[R01] Role of P4HA2 in metastatic dormancy
Ente: National Cancer Institute
Scadenza: 2031-06-30
Importo max: 827.111 EUR
Paese: US
Descrizione
Project Summary/Abstract
Background: Metastasis is the primary cause of death of cancer patients. Disseminated tumor cells (DTCs)
leave the primary tumor and seed target organs originating metastasis, years or decades after treatment. This
delay in growth is mediated by a process called tumor dormancy. The collagen extracellular matrix (ECM) has
been shown to regulate dormancy. Production of collagens is a multistep process that requires post-translational
modifications including proline hydroxylation, critical for the formation of the collagen triple helix, proper assembly
into the ECM and signaling. The enzymes regulating collagen proline hydroxylation include P4H hydroxylases,
however, their role in tumor cell dormancy is unknown. We will explore the hypothesis that dormant cancer cells
regulate the formation of dormancy-supportive collagen niches through tight control of proline hydroxylation.
Hypothesis: Our overall hypothesis is that the activity of the proline hydroxylase P4HA2, regulates the levels
of proline hydroxylation of collagens in dormant cells, impacting collagen proteostasis through activation of
autophagy. This mechanism contributes to the dormancy-to-awaken transition by a novel pathway involving
ALDH4A1 and mitochondria function.
Objective: The overall goal of this project is two-fold: 1) to understand the role of P4HA2 on the regulation of
collagen proline hydroxylation and its impact on dormancy; 2) to determine how P4HA2 activity regulates
autophagy and mitochondria function during the dormancy-to-reactivation transition.
Specific Aims: #1: To determine the role of P4HA2 in maintaining the collagen proline hydroxylation landscape
and quiescence of dormant DTCs. #2: To determine how P4HA2 impacts autophagy activity and mitochondrial
function in dormant DTCs.
Study design/Methods: 1) High-resolution imaging tools to study the role of P4HA2 in DTC dormancy. Our
approaches include multiphoton imaging and second harmonic generation. 2) To analyze collagen proline
hydroxylation, we will use spatial collagenomics in collaboration with Dr. Angel. 3) Novel artificial intelligence
methods to classify DTCs based on mitochondria topology. 4) We will use cellular models of dormancy, mouse
models and autopsy samples from breast cancer patients.
Relevance: This project is innovative both at the conceptual and at the methodological level. We propose to
study the following aspects of metastasis: 1. Dormant cancer cells sustain dormancy through changes in proline
hydroxylation. 2. P4HA2 regulates autophagy and the collagen proteome of dormant cells. 3. Impaired collagen
hydroxylation affects mitochondria function 4. The crosstalk between lung epithelial AT2 cells and tumor cells
influence tumor cells fate, triggering quiescence and P4HA2 upregulation. We expect our studies to have a
significant impact on biomedicine because they will uncover the mechanisms regulating dormant cells, which will
be an efficient way of identifying targets to pr
Istituzione: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
PI: Jose Javier Bravo-Cordero
Progetto: 1R01CA305930-01A1
Settori: National Cancer Institute
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