2017 — 2020 |
Kelber, Jonathan A. |
SC1Activity Code Description: Individual investigator-initiated research projects aimed at developing researchers at minority-serving institutions (MSIs) to a stage where they can transition successfully to other s extramural support (R01 or equivalent). |
Non-Transcriptional Mechanisms of Peak1 Action During Tgfbeta-Induced Emt @ California State University Northridge
PROJECT SUMMARY Transforming Growth Factor ? (TGF?) is a secreted protein and the first member of the TGF? su- perfamily of ligands to be described. However, the molecular mechanisms that govern TGF??s ability to switch between its paradoxical growth suppressing and epithelial-mesenchymal transition (EMT) promoting functions remain to be fully elucidated. Since TGF? elicits pleiotropic functions during normal development, adult tissue homeostasis and pathophysiological processes such as cancer and fibrosis, it is essential that future research efforts focus on producing a complete mechanistic understanding of TGF? function. To this end, the objective of this proposal is to investigate the cellular and molecular mechanisms by which PEAK1 (pseudopodium-enriched atypical kinase one) regulates TGF? signaling and mediates TGF?-induced EMT during disease progression. The proposed work is an extension of our recently published and compelling preliminary data showing that (i) PEAK1 mediates TGF?-induced EMT, migration, proliferation and cancer metastasis; (ii) PEAK1 localizes to membrane actin structures and regulates Src/Grb2/MAPK signaling in response to TGF?/fibronectin stimulation; and (iii) inhibition of PEAK1 translation blocks the pathophysiological effects of TGF? signaling. Thus, the central hypoth- esis of this proposal is that eIF5A-driven PEAK1 translation promotes the assembly of a Src/Grb2/PEAK1 complex in the context of membrane ITGB3 activation to enable TGF?-induced MAPK signaling, ZEB1 upregulation and EMT. The approach is innovative because it will employ a combina- tion of state-of-the-art cellular, molecular, biochemical, microscopy, proteomic and model organism methods to elucidate the mechanisms of action for the novel eIF5A/PEAK1 translation and Src/Grb2/PEAK1/MAPK cytoskeletal signaling nodes as novel regulators of TGF?-induced EMT. Furthermore, the proposed research is significant because it will address the following two major challenges and needs within the field of TGF? research: Specific Aim 1 will characterize translational and post-translational mechanisms of TGF?-induced EMT; and Specific Aim 2 will identify context- dependent spatiotemporal dynamics for molecular regulators of TGF? responses. The collective knowledge gained from these mechanistic studies will identify and characterize details of the cellular and molecular contexts in which TGF? is dysregulated to cause disease, and novel methods for block- ing the negative consequences of TGF? signaling.
|
1 |
2020 |
Bermudes, David G De Bellard, Maria Elena Kelber, Jonathan A. Tamae, Daniel (co-PI) [⬀] |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
California State University - Interdisciplinary Cancer Meeting (Csu-Icm) @ California State University Northridge
R13 Application Kelber, Tamae, De Bellard, Bermudes Title: The California State University ? Interdisciplinary Cancer Meeting (CSU-ICM) ? Targeting Mechanisms of Therapy Resistance PROJECT SUMMARY According to the most recent studies, the average mortality across all cancer types remains at over 30%. To develop transformative solutions to central problems in oncology research, we have established the biennial California State University ? Interdisciplinary Cancer Meeting (CSU-ICM). This application is to support the 2020 meeting that will be held on Friday, November 6 at the California State University Northridge, Plaza del Sol Performance Hall. The theme for the 2020 CSU-ICM will be Targeting Mechanisms of Therapy Resistance. Currently, there is a need for cancer research meetings that provide an affordable and focused platform for interdisciplinary exchange between life scientists, non-life scientists and cancer experts. The first CSU-ICM meeting held in 2018 welcomed keynote speaker Dr. Joan Brugge from Harvard Medical School and involved over 150 participants from 10 CSU and 2 UC campuses in California and 1 non-California university. This funding application is based upon preliminary data that we collected from this inaugural event demonstrating diversity of participation at ethnic, discipline, geographic and institute levels. Thus, we postulate that strategic expansion of this meeting will further stimulate novel, collaborative lines of investigation that lead to transformative advances in cancer research and increase diversity in oncology research. The short talk sessions will be chaired by faculty leaders in their respective fields and designed to involve trainees from the undergraduate to postdoctoral levels - increasing the upward mobility of those traditionally underrepresented in cancer research. Involvement of a survivor-advocate will enhance the real need to ensure that even the most basic science research is grounded in clear personal need. The world-renowned keynote speakers ensure the highest quality of scientific exchange. The faculty flash-talk session will highlight ongoing cancer-related work from within the diverse CSU community. Finally, the poster session is designed to foster scientific exchange, networking opportunities and constructive feedback on work-in-progress. In summary, the CSU-ICM is designed to put into action core mission of the California State University system, which includes the advancement of scientific knowledge, learning, and discovery; the promotion of professional development; and the preparation of a diverse scientific workforce while also fulfilling an important need in the broader cancer research community.
