Cancer Biology Commons^™

Desmoglein-2 As A Cancer Modulator: Friend Or Foe?, Kay Myo Min, Charlie Ffrench, Barbara Mcclure, Michael Ortiz, Emma Dorward, Michael Samuel, Lisa Ebert, Mỹ Mahoney, Claudine Bonder

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Desmoglein-2 (DSG2) is a calcium-binding single pass transmembrane glycoprotein and a member of the large cadherin family. Until recently, DSG2 was thought to only function as a cell adhesion protein embedded within desmosome junctions designed to enable cells to better tolerate mechanical stress. However, additional roles for DSG2 outside of desmosomes are continuing to emerge, particularly in cancer. Herein, we review the current literature on DSG2 in cancer and detail its impact on biological functions such as cell adhesion, proliferation, migration, invasion, intracellular signaling, extracellular vesicle release and vasculogenic mimicry. An increased understanding of the diverse repertoire of the biological …

27-Hydroxycholesterol And Dna Damage Repair: Implication In Prostate Cancer, Gloria Cecilia Galvan, Nadine Friedrich, Sanjay Das, James Daniels, Sara Pollan, Shweta Dambal, Ryusuke Suzuki, Sergio Sanders, Sungyong You, Hisashi Tanaka, Yeon-Joo Lee, Wei Yuan, Johann De Bono, Irina Vasilevskaya, Karen Knudsen, Michael Freeman, Stephen Freedland

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

INTRODUCTION: We previously reported that cholesterol homeostasis in prostate cancer (PC) is regulated by 27-hydroxycholesterol (27HC) and that CYP27A1, the enzyme that converts cholesterol to 27HC, is frequently lost in PCs. We observed that restoring the CYP27A1/27HC axis inhibited PC growth. In this study, we investigated the mechanism of 27HC-mediated anti-PC effects.

METHODS: We employed in vitro models and human transcriptomics data to investigate 27HC mechanism of action in PC. LNCaP (AR+) and DU145 (AR-) cells were treated with 27HC or vehicle. Transcriptome profiling was performed using the Affymetrix GeneChip™ microarray system. Differential expression was determined, and gene set enrichment …

Needle Biopsy Accelerates Pro-Metastatic Changes And Systemic Dissemination In Breast Cancer: Implications For Mortality By Surgery Delay, Hiroyasu Kameyama, Priya Dondapati, Reese Simmons, Macall Leslie, John Langenheim, Yunguang Sun, Misung Yi, Aubrey Rottschaefer, Rashmi Pathak, Shreya Nuguri, Kar-Ming Fung, Shirng-Wern Tsaih, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

ncreased breast cancer (BC) mortality risk posed by delayed surgical resection of tumor after diagnosis is a growing concern, yet the underlying mechanisms remain unknown. Our cohort analyses of early-stage BC patients reveal the emergence of a significantly rising mortality risk when the biopsy-to-surgery interval was extended beyond 53 days. Additionally, histology of post-biopsy tumors shows prolonged retention of a metastasis-permissive wound stroma dominated by M2-like macrophages capable of promoting cancer cell epithelial-to-mesenchymal transition and angiogenesis. We show that needle biopsy promotes systemic dissemination of cancer cells through a mechanism of sustained activation of the COX-2/PGE₂/EP2 feedforward loop, …

Kinome Profiling Identifies Mark3 And Stk10 As Potential Therapeutic Targets In Uveal Melanoma, Usman Baqai, Alison M. Kurimchak, Isabella Trachtenberg, Timothy J. Purwin, Jelan I. Haj, Anna Han, Kristine Luo, Nikole Fandino Pachon, Angela Jeon, Vivian Chua, Michael A. Davies, J Silvio Gutkind, Jeffrey L. Benovic, James S. Duncan, Andrew E. Aplin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the "dark kinome". Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. …

Enteroendocrine Cell Regulation Of The Gut-Brain Axis, Joshua Barton, Annie Londregan, Tyler Alexander, Ariana Entezari, Manuel Covarrubias, Scott Waldman

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Enteroendocrine cells (EECs) are an essential interface between the gut and brain that communicate signals about nutrients, pain, and even information from our microbiome. EECs are hormone-producing cells expressed throughout the gastrointestinal epithelium and have been leveraged by pharmaceuticals like semaglutide (Ozempic, Wegovy), terzepatide (Mounjaro), and retatrutide (Phase 2) for diabetes and weight control, and linaclotide (Linzess) to treat irritable bowel syndrome (IBS) and visceral pain. This review focuses on role of intestinal EECs to communicate signals from the gut lumen to the brain. Canonically, EECs communicate information about the intestinal environment through a variety of hormones, dividing EECs into …

Parkin Ubiquitination Of Kindlin-2 Enables Mitochondria-Associated Metastasis Suppression, Minjeong Yeon, Irene Bertolini, Ekta Agarwal, Jagadish C Ghosh, Hsin-Yao Tang, David W. Speicher, Frederick Keeney, Khalid Sossey-Alaoui, Elzbieta Pluskota, Katarzyna Bialkowska, Edward F. Plow, Lucia R. Languino, Emmanuel Skordalakes, M Cecilia Caino, Dario C. Altieri

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson's disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.5 h. Loss of K2 inhibits focal adhesion turnover and β1 integrin activation, impairs membrane lamellipodia size and frequency, and inhibits mitochondrial dynamics, altogether suppressing tumor cell-extracellular matrix interactions, migration, and invasion. Conversely, Parkin does …