Elucidating the role of c-ABL in WNT-dependent tumors - title: elucidating the role of c-ABL in WNT-dependent tumors

The National Cancer Institute awarded Georgetown University $111,090 on January 21, 2026, under the Cancer Research Manpower program (CFDA 93.398) to support research training in basic, clinical, and prevention research aligned with the National Cancer Program.

The project, "Elucidating the Role of C-ABL in Wnt-Dependent Tumors," investigates the role of Abelson tyrosine kinase 1 (C-ABL) as a regulator of Wnt/β-catenin signaling in cancer. The research evaluates C-ABL overexpression, ABL mutants, and small molecule ABL inhibitors in Wnt-responsive cell lines and intestinal organoids. An epistasis analysis will determine where ABL regulates the Wnt/β-catenin pathway relative to the destruction complex. In silico analysis and molecular genetics engineering will identify Wnt-regulated C-ABL interactors to clarify the mechanism of C-ABL-mediated Wnt signaling regulation. The work concludes by determining whether C-ABL is required for Wnt-dependent tumor initiation or maintenance.

Performance occurs at Georgetown University in Washington, DC 20057. The period of performance runs from the award date through July 20, 2027. This is a Project Grant, an assistance type supporting discrete research or training activities.

Project summary: WNT signaling is a ubiquitous cell signaling pathway that has been studied for decades, with critical roles in organism development and tissue homeostasis. WNT signaling is a tightly controlled system, which requires WNT ligand binding to the receptor complex to lead to a cascade of events, resulting in -catenin translocation to the nucleus to activate downstream transcription programs. There are numerous negative regulators in this process - including the rate limiting step of WNT ligands binding to the receptor, and the destruction complex which degrades -catenin when the receptor complex is unbound by WNT ligands. However, when these negative regulators fail and WNT signaling is aberrantly activated, various developmental defects and numerous diseases, including cancer, arise. Therefore, regulators of WNT signaling have been extensively studied, yet there are no FDA-approved therapies to target aberrantly active WNT signaling. Our preliminary data suggests that abelson tyrosine kinase 1 (c-ABL) is a novel, positive regulator of WNT/-catenin signaling. To identify the how c-ABL regulates WNT/-catenin signaling, the effects of ABL over- expression (c-ABL and ABL2), ABL mutants of constitutive activity and domain knockouts using pcdna based plasmids, small interfering RNA, and small molecule inhibitors of ABL, will be evaluated in WNT-responsive cell lines and intestinal organoids. Next, an epistasis analysis will be performed to ascertain where ABL regulates the WNT/-catenin pathway - upstream or downstream of the destruction complex. Subsequently, a combination of an in silico analysis and molecular genetics engineering will identify WNT-regulated c-ABL interactors to further underpin how c-ABL regulates WNT signaling. Then, after extensively studying the mechanism of c-ABL regulating WNT signaling, i will determine if c-ABL is required for WNT-dependent pdac models. I will use pdac cell lines and patient derived organoids (pdos) to study its requirement in vitro, which will be followed up by orthotopically transplanted patient derived organoids and xenografts, derived from matched tumors and patients to the pdos, to study ABL's requirement for WNT-dependent tumorigenesis in models which most accurately recapitulate human disease. Successfully completing the project outlined within this award application will advance scientific knowledge on cell signaling, and will potentially outline a novel approach to treat a subset of WNT-dependent cancer with FDA approved small molecules.