Description:

The Department of Biochemistry & Molecular Genetics presents:

Brian J. Altman, PhD
Assistant Professor, Department of Biomedical Genetics
Chair of Translational Science, URCC NCORP Research Base
Assistant Director of Education and Career Development, Wilmot Cancer Institute
University of Rochester Medical Center

Presentation: 

"BMAL1 and circadian rhythms support epithelial identity and innate immune signaling in lung cancer"

Abstract:

Non-small cell lung cancers (NSCLCs) exhibit a disrupted molecular circadian clock, and associated alterations in circadian gene expression indicate a poor prognosis. In healthy cells, circadian rhythms arise from an internal ‘molecular clock’ that produces 24-hour cycles to coordinate biological processes across cells and tissues and are controlled by the essential transcription factor complex CLOCK-BMAL1. We found thatBMAL1 is downregulated in human NSCLCs (indicative of circadian disruption) and low BMAL1 is an indicator of poor prognosis in lung adenocarcinoma (LUAD), the most common subtype of NSCLC. However, it remained unclear how clock disruption occurs in LUAD and what these cancers gain from this disturbance. A potential cause for BMAL1 suppression is the upregulation of MYC-family oncoproteins, which are amplified50% of LUADs. We found that MYC interferes with the molecular clock by suppressing BMAL1 expression in vivo in lung and in vitro in an organoid model of alveolar type 2 (ATII) cells, the cells that give rise to lung adenocarcinoma and normally participate in lung regeneration and immune signaling. Our data suggest that a main consequence of MYC suppression of BMAL1 in ATII cells and cancer cells is loss of epithelial identity, and that BMAL1 positively regulates epithelial cell identity. Since ATII cells normally communicate with the immune system, one of the potential outcomes of a loss of circadian rhythms and epithelial identity in lung cancer cells is a loss of immune signaling, leading to an immunologically cold tumor. We found that human LUAD tumors with lower BMAL1 also bear lower transcriptional signatures of innate immune activity. To test this in an in vivo model, we performed single cell RNA-sequencing on tumors formed from LUAD cancer cells ±BMAL1, and found that the infiltrating myeloid (innate immune) cells in tumors without cancer cell BMAL1lacked signatures of an active inflammatory (anti-tumor) immune response and instead expressed a strong angiogenesis signature (bringing in new blood vessels to the tumor), which is pro-tumorigenic. This raised the interesting possibility that circadian changes in the tumor microenvironment itself may lead to changes in rhythms in tumor-infiltrating immune cells, potentially turning these immune cells to a more pro-tumorigenic phenotype. Indeed, we found that tumor-associated macrophages showed evidence of disordered and disrupted rhythms and deleting BMAL1 specifically in tumor-associated macrophages enhanced tumor growth. Together, these data suggest that tumors with fully synchronized, or coupled rhythms, may be less aggressive and have a more favorable immune phenotype, while those where cancer cells and immune cells are desynchronized, or decoupled, may instead be more aggressive and have a more immunosuppressive and pro-tumor immune population.

Host: Dr. Ariana Kupai, Post-Doctoral Fellow, Biochemistry and Molecular Genetics, Peek Lab