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A New Window into the in vivo tumor Microenvironment: Rapid harvesting and isolation of tissue interstitial space extracellular vesicles while preserving tissue functional state and cytomorphology

Award Number: R61CA315165
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/04/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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A New Window into the in vivo tumor Microenvironment: Rapid harvesting and isolation of tissue interstitial space extracellular vesicles while preserving tissue functional state and cytomorphology - Extracellular vesicles (EVs) are an important class of cancer biomarkers . In contrast to the progress characterizing tumor EVs in body fluids such as blood, our understanding of the production, and molecular composition of EVs at their source, the tumor extracellular microenvironment, is very rudimentary. Technology did not previously exist to harvest intact resident EVs from the extracellular tissue space (IFEVs). Therefore, we developed a rapid two-step column technology that evacuates resident tumor IF and isolates intact, highly concentrated, high yield (1014-1016 IFEV particles/0.5 gms of tissue) EVs within 15 minutes, preserving both the tissue for histopathology and the vesicles for analysis. We reported that the tumor interstitial fluid (IF), composing about 12-17% of the tumor tissue volume, is exceedingly rich in EVs. The molecular composition of EVs reflects both the cell of origin and the physiologic state of the tumor cell, or host cell, secreting the EV. IFEVs are a real- time window into the tumor microenvironment. Using our IF EV purification technology we identified two completely new classes of functionally important EV particles that are the focus of this project. The first is a mitochondria derived EV particle containing a full set of active mitophagy molecules. The mitophagy EV is a product of secretory mitophagy-derived EVs (SM-EVs) enriched for oxidative stress markers (PINK1, TOM20). We have proven the functional importance of SM-EVs as a cancer survival mechanism elevated by therapeutic stress. Secondly, we discovered that tumor IFEVs contain a subclass of particle housing ongoing ERBB signaling: heterodimerization of HER2 and EGFR, indicated by concordant phosphorylation of the cytoplasmic domains of each receptor monomer HER2 Y1248 and EGFR Y1173, required for active downstream oncogenic signaling. In the microdissected carcinoma cells of the diagnostic biopsy, this same membrane associated heterodimer was a strong predictor of response (pCR) for HER2 neoadjuvant therapy in published large blinded, clinical studies specificity of 89-92% with complete pathologic response (pCR) in both HER2-positive and HER2-low breast cancer. Remarkably, our IF EV harvesting method revealed that the same predictive HER2/EGFR heterodimer bound in an EV particle was shed in abundance into the local tumor interstitial space for HER2 Pos and HER2 LOW tumors. Thus, IFEVs provide a dual-axis biospecimen system that records both oncogenic receptor signaling and mitochondrial stress states. We hypothesize that HER2/EGFR heterodimer positive EVs, and mitophagy-derived EVs (SM-EVs) harvested from tumor IF mirror active signaling and metabolic stress pathways in matched tumor tissue. Because IF EVs are harvested at the time of the tissue biopsy they preserve their packaged biomolecules before phosphatases or hypoxia degradation can take place . Under the Aims we will study the feasibility and quantitative performance measures for harvesting breast cancer IF EVs from consented, donor patient lumpectomy and mastectomy tissue. The outcome will be a new class of real-time biomarker information, otherwise lost during tissue processing, relevant to personalized therapy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $226,876 )
2026	2026	GEORGE MASON UNIVERSITY	4400 UNIVERSITY DR	FAIRFAX	VA	22030	FAIRFAX CITY	USA	Cancer Treatment Research	000	1	9/4/2026	NEW	$226,876
														Subtotal = $226,876

Grand Total All Awards = $226,876

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A New Window into the in vivo tumor Microenvironment: Rapid harvesting and isolation of tissue interstitial space extracellular vesicles while preserving tissue functional state and cytomorphology

Award Number: R61CA315165

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/04/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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