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Full-Text Articles in Medicine and Health Sciences
Ghost Mitochondria Drive Metastasis Through Adaptive Gcn2/Akt Therapeutic Vulnerability, Jagadish C Ghosh, Michela Perego, Ekta Agarwal, Irene Bertolini, Yuan Wang, Aaron R Goldman, Hsin-Yao Tang, Andrew V Kossenkov, Catherine J Libby, Lucia R Languino, Edward F Plow, Annamaria Morotti, Luisa Ottobrini, Marco Locatelli, David W Speicher, M Cecilia Caino, Joel Cassel, Joseph M Salvino, Marie E Robert, Valentina Vaira, Dario C Altieri
Ghost Mitochondria Drive Metastasis Through Adaptive Gcn2/Akt Therapeutic Vulnerability, Jagadish C Ghosh, Michela Perego, Ekta Agarwal, Irene Bertolini, Yuan Wang, Aaron R Goldman, Hsin-Yao Tang, Andrew V Kossenkov, Catherine J Libby, Lucia R Languino, Edward F Plow, Annamaria Morotti, Luisa Ottobrini, Marco Locatelli, David W Speicher, M Cecilia Caino, Joel Cassel, Joseph M Salvino, Marie E Robert, Valentina Vaira, Dario C Altieri
Department of Cancer Biology Faculty Papers
Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood. Here, we show that many human tumors have heterogeneous and often reduced levels of Mic60, or Mitofilin, an essential scaffold of mitochondrial structure. Despite a catastrophic collapse of mitochondrial integrity, loss of bioenergetics, and oxidative damage, tumors with Mic60 depletion slow down cell proliferation, evade cell death, and activate a nuclear gene expression program of innate immunity and cytokine/chemokine signaling. In turn, this induces epithelial-mesenchymal transition (EMT), activates tumor cell movements through exaggerated mitochondrial dynamics, and promotes metastatic dissemination in vivo. In …
Redefining Cancer Of Unknown Primary: Is Precision Medicine Really Shifting The Paradigm?, Timothée Olivier, Eugenio Fernandez, Intidhar Labidi-Galy, Pierre-Yves Dietrich, Veronica Rodriguez-Bravo, Giulia Baciarello, Karim Fizazi, Anna Patrikidou
Redefining Cancer Of Unknown Primary: Is Precision Medicine Really Shifting The Paradigm?, Timothée Olivier, Eugenio Fernandez, Intidhar Labidi-Galy, Pierre-Yves Dietrich, Veronica Rodriguez-Bravo, Giulia Baciarello, Karim Fizazi, Anna Patrikidou
Department of Cancer Biology Faculty Papers
The concept of Cancer of Unknown Primary (CUP) has evolved with the advent of medical oncology. CUP can be difficult to diagnose and represents 2 to 5% of new cancers, therefore not exceptionally rare. Within CUPs can be identified a subset of favourable prognosis tumours, however the vast majority of CUP patients belongs to a poor prognosis group. CUP features significant oncological challenges, such as unravelling biological and transversal issues, and most importantly, improving patient's outcomes. In that regard, CUP patients’ outcomes regrettably showed minimal improvement for decades and CUP remains a cancer group of very poor prognosis. The biology …
Printing The Pathway Forward In Bone Metastatic Cancer Research: Applications Of 3d Engineered Models And Bioprinted Scaffolds To Recapitulate The Bone-Tumor Niche., Anne M. Hughes, Alexus D. Kolb, Alison B. Shupp, Kristy M. Shine, Karen M. Bussard
Printing The Pathway Forward In Bone Metastatic Cancer Research: Applications Of 3d Engineered Models And Bioprinted Scaffolds To Recapitulate The Bone-Tumor Niche., Anne M. Hughes, Alexus D. Kolb, Alison B. Shupp, Kristy M. Shine, Karen M. Bussard
Department of Cancer Biology Faculty Papers
Breast cancer commonly metastasizes to bone, resulting in osteolytic lesions and poor patient quality of life. The bone extracellular matrix (ECM) plays a critical role in cancer cell metastasis by means of the physical and biochemical cues it provides to support cellular crosstalk. Current two-dimensional in-vitro models lack the spatial and biochemical complexities of the native ECM and do not fully recapitulate crosstalk that occurs between the tumor and endogenous stromal cells. Engineered models such as bone-on-a-chip, extramedullary bone, and bioreactors are presently used to model cellular crosstalk and bone-tumor cell interactions, but fall short of providing a bone-biomimetic microenvironment. …
'Educated' Osteoblasts Reduce Osteoclastogenesis In A Bone-Tumor Mimetic Microenvironment., Alexus D. Kolb, Jinlu Dai, Evan T. Keller, Karen M. Bussard
'Educated' Osteoblasts Reduce Osteoclastogenesis In A Bone-Tumor Mimetic Microenvironment., Alexus D. Kolb, Jinlu Dai, Evan T. Keller, Karen M. Bussard
Department of Cancer Biology Faculty Papers
Breast cancer (BC) metastases to bone disrupt the balance between osteoblasts and osteoclasts, leading to excessive bone resorption. We identified a novel subpopulation of osteoblasts with tumor-inhibitory properties, called educated osteoblasts (EOs). Here we sought to examine the effect of EOs on osteoclastogenesis during tumor progression. We hypothesized that EOs affect osteoclast development in the bone-tumor niche, leading to suppressed pre-osteoclast fusion and bone resorption. Conditioned media (CM) was analyzed for protein expression of osteoclast factors receptor activator of nuclear factor kappa-β ligand (RANKL), osteoprotegerin (OPG), and tumor necrosis factor alpha (TNFα) via ELISA. EOs were co-cultured with pre-osteoclasts on …
