NCI Division of Cancer Biology Junior Investigators Meeting (Abstract): Submission #14

serial: '14'
sid: '194270'
uuid: 62963bf8-199c-4134-9cfc-eb4c8df97d4a
uri: /dcb/ji-meeting/abstract
created: '1788902924'
completed: '1788902924'
changed: '1788902924'
in_draft: '0'
current_page: ''
remote_addr: 10.208.24.147
uid: '0'
langcode: en
webform_id: nci_junior_investigator_abstract
entity_type: node
entity_id: '1818'
locked: '0'
sticky: '0'
notes: ''
metatag: meta
data:
  category: 'Consider my abstract for a Methodology/Technology presentation'
  degree_s_: M.Sc.
  email: moha1722@umn.edu
  first_name: Ali
  keywords_abstracts: 'T cell activation, Cell volume regulation, Amino acid transport, Protein synthesis, Cell density'
  last_name: Mohammad
  middle_initial: ''
  organization: 'University of Minnesota'
  organization_address:
    address: ''
    address_2: ''
    city: Minneapolis
    country: ''
    postal_code: ''
    state_province: ''
  summary: |
    Abstract:
    Experimental measurements show that resting CD8⁺ T cells increase their volume approximately fourfold within 48 hours of activation while simultaneously accumulating biomass and increasing their fractional water content, resulting in a decrease in cell density. To investigate how activated T cells coordinate water uptake and biomass accumulation, we developed a mechanistic ODE-based Cell Growth Simulator that couples ion transport, osmotically driven water flux, amino acid transport, and protein biosynthesis during the first 48 hours following activation. The model tracks ten state variables representing cellular water volume, intracellular inorganic ion concentrations, free amino acid concentrations, and macromolecular mass, and is calibrated using high-resolution single-cell measurements of volume and density obtained with the suspended microchannel resonator (fxSMR; Wu et al., Nature Biomedical Engineering, 2025) together with intracellular free amino acid concentrations from metabolomic analysis (O’Keeffe et al., bioRxiv, 2025). 
    To determine whether the amino acid transport is uniquely required or whether alternative mechanisms could explain the observed growth, we performed a structural non-identifiability analysis across five candidate ion-transport models. Although multiple mechanisms could be tuned to reproduce the measured volume trajectory, all failed to simultaneously reproduce density, missing the experimental buoyant mass target by 40–65% despite correctly matching volume. Mechanistically, ion-driven growth increases water content without proportionally increasing dry mass (primarily protein), yielding cells of the correct size but incorrect composition. In contrast, a model further incorporating amino-acid-transport and protein biosynthesis satisfied all experimental observables. These results establish cell density as critical constraint for discriminating among competing growth mechanisms and provide a quantitative framework for linking T cell metabolic activation to its biophysical growth phenotype. Our integrated model contributes to the identification of metabolically and biophysically motivated targets for accelerating T cell expansion for therapeutic benefit.
  title: 'PhD Candidate'
  ttile: 'Mechanistic modeling of water uptake and biomass accumulation during CD8⁺ T cell growth following activation'