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1. <scp>RNA</scp> polymerase I inhibition induces terminal differentiation, growth arrest, and vulnerability to senolytics in colorectal cancer cells

Author

Christoph Otto, Carolin Kastner, Stefanie Schmidt, Konstantin Uttinger, Apoorva Baluapuri, Sarah Denk, Mathias T. Rosenfeldt, Andreas Rosenwald, Florian Roehrig, Carsten P. Ade, Christina Schuelein‐Voelk, Markus E. Diefenbacher, Christoph‐Thomas Germer, Elmar Wolf, Martin Eilers, and Armin Wiegering

Subjects
Ribosomal Proteins, Cancer Research, General Medicine, Mice, Oncology, RNA Polymerase I, Senotherapeutics, Genetics, Animals, Humans, Molecular Medicine, ddc:610, Colorectal Neoplasms, Cell Nucleolus
Abstract

Ribosomal biogenesis and protein synthesis are deregulated in most cancers, suggesting that interfering with translation machinery may hold significant therapeutic potential. Here, we show that loss of the tumor suppressor adenomatous polyposis coli (APC), which constitutes the initiating event in the adenoma carcinoma sequence for colorectal cancer (CRC), induces the expression of RNA polymerase I (RNAPOL1) transcription machinery, and subsequently upregulates ribosomal DNA (rDNA) transcription. Targeting RNAPOL1 with a specific inhibitor, CX5461, disrupts nucleolar integrity, and induces a disbalance of ribosomal proteins. Surprisingly, CX5461-induced growth arrest is irreversible and exhibits features of senescence and terminal differentiation. Mechanistically, CX5461 promotes differentiation in an MYC-interacting zinc-finger protein 1 (MIZ1)- and retinoblastoma protein (Rb)-dependent manner. In addition, the inhibition of RNAPOL1 renders CRC cells vulnerable towards senolytic agents. We validated this therapeutic effect of CX5461 in murine- and patient-derived organoids, and in a xenograft mouse model. These results show that targeting ribosomal biogenesis together with targeting the consecutive, senescent phenotype using approved drugs is a new therapeutic approach, which can rapidly be transferred from bench to bedside.

Published
2022

2. MiR-205-driven downregulation of cholesterol biosynthesis through SQLE-inhibition identifies therapeutic vulnerability in aggressive prostate cancer

Author

Johannes Linxweiler, Mathias T. Rosenfeldt, Martin Eckstein, Burkhard Kneitz, Sven Wach, Kerstin Junker, Markus Krebs, F. Röhrig, M. Puhr, Martin Eilers, T. Frank, Hubert Kübler, H. Marouf, Matthias Saar, Charis Kalogirou, Anna Katharina Seitz, Werner Schmitz, P. Schmucker, Martin Spahn, E. Hartmann, Gabriele Büchel, Marteinn Thor Snaebjornsson, Andreas Müller, and Almut Schulze

Subjects
Male, Squalene monooxygenase, Antifungal drug, General Physics and Astronomy, Mice, SCID, urologic and male genital diseases, Cohort Studies, Mice, Prostate cancer, chemistry.chemical_compound, Transactivation, Neoplasm Metastasis, Cancer, Aged, 80 and over, Multidisciplinary, Middle Aged, Lipids, Gene Expression Regulation, Neoplastic, Prostatic Neoplasms, Castration-Resistant, Cholesterol, Receptors, Androgen, lipids (amino acids, peptides, and proteins), Transcriptional Activation, Cell death, Cell Survival, Science, Down-Regulation, Urological cancer, General Biochemistry, Genetics and Molecular Biology, Article, Downregulation and upregulation, Cell Line, Tumor, medicine, Animals, Humans, Enzalutamide, Metabolomics, Computer Simulation, Neoplasm Invasiveness, Terbinafine, Aged, Cell Proliferation, Neoplasm Staging, Base Sequence, business.industry, Prostatic Neoplasms, General Chemistry, Prostate-Specific Antigen, medicine.disease, Androgen receptor, Disease Models, Animal, MicroRNAs, Squalene Monooxygenase, chemistry, Drug Resistance, Neoplasm, Cancer research, business
Abstract

Prostate cancer (PCa) shows strong dependence on the androgen receptor (AR) pathway. Here, we show that squalene epoxidase (SQLE), an enzyme of the cholesterol biosynthesis pathway, is overexpressed in advanced PCa and its expression correlates with poor survival. SQLE expression is controlled by micro-RNA 205 (miR-205), which is significantly downregulated in advanced PCa. Restoration of miR-205 expression or competitive inhibition of SQLE led to inhibition of de novo cholesterol biosynthesis. Furthermore, SQLE was essential for proliferation of AR-positive PCa cell lines, including abiraterone or enzalutamide resistant derivatives, and blocked transactivation of the AR pathway. Inhibition of SQLE with the FDA approved antifungal drug terbinafine also efficiently blocked orthotopic tumour growth in mice. Finally, terbinafine reduced levels of prostate specific antigen (PSA) in three out of four late-stage PCa patients. These results highlight SQLE as a therapeutic target for the treatment of advanced PCa., Cholesterol metabolism is involved in the progression of aggressive prostate cancer (PCa). Here the authors show that miR-205 downregulation promotes cholesterol synthesis and androgen receptor signalling in PCa through enhancing the expression of the rate-limiting enzyme of cholesterol synthesis, squalene epoxidase.

Published
2021

3. Mevalonate Pathway Provides Ubiquinone to Maintain Pyrimidine Synthesis and Survival in p53-Deficient Cancer Cells Exposed to Metabolic Stress

Author

Irem Kaymak, Carina R. Maier, Werner Schmitz, Andrew D. Campbell, Beatrice Dankworth, Carsten P. Ade, Susanne Walz, Madelon Paauwe, Charis Kalogirou, Hecham Marouf, Mathias T. Rosenfeldt, David M. Gay, Grace H. McGregor, Owen J. Sansom, and Almut Schulze

Subjects
0301 basic medicine, Cancer Research, Cell Survival, Ubiquinone, Citric Acid Cycle, Mevalonic Acid, Apoptosis, Mice, Transgenic, Context (language use), medicine.disease_cause, Mice, 03 medical and health sciences, 0302 clinical medicine, Stress, Physiological, Cell Line, Tumor, Neoplasms, Tumor Microenvironment, medicine, Animals, Humans, Intestinal Mucosa, Chemistry, Metabolism, Xenograft Model Antitumor Assays, Cell biology, Pyrimidines, 030104 developmental biology, Oncology, Cell culture, 030220 oncology & carcinogenesis, Pyrimidine metabolism, Cancer cell, Mevalonate pathway, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Tumor Suppressor Protein p53, Oxidative stress, Signal Transduction, Sterol Regulatory Element Binding Protein 2
Abstract

Oncogene activation and loss of tumor suppressor function changes the metabolic activity of cancer cells to drive unrestricted proliferation. Moreover, cancer cells adapt their metabolism to sustain growth and survival when access to oxygen and nutrients is restricted, such as in poorly vascularized tumor areas. We show here that p53-deficient colon cancer cells exposed to tumor-like metabolic stress in spheroid culture activated the mevalonate pathway to promote the synthesis of ubiquinone. This was essential to maintain mitochondrial electron transport for respiration and pyrimidine synthesis in metabolically compromised environments. Induction of mevalonate pathway enzyme expression in the absence of p53 was mediated by accumulation and stabilization of mature SREBP2. Mevalonate pathway inhibition by statins blocked pyrimidine nucleotide biosynthesis and induced oxidative stress and apoptosis in p53-deficient cancer cells in spheroid culture. Moreover, ubiquinone