Biology subjects

Barcellos-Hoff, M. H.

Publications and source records attributed to Barcellos-Hoff, M. H..

3 recordsLinked to original sources

bioRxiv2024

Super-enhancer profiling reveals ThPOK/ZBTB7B, a CD4+ cell lineage commitment factor, as a master regulator that restricts breast cancer cells to a luminal non-migratory phenotype

Despite efforts to understand breast cancer biology, metastatic disease remains a clinical challenge. Identifying suppressors of breast cancer progression and mechanisms of transition to more invasive phenotypes could provide game changing therapeutic opportunities. Transcriptional deregulation is central to all malignancies, highlighted by the extensive reprogramming of regulatory elements that underlie oncogenic programs. Among these, super-enhancers (SEs) stand out due to their enrichment in genes controlling cancer hallmarks. To reveal novel breast cancer dependencies, we integrated the analysis of the SE landscape with master regulator activity inference for a series of breast cancer cell lines. As a result, we identified T-helper-inducing Poxviruses and Zinc-finger (POZ)/Kruppel-like factor (ThPOK, ZBTB7B), a CD4+ cell lineage commitment factor, as a breast cancer master regulator that is recurrently associated with a SE. ThPOK expression is highest in luminal breast cancer but is significantly reduced in the basal subtype. Manipulation of ThPOK levels in cell lines shows that its repressive function restricts breast cancer cells to an epithelial phenotype by suppressing the expression of genes involved in the epithelial-mesenchymal transition (EMT), WNT/{beta}-catenin target genes, and the pro-metastatic TGF{beta} pathway. Our study reveals ThPOK as a master transcription factor that restricts the acquisition of metastatic features in breast cancer cells.

cancer biology↗

bioRxiv2024

Lack of TGFβ signaling competency predicts immune poor cancer conversion to immune rich and response to checkpoint blockade

BackgroundThe efficacy of immune checkpoint blockade (ICB) depends on restoring immune recognition of cancer cells that have evaded immune surveillance. At the time of diagnosis, patients with lymphocyte-infiltrated cancers are the most responsive to ICB, yet a considerable fraction of patients have immune-poor tumors. MethodsWe analyzed transcriptomic data from IMvigor210, TCGA, and TISMO datasets to evaluate the predictive value of {beta}Alt, a score representing the negative correlation of signatures consisting of transforming growth factor beta (TGF{beta}) targets and genes involved in error-prone DNA repair. The immune context of {beta}Alt was assessed by evaluating tumor-educated immune signatures. An ICB-resistant, high {beta}Alt preclinical tumor model was treated with a TGF{beta} inhibitor, radiation, and/or ICB and assessed for immune composition and tumor control. ResultsHere, we show that high {beta}Alt is associated with an immune-poor context yet is predictive of ICB response in both humans and mice. A high {beta}Alt cancer in which TGF{beta} signaling is compromised generates a TGF{beta} rich, immunosuppressive tumor microenvironment. Accordingly, preclinical modeling showed that TGF{beta} inhibition followed by radiotherapy could convert an immune-poor, ICB-resistant tumor to an immune-rich, ICB-responsive tumor. Mechanistically, TGF{beta} blockade in irradiated tumors activated natural killer cells that were required to recruit lymphocytes to respond to ICB. In support of this, natural killer cell activation signatures were also increased in immune-poor mouse and human tumors that responded to ICB. ConclusionsThese studies suggest that loss of TGF{beta} competency identifies a subset of cold tumors that are candidates for ICB. Our mechanistic studies show that inhibiting TGF{beta} activity converts high {beta}Alt, cold tumors into ICB-responsive tumors via NK cells. Thus, a biomarker consisting of combined TGF{beta}, DNA repair, and immune context signatures provides a means to prospectively identify patients whose cancers may be converted from cold to hot, which could be exploited for therapeutic treatment. O_LIWhat is already known on this topic - For some cancer patients, response to ICB provides durable tumor control. Current biomarkers are insufficient to reliably predict the immunotherapy response for most patients, particularly those whose tumors lack lymphocytic infiltration. C_LIO_LIWhat this study adds - The {beta}Alt score, which reports a DNA damage deficiency caused by lack of TGF{beta} signaling, predicts response to ICB in clinical trial data from IMvigor210 metastatic bladder cancer patients and for melanoma patients. Notably, transcriptomic assessment of the immune context shows that these are immune-poor, so-called "cold" tumors. Preclinical modeling indicates that alleviating TGF{beta} inhibition of NK cells is critical to relieving immunosuppression. C_LIO_LIHow this study might affect research, practice or policy - Our work identifies a novel tumor phenotype consisting of cancer cells that have lost TGF{beta} signaling and gained error-prone DNA repair embedded in a TGF{beta} rich, immune-poor microenvironment, which is conserved across cancer types in humans and among preclinical tumor models. Patients whose immune-poor tumors have high {beta}Alt scores are strong candidates for ICB and radiotherapy combinations that may be further augmented by TGF{beta} inhibition. Hence, the {beta}Alt score can be used to stratify immune-poor cancer patients for optimal therapeutic strategies. C_LI

cancer biology↗

bioRxiv2018

Subjugation of TGFβ Signaling by Human Papilloma Virus in Head and Neck Squamous Cell Carcinoma Shifts DNA Repair from Homologous Recombination to Alternative End-Joining

Purpose: Following cytotoxic therapy, 70% of patients with human papillomavirus (HPV) positive oropharyngeal head and neck squamous cell carcinoma (HNSCC) are alive at 5 years compared to 30% of those with similar HPV-negative cancer, which is thought to be due to dysregulation of DNA repair. Loss of transforming growth factor {beta} (TGF{beta}) signaling is a poorly studied consequence of HPV that could contribute to this phenotype.\n\nExperimental Design: Human HNSCC cell lines (n=9), patient-derived xenografts (n=9), tissue microarray (n=194), TCGA expression data and primary tumor specimens (n=10) were used to define the relationship between TGF{beta} competency, response to DNA damage, and type of DNA repair.\n\nResults: Analysis of HNSCC specimens in situ and in vitro showed that HPV associates with loss of TGF{beta} signaling that increases the response to radiation or cisplatin. TGF{beta} suppressed miR-182 that inhibited both BRCA1, necessary for homologous recombination repair, and FOXO3, which is required for ATM kinase activity. TGF{beta} signaling blockade by either HPV or inhibitors released this control, compromised HRR and increased response to PARP inhibition. Antagonizing miR-182 rescued the homologous recombination deficit in HPV+ cells. Loss of TGF{beta} signaling unexpectedly increased error-prone, alternative end-joining repair.\n\nConclusions: HPV-positive HNSCC cells are unresponsive to TGF{beta}. Abrogated TGF{beta} signaling compromises homologous recombination and shifts reliance on alt-EJ repair that provides a mechanistic basis for sensitivity to PARP inhibitors. The effect of HPV in HNSCC provides critical validation of TGF{beta}s role in DNA repair proficiency and further raises the translational potential of TGF{beta} inhibitors in cancer therapy.

cancer biology↗