NCI Division of Cancer Biology Junior Investigators Meeting (Abstract): Submission #4

serial: '4'
sid: '190875'
uuid: 87b33c47-fd1b-4390-8696-55ec0056e63c
uri: /dcb/ji-meeting/abstract
created: '1786633704'
completed: '1786633704'
changed: '1786633704'
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langcode: en
webform_id: nci_junior_investigator_abstract
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entity_id: '1818'
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metatag: meta
data:
  category: 'Use my abstract for team formation only (do not consider it for a presentation)'
  degree_s_: 'B.S. M.S.'
  email: uem3ed@virginia.edu
  first_name: Jeffrey
  keywords_abstracts: ''
  last_name: Hsu
  middle_initial: ''
  organization: 'University of Virginia'
  organization_address:
    address: ''
    address_2: ''
    city: Charlottesville
    country: ''
    postal_code: ''
    state_province: ''
  summary: 'Ductal carcinoma in situ (DCIS) breast premalignancies account for ≥20% of all new diagnoses yet they do not align with standard invasive breast cancer subtypes. In DCIS, amplification of the HER2 receptor tyrosine kinase is two times more common than in invasive breast cancer, suggesting distinct roles in premalignancy. Using highly multiplexed imaging and biocomputational statistics to profile HER2-associated DCIS microenvironments, we asked whether HER2 expression coincides with different cellular constituents around DCIS lesions that are hormone receptor (HR)–negative and immune infiltrated. HER2 protein expression was variable across and within patient samples and was associated with the largest change in stromal cellularity relative to other profiled DCIS cell states (KRT5, γH2AX, Ki67). Compared to DCIS lesions with low or absent HER2 (HER2-low), lesions with high HER2 expression (HER2-high) had significantly fewer fibroblasts, CD8+ T cells, and macrophages. Interestingly, co-variation analysis of cell-type pairs revealed increased associations between cancer-associated fibroblast (CAF)/myofibroblastic CAF (myCAF) densities and resting fibroblast/myofibroblast densities, suggesting tighter coupling among fibroblast states in HER2-high regions. Separately, we compared HER2-positive and HER2-negative HR–negative DCIS patient cases from the Human Tumor Atlas Network by differential expression analysis of secretome genes, identifying a depletion in the matrisome-associated gene, lysyl oxidase (LOX), in HER2-positive cases. In vivo studies suggested that periductal CAF and myCAF densities were depleted following HER2 overexpression, whereas LOX overexpression produced a reciprocal increase in these populations. Collectively, these results suggest that HER2 locally shifts fibroblast-state coordination and dilutes immune presence in the DCIS microenvironment through LOX. '
  title: ''
  ttile: 'HER2 locally modulates the hormone receptor-negative DCIS microenvironment'