Tumor Intrinsic and Extrinsic Functions of Lipocalin-2
Focus: Given the pleiotropic functions of Lcn2 in the context of cancer progression, we are investigating the roles of Lcn2 in triple negatvie breast cancer invasion and collective cell behavior using spheroid/organoid systems. Simultaneously, we aim to understand how Lcn2 secreted from triple negative breast cancer cells can act systemically to modify tissues to which these cancer cells can metastasize.
Relevant publication: Meade et al. 2019 Oncotarget
Collaborators: Isaac Harris and Jack Bui
Mechanistic Determinants of a Multicellular Signaling Cascade in HER2-Positive Breast Cancer
Focus: We have identified a previously unrecognized PEAK1 pseudokinase dependent intercellular signaling program initiated within HER2-positive breast cancer associated fibroblasts (CAFs), that promotes metastasis and therapy resistance via activin-A responses in both stromal and tumor cell compartments. We aim to determine the spatiotemporal mechanisms by which PEAK1 governs CAF heterogeneity and intercellular activin-A signaling to potentiate stromal state changes and HER2-positive breast cancer progression.
Relevant publication: Hamalian et al. 2021 Oncogene
Collaborators: Thea Tlsty, Martin Humphries, Michael Lewis, Julia Tchou, Anupma Nayak, Patrick Caswell, Christoph Ballestrem, Joseph Taube and Touraj Solouki
Modeling the Cancer Microenvironment in 3D to Screen New Therapeutics
Focus: While patient-derived organoids hold promise for personalizing oncology treatment regimens, the time required to generate these models is not time-efficient for drug screening. Additionally, we have identified a tumor cell-matrix signaling axis that controls cancer cell dormancy in spheroid cultures. Therefore, we aim to develop and leverage unique bioengineering platforms to efficiently produce patient-derived organoids that can be used to interrogate therapy responsiveness and dormancy.
Relevant publication: Gharibi et al. 2017 Scientific Reports
Collaborators: Marcin Iwanicki, Natan Barros, Todd Aguilera and Michael Bouvet
RAI14 in Pancreatic Tumorigenesis
Focus: We previously reported on proteins enriched within the pseudopodia of migratory cells. RAI14 (or Ankycorbin) was a novel candidate identified in this screen that holds prognostic utility in pancreatic cancer. Ongoing efforts include knocking RAI14 out in established pancreatic cancer mouse models.
Relevant publication: Wang et al. 2010 PNAS
Collaborators: Marcin Iwanicki, Michael Boyce, Michael Bouvet, and Robert Hoffman
Fibronectin and Adhesion Signaling in Protein Translation
Focus: We have identified a role for posttranslational hypusination and cytoplasmic localization of eIF5A1/2 in controlling the translation of the PEAK1 pseudokinase. Given the established role for PEAK1 in mediating cellular adhesion to extracellular matrix proteins like fibronectin, we are currently investigating how fibronectin matrix signaling regulates eIF5A1/2 signaling and function.
Relevant publication: Güth et al. 2019 BBRC
Collaborators: Jack Bui, Isaac Harris and Julia Tchou
Extracellular Remodeling of TGFβ-2 Stores by Fibrillin
Focus: We have identified that mutations of fibrillin-1, a repository for latent TGFβ, are associated with characteristics of human primary open angle glaucoma (POAG). Our ongoing work aims to decifer the mechanisms by which fibrillin-1 increases access of recipient cell to active pools of TGFβ-2 in this disease context.
Relevant publication: Ko et al. 2022 Scientific Reports
Collaborators: James C. Tan