The Bone Extracellular Matrix As An Ideal Milieu For Cancer Cell Metastases., Alexus D. Kolb, Karen M. Bussard
The Bone Extracellular Matrix As An Ideal Milieu For Cancer Cell Metastases., Alexus D. Kolb, Karen M. Bussard
Department of Cancer Biology Faculty Papers
Bone is a preferential site for cancer metastases, including multiple myeloma, prostate, and breast cancers.The composition of bone, especially the extracellular matrix (ECM), make it an attractive site for cancer cell colonization and survival. The bone ECM is composed of living cells embedded within a matrix composed of both organic and inorganic components. Among the organic components, type I collagen provides the tensile strength of bone. Inorganic components, including hydroxyapatite crystals, are an integral component of bone and provide bone with its rigidity. Under normal circumstances, two of the main cell types in bone, the osteoblasts and osteoclasts, help to …
Myc-Mediated Transcriptional Regulation Of The Mitochondrial Chaperone Trap1 Controls Primary And Metastatic Tumor Growth., Ekta Agarwal, Brian J. Altman, Jae Ho Seo, Jagadish C. Ghosh, Andrew V Kossenkov, Hsin-Yao Tang, Shiv Ram Krishn, Lucia R. Languino, Dmitry I. Gabrilovich, David W. Speicher, Chi V. Dang, Dario C. Altieri
Myc-Mediated Transcriptional Regulation Of The Mitochondrial Chaperone Trap1 Controls Primary And Metastatic Tumor Growth., Ekta Agarwal, Brian J. Altman, Jae Ho Seo, Jagadish C. Ghosh, Andrew V Kossenkov, Hsin-Yao Tang, Shiv Ram Krishn, Lucia R. Languino, Dmitry I. Gabrilovich, David W. Speicher, Chi V. Dang, Dario C. Altieri
Department of Cancer Biology Faculty Papers
The role of mitochondria in cancer continues to be debated, and whether exploitation of mitochondrial functions is a general hallmark of malignancy or a tumor- or context-specific response is still unknown. Using a variety of cancer cell lines and several technical approaches, including siRNA-mediated gene silencing, ChIP assays, global metabolomics and focused metabolite analyses, bioenergetics, and cell viability assays, we show that two oncogenic Myc proteins, c-Myc and N-Myc, transcriptionally control the expression of the mitochondrial chaperone TNFR-associated protein- 1 (TRAP1) in cancer. In turn, this Myc-mediated regulation preserved the folding and function of mitochondrial oxidative phosphorylation (OXPHOS) complex II …
Osteoblasts Are "Educated" By Crosstalk With Metastatic Breast Cancer Cells In The Bone Tumor Microenvironment., Alexus D. Kolb, Alison B. Shupp, Dimpi Mukhopadhyay, Frank C. Marini, Karen M. Bussard
Osteoblasts Are "Educated" By Crosstalk With Metastatic Breast Cancer Cells In The Bone Tumor Microenvironment., Alexus D. Kolb, Alison B. Shupp, Dimpi Mukhopadhyay, Frank C. Marini, Karen M. Bussard
Department of Cancer Biology Faculty Papers
INTRODUCTION: In a cancer-free environment in the adult, the skeleton continuously undergoes remodeling. Bone-resorbing osteoclasts excavate erosion cavities, and bone-depositing osteoblasts synthesize osteoid matrix that forms new bone, with no net bone gain or loss. When metastatic breast cancer cells invade the bone, this balance is disrupted. Patients with bone metastatic breast cancer frequently suffer from osteolytic bone lesions that elicit severe bone pain and fractures. Bisphosphonate treatments are not curative. Under ideal circumstances, osteoblasts would synthesize new matrix to fill in erosion cavities caused by osteoclasts, but this is not what occurs. Our prior evidence demonstrated that osteoblasts are …
Pharmacologic Or Genetic Targeting Of Glutamine Synthetase Skews Macrophages Toward An M1-Like Phenotype And Inhibits Tumor Metastasis., Erika M. Palmieri, Alessio Menga, Rosa Martín-Pérez, Annamaria Quinto, Carla Riera-Domingo, Giacoma De Tullio, D Craig Hooper, Wouter H. Lamers, Bart Ghesquière, Daniel W. Mcvicar, Attilio Guarini, Massimiliano Mazzone, Alessandra Castegna
Pharmacologic Or Genetic Targeting Of Glutamine Synthetase Skews Macrophages Toward An M1-Like Phenotype And Inhibits Tumor Metastasis., Erika M. Palmieri, Alessio Menga, Rosa Martín-Pérez, Annamaria Quinto, Carla Riera-Domingo, Giacoma De Tullio, D Craig Hooper, Wouter H. Lamers, Bart Ghesquière, Daniel W. Mcvicar, Attilio Guarini, Massimiliano Mazzone, Alessandra Castegna
Department of Cancer Biology Faculty Papers
Glutamine-synthetase (GS), the glutamine-synthesizing enzyme from glutamate, controls important events, including the release of inflammatory mediators, mammalian target of rapamycin (mTOR) activation, and autophagy. However, its role in macrophages remains elusive. We report that pharmacologic inhibition of GS skews M2-polarized macrophages toward the M1-like phenotype, characterized by reduced intracellular glutamine and increased succinate with enhanced glucose flux through glycolysis, which could be partly related to HIF1α activation. As a result of these metabolic changes and HIF1α accumulation, GS-inhibited macrophages display an increased capacity to induce T cell recruitment, reduced T cell suppressive potential, and an impaired ability to foster endothelial …