers of immunosuppressive cell populations like Myeloid-Derived Suppressor Cells (MDSCs) to the tumor site, directly inhibiting the activation and proliferation of effector T cells. Studies also found that FAP itself can be expressed on MDSCs and, by activating the AKT signaling pathway, directly induces T cell exhaustion and aberrant differentiation, thereby weakening anti-tumor immune responses and contributing to resistance against therapies like immune checkpoint inhibitors.
 

III) Inducing Tumor Angiogenesis
 

FAP participates in tumor angiogenesis through direct and indirect mechanisms. The direct mechanism involves its expression on neovascular endothelial cells, where it cleaves substrates (e.g., neuropeptide Y) to generate fragments with pro-angiogenic activity. The indirect mechanism stems from its ECM-degrading activity, providing space for endothelial cell migration and capillary sprouting, while factors like Vascular Endothelial Growth Factor (VEGF) secreted by FAP+ cells further accelerate angiogenesis.
 

IV) Regulating Key Oncogenic Signaling Pathways
 

FAP expression can directly perturb several key signaling pathways within cancer cells, affecting proliferation, survival, and malignant transformation.
 

PI3K/AKT Pathway: In models like oral squamous cell carcinoma, FAP knockdown led to decreased p-AKT levels and reduced cyclin expression, inhibiting proliferation. This suggests FAP is an upstream activator of the PI3K/AKT pathway.
 

SHH/GLI Pathway: In lung cancer cells, FAP overexpression activates the transcription factor GLI1, a downstream effector of the SHH pathway, inducing epithelial-mesenchymal transition and enhancing invasive capacity.
 

Dual Role of FAK: In breast cancer, FAP overexpression conversely reduced FAK phosphorylation, correlating with decreased cell motility. This reveals the cell-type specificity of FAP function.

 

Image placeholder: The role of fibroblast activation protein in health and malignancy

 

Mouse Models
 

FAP-/- Mice: Knockout of the FAPgene. Used to study the role of FAP in normal physiology and pathology, these mice exhibit a significant tumor-suppressive phenotype during tumorigenesis and development.
 

hFAP Mice: Transgenic mice expressing human FAP protein. Used to evaluate the efficacy of drugs targeting human FAP, particularly in cancer therapy research.

 

MingCeler Biotech Facilitates Mechanism Research and Drug Development
 

Gene therapy offers hope for common diseases, but its development and validation are inseparable from animal model support. Leveraging its self-developed TurboMice™ technology, MingCeler Biotech has established multiple disease mouse models. The TurboMice™ technology overcomes the challenges of long modeling cycles and low success rates for complex models. It enables editing at virtually any target genomic locus and can generate complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as two months.
 

MingCeler Biotech can customize various FAP-related mouse models according to client needs, such as FAP-/- and hFAP mice. We welcome inquiries.
 

References:

[1] van der Heide CD, Campeiro JD, Ruigrok EAM, van den Brink L, Ponnala S, Hillier SM, Dalm SU. In vitro and ex vivo evaluation of preclinical models for FAP-targeted theranostics: differences and relevance for radiotracer evaluation. EJNMMI Res. 2024 Dec 24;14(1):125. doi: 10.1186/s13550-024-01191-6. PMID: 39718718; PMCID: PMC11668701.

[2] Fitzgerald AA, Weiner LM. The role of fibroblast activation protein in health and malignancy. Cancer Metastasis Rev. 2020 Sep;39(3):783-803. doi: 10.1007/s10555-020-09909-3. PMID: 32601975; PMCID: PMC7487063.

 

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