Fred Hutch Cancer Center has received a USD 1.8 million NCI R01 renewal to investigate how the tumor suppressor Par-4 regulates actomyosin contractility as a mechanism for eliminating residual breast cancer cells — a research area with direct implications for preventing disease recurrence after treatment.
The grant, running through May 2029, targets one of the most clinically intractable problems in breast oncology: the survival of dormant residual cells that persist after therapy and eventually drive recurrence. Led by James V. Alvarez, the project builds on prior work demonstrating that Par-4 (encoded by PAWR) is downregulated in recurrent tumors across multiple genetically engineered mouse models, and that this loss is both necessary and sufficient for tumor recurrence. In patients, low Par-4 expression correlates with poor response to neoadjuvant therapy and elevated recurrence risk.
The current work focuses on a specific mechanistic hypothesis: that Par-4 promotes cell death partly by inducing actomyosin contractility — inducing actomyosin contractility, the force-generating machinery that controls cell shape, tension, and survival — and that this biomechanical pathway contributes to its tumor suppressive function. The research will examine this in two contexts: dormant residual cell survival and invasive lobular carcinoma, a breast cancer subtype with distinct biology and limited targeted treatment options. Genetically engineered mouse models and 3D cell culture systems will be used to dissect these mechanisms.
The translational rationale is notable. Most efforts to prevent breast cancer recurrence focus on systemic adjuvant therapies targeting proliferating cells; dormant residual cells are largely refractory to these approaches. A mechanistic understanding of how Par-4 and actomyosin contractility regulate dormant cell fate could point toward strategies to actively eliminate residual disease rather than simply suppress proliferation. Invasive lobular carcinoma, which frequently lacks E-cadherin expression and exhibits altered cell mechanics, represents a setting where biomechanical tumor suppression mechanisms may be particularly relevant.