|
1 |
2021 |
Kelber, Jonathan A. |
SC1Activity Code Description: Individual investigator-initiated research projects aimed at developing researchers at minority-serving institutions (MSIs) to a stage where they can transition successfully to other s extramural support (R01 or equivalent). |
Spatiotemporal Mechanisms of Eif5a1/2-Mediated Metastasis in Triple-Negative Breast Cancer @ California State University Northridge
PROJECT SUMMARY Metastasis is the leading cause of mortality in patients with solid tumors. Since there are no clinically- approved targeted therapies for treating triple-negative breast cancer (TNBC), metastatic TNBC pre- sents a dire clinical situation for which intervention strategies are urgently needed. The long-term goal of this proposal is to elucidate novel tumor cell autonomous and non-autonomous mechanisms that drive TNBC progression and metastasis. The overall objective of this proposal is to define the molecu- lar/cellular basis by which post-translational hypusination and nucleocytoplasmic transport of eukaryotic initiation factor 5A (eIF5A1/2) governs pseudopodium-enriched atypical kinase one (PEAK1)-dependent invasion/dissemination and lipocalin two (LCN2)-mediated reprogramming of the premetastatic niche (PMN). Toward this end, evidence is presented that the eIF5A1/2 hypusination/activation pathway associates with poor TNBC prognosis and is required for TGF?/PEAK1-driven metastasis and LCN2 expression in TNBC cells. Furthermore, the eIF5A1/2-LCN2 axis is identified as a novel mechanism through which primary tumor cells remodel the PMN to support TNBC cell expansion. Thus, the central hypothesis of this proposal is that hypusination and cytoplasmic localization of eIF5A1/2 in TNBC cells drives PEAK1-dependent TGF?/fibronectin signaling crosstalk and LCN2-mediated anti-inflammatory reprogramming of the premetastatic niche to support metastasis. The approach is innovative because it represents a substantive departure from the status quo by elucidating targetable eIF5A1/2-dependent translational mechanisms of cell state plasticity at early and late stages in the metastatic cascade using the single-cell Cyclic ImmunoFluorescence (CycIF) platform, our novel in vivo/ex vivo tumor cell-free PMN reprogramming assay, the Multifunctional Approach to Pharmacological Screening (MAPS) platform and a suite of preclinical mouse models that faithfully recapitulate complementary aspects of human TNBC metastasis and progression. Furthermore, the proposed research is significant because it will define spatiotemporal mechanisms by which dysregulation of eIF5A1/2 expression, hypusination and subcellular localization drive TNBC pathogenesis and identify targeted treatment strategies for metastatic TNBC. Specific Aim 1 will determine cancer cell autonomous mechanisms of eIF5A1/2- mediated TNBC cell invasion and dissemination. Specific Aim 2 will identify eIF5A1/2-dependent mechanisms of premetastatic niche reprogramming that support TNBC cell seeding and expansion. The collective knowledge gained from these studies will elucidate targetable mechanisms that govern both early and late stages of TNBC metastasis and establish rationale for new therapeutic combina- tions to overcome TNBC progression and improve patient outcomes.
|
1 |