Uncovering the mechanisms by which CAMK2B loss promotes metastasis and immune suppression in pancreatic cancer

The National Cancer Institute, a division of the National Institutes of Health under the Department of Health and Human Services, awarded $134,000 to the University of Massachusetts Medical School on September 3, 2026, under the Cancer Biology Research program (CFDA 93.396).

The recipient will conduct research employing genetically engineered mouse models to elucidate mechanisms by which loss of CAMK2B (calcium/calmodulin-dependent protein kinase II beta) promotes metastasis and immune suppression in pancreatic cancer. Research aims include exploring tumor cell intrinsic mechanisms through which CAMK2B deletion promotes metastasis by determining effects on epithelial cell identity and plasticity, and attempting to block this plastic state through inhibition of lysyl oxidase signaling; and determining the role of tumor cell CAMK2B loss in organizing an immunosuppressive metastatic niche by fostering M2 macrophage recruitment and exploring mechanisms of immune suppression through cGAS-STING signaling components.

Performance will occur in Worcester, Massachusetts. The period of performance extends from the award date through August 31, 2027. The Cancer Biology Research program funds fundamental research on the cause and nature of cancer in people with the expectation of generating better methods of prevention, detection, diagnosis, and treatment of neoplastic diseases.

Abstract

Our proposed research employs innovative and novel genetically engineered mouse models of metastatic pancreatic cancer to elucidate mechanisms of metastasis both within tumor cells and with their interactions with the host. Pancreatic cancer patients are often not diagnosed until metastases have already formed, with the vast majority of patients presenting with oligometastatic disease. The study of metastatic drivers has been limited by current genetically engineered mouse models, which show low metastatic competency. We have identified calcium/calmodulin dependent protein kinase II beta (CAMK2B), a calcium-responsive kinase, as a metastasis suppressing gene whose loss enhances tumor metastasis and creates a highly immunosuppressive tumor microenvironment (TME). Genetically engineered mice with tumor cell-specific CAMK2B knockout form metastases in 80% of animals and present with >25 metastatic lesions per mouse, leading to a dramatic reduction in overall survival. Additionally, these animals have an immunosuppressed metastatic niche that is dominated by pro-tumor M2 macrophages and lacks CD8+ T and NK effector immune cells. Unbiased sequencing approaches revealed that deletion of CAMK2B enhances the expression of lysyl oxidase (LOX) family members and cgas-sting signaling components, which we propose mediate the metastatic and immunosuppressive phenotypes, respectively. Aim 1 will focus on exploring tumor cell intrinsic mechanisms through which CAMK2B-deletion promotes tumor cell metastasis by determining the effect of this loss on epithelial cell identity and plasticity and will attempt to block this highly plastic state through inhibition of LOX signaling. Aim 2 will determine the role of tumor cell CAMK2B loss in organizing a congenial metastatic niche by fostering immunosuppressive M2 macrophage cell recruitment and will seek to exploit vulnerabilities in cgas-sting signaling to revert this immunosuppression. Thus, our central hypothesis is that tumor cell CAMK2B loss enhances pdac metastasis by altering tumor cell intrinsic mechanisms of dissemination (aim 1) and by creating a favorable metastatic niche through interactions with the host microenvironment (aim 2). The proposed aims will delineate how loss of CAMK2B signaling networks promote pancreatic cancer metastasis and assess the efficacy of LOX-targeted and sting- targeted therapies to block metastasis.