Hiltbrunner, S. | bioRxiv Science

bioRxiv2020

Coincidence detection of mitogenic signals via cytosolic pH regulates Cyclin D1 expression

Enhanced cell growth and proliferation are accompanied by profound changes in cellular metabolism. Originally identified as the Warburg effect in cancer, such metabolic changes are also common under physiological conditions and include increased fermentation and elevated cytosolic pH (pHc)1,2. However, how these changes contribute to enhanced cell growth and proliferation is unclear. Here, we demonstrate that elevated pHc specifically orchestrates an E2F-dependent transcriptional program to drive cell proliferation by promoting Cyclin D1 expression. pHc-dependent transcription of Cyclin D1 requires the transcription factors CREB1/ATF1 and ETS1 and the Histone Acetyltransferases p300/CBP. Interestingly, biochemical characterization revealed that the CREB1-p300/CBP interaction acts as a pH-sensor and coincidence detector linking different mitotic signals to Cyclin D1 transcription. We also show that elevated pHc contributes to increased Cyclin D1 expression in Malignant Pleural Mesotheliomas (MPMs) and renders them hypersensitive to pharmacological reduction of pHc. Taken together, these data demonstrate that elevated pHc is a critical cellular signal regulating G1 progression and provide a mechanism linking elevated pHc to oncogenic activation of Cyclin D1 in MPMs and possibly other Cyclin D1-dependent tumors. Thus, an increase of pHc may represent a functionally important, early event in the etiology of cancer amenable to therapeutic intervention.

cell biology↗

bioRxiv2020

CD39+PD-1+CD8+ T cells mediate metastatic dormancy in breast cancer

Some breast tumors metastasize aggressively whereas others remain in a state of metastatic dormancy for months or even years. The mechanism governing such metastatic dormancy remains largely unknown. Through high-parametric single-cell mapping in mice, we identified a discrete population of CD39+PD-1+CD8+ T cells present both in primary tumors and in dormant metastasis, which was hardly found in aggressively metastasizing tumors. Using blocking antibodies, we found that dormancy depended on TNF and IFN{gamma}. Of note, immunotherapy reduced the number of dormant cancer cells in the lungs. Adoptive transfer of purified CD39+PD-1+CD8+ T cells prevented metastatic outgrowth. In human breast cancer, the frequency of CD39+PD-1+CD8+ but not of total CD8+ T cells correlated with delayed metastatic relapse after resection (disease-free survival), thus underlining the biological relevance of CD39+PD-1+CD8+ T cells for controlling experimental and human breast cancer. Furthermore, density of CD39+PD-1+CD8+ T cells may serve as a novel biomarker and may serve as a potential immunotherapy target. Thus, we discovered that a primary breast tumor primes a systemic, CD39+PD-1+CD8+ T cell response that is essential for metastatic dormancy in the lungs.

cancer biology↗