Biology subjects

Hanna, D. N.

Publications and source records attributed to Hanna, D. N..

3 recordsLinked to original sources

bioRxiv2022

SMAD4 suppresses colitis-associated carcinoma through inhibition of CCL20/CCR6-mediated inflammation

Background & AimsChronic inflammation in the colon is a predisposing factor for colon cancer. We previously reported that colon epithelial cell silencing of Smad4, the central downstream mediator of TGF{beta} family signaling, increased epithelial expression of inflammatory genes, including the chemokine CCL20, and increased susceptibility to colitis-associated cancer. Here, we examine the role of the chemokine/receptor pair CCL20/CCR6 in mediating colitis-associated colon carcinogenesis induced by SMAD4 loss. MethodsMice with conditional, epithelial-specific Smad4 loss with and without germline deletion of the Ccr6 gene were subjected to three rounds of dextran sodium sulfate and followed for up to 3 months. Tumors were quantified histologically, and immune cell populations were analyzed by flow cytometry and immunostaining. ResultsIn humans, SMAD4 expression inversely correlated with CCL20 expression. Smad4 loss in mouse colon epithelium led to enlarged gut-associated lymphoid tissues and recruitment of specific immune cell subsets to the mouse colon epithelium and underlying stroma, particularly Treg, Th17, and dendritic cells. Loss of CCR6 abrogated these immune responses and significantly reduced the incidence of colitis-associated tumors observed with loss of SMAD4 alone. ConclusionsRegulation of mucosal inflammation is a critical role of SMAD4 signaling within the colon epithelium and central to its tumor suppressor function in the colon. A key downstream node in this regulation is suppression of CCL20 signaling by the epithelium to CCR6 in immune cells. Loss of SMAD4 in the colon epithelium increases CCL20 expression and chemoattraction of CCR6+ immune cells, contributing to greater susceptibility to colon cancer.

cancer biology↗

bioRxiv2021

Multiplatform Computational Analysis of Mast Cells in Adrenocortical Carcinoma Tumor Microenvironment

IntroductionImmunotherapeutic response failure of adrenocortical carcinomas (ACC) highlights a need for novel strategies targeting immune cell populations in the tumor microenvironment (TME) to overcome tumor resistance and enhance therapeutic response. A recent study explored a new link between tumor mast cell (MC) infiltration and improved outcomes in patients with ACC. We further dissect the role of MC in TME of ACC by examining the tumor MC expression signatures and MC activity within TME to provide additional insight into potential novel immunotherapeutic targets. MethodsUsing CIBERSORTx computational immunogenomic deconvolution algorithm to analyze ACC tumor gene mRNA expression data (TCGA, N=79), we estimated the abundance of tumor immune infiltrating MC, and assessed prognostic potential of MC signaling genes as pro- or anti- tumor signatures, as well as the impact on overall (OS) and disease-free (DFS) survival. ResultsWe stratified MC signaling genes with survival prognostic values (OS, DFS, p<0.05) into anti-tumor (ALOX5, CCL2, CCL5, CXCL10, HDC, IL16, TNF, TPSAB1, VEGFD) and pro-tumor (CXCL1, CXCL3, CXCL8, IL4, IL13, PTGS3, TNSF4, VEGFD) groups. Anti-tumor MC signature, as the predominant phenotype, was associated with improved OS and DFS. ConclusionThe deconvolution analysis of TCGA data identified MC infiltration in ACC microenvironment as predominantly associated with anti-tumor activity. Future studies stemming from our findings may help define the role of MC in TME and the impact on patient survival in patients with ACC. Modulation of tumor MC infiltration may serve as a potential target for novel synergistic immunotherapies for the treatment and improved survival of patients with ACC.

cancer biology↗

bioRxiv2021

Multiplatform Integrative Analyses of Immunosuppressive Signatures in Cortisol-secreting Adrenocortical Carcinoma

Adrenocortical carcinoma (ACC) is a rare but highly aggressive malignancy and nearly half of ACC tumors have been shown to overproduce and secrete adrenal steroids. Excess cortisol secretion, in particular, has been associated with poor prognosis among ACC patients. Furthermore, recent immunotherapy clinical trials demonstrated significant immunoresistance among cortisol-secreting ACC (CS-ACC) patients when compared to their non-Cortisol-secreting (nonCS-ACC) counterparts. The immunosuppressive role of excess glucocorticoid therapies and secretion is well established, however, the impact of the cortisol hypersecretion on ACC tumor microenvironment (TME), immune expression profiles, and immune cell responses remain largely undefined. In this study, we characterized the TME of ACC patients and compared the immunogenomic profiles of nonCS-ACC and CS-ACC tumors to assess the impact of differentially expressed genes (DEGs) related to immune processes on patient prognosis. Comprehensive multiplatform immunogenomic computational analyses of ACC tumors deciphered an immunosuppressive expression profile with a direct impact on patient survival. We identified several primary immunogenomic prognostic indicators and potential targets within the tumor immune landscape of CS-ACC that define a distinct TME and provide additional insight into the understanding of potential contributory mechanisms underlying failure of initial immunotherapeutic trials and poor prognosis of patients with CS-ACC.

cancer biology↗