NIH grant: Weak Cell Adhesion is a Prognostic Signature of Invasive Cancer (1R01CA300198-01A1)

retained text

NIH grant 1R01CA300198-01A1: Weak Cell Adhesion is a Prognostic Signature of Invasive Cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Adam J Engler. Award: $486094.
Start: 2026-06-19T00:00:00.
Project Summary
Despite early detection, low-grade and localized breast cancers such as ductal carcinoma in situ (DCIS) can
relapse in up to 20% of cases despite standard of care. For DCIS, relapse affects over 12,000 U.S. women
annually and has increased 60% in the last 40 years. Current diagnostic assessments including histopathological
markers often miss early disseminating cells, lack specificity, or cannot distinguish cancer from non-cancer cells
in the stroma. Hence there is an unmet need for cancer diagnostic technologies that employ radically different
characterization methods. For example, significant physical differences exist between metastasizing and benign
breast cancer cells, owing to metastasizing cells detaching from the primary tumor, migrating through the
surrounding stroma, intravasating and extravasating, and ultimately engrafting in distant tissues. We recently
demonstrated that cancer cells with weaker adhesion migrate faster and metastasize more frequently in murine
breast cancer models than strongly adherent cells. In a small pilot study of human breast tumors, we also
observed that the abundance of weakly adherent (WA) cells scales with disease severity; subpopulations from
invasive carcinomas were the least adherent. However, a subset of DCIS cases displayed much less adhesion,
suggesting that these patients may have a tumor subpopulation that progresses to metastatic disease despite
standard-of-care treatment.
Weak adhesion is a defining physical characteristic of tumors, but to establish their role in initiation, metastasis,
and patient outcomes, we will leverage model systems and our newly patented adhesion technology to answer
these fundamental questions of cancer biology and clinical translation. To understand the impact of adhesion on
cancer progression, we will evaluate the tumor-initiating potential of WA versus strongly adherent (SA) tumor
cells in a murine breast cancer model before confirming how weak adhesion advantages cells to cause
secondary disease using bioengineered in vitro models. In dissecting the stages of metastasis where WA cells
exhibit advantages, e.g., recapitulating stromal niche, transendothelial migration, and tissue-specific
colonization, we will identify mechanisms that enable WA cells to thrive and evaluate therapeutic targets that
disrupt these pathways. Finally, we will analyze the adhesion profiles of resected tumors and stroma from 80
breast cancer patients with DCIS or invasive disease. Adhesion data will be correlated with conventional
assessment methods and ultimately with patient outcomes, e.g., disease-free and progression-free intervals. We
anticipate that the DCIS subpopulation that aligns with the adhesion signature of invasive carcinomas will have
shorter intervals and survival time. This integrated study design bridges mouse models, mechanistic
bioengineering assays, and human samples to clarify the metastatic potential and prognostic value of WA breast
cancer cells. Our use of mouse models in this grant is required to study the interactions among tumor cells,
immune cells, vasculature, and stromal tissues that drive tumor formation in vivo. Bioengineered in vitro systems
lack the complexity to ask such questions and using injected tumor cells is not possible in humans.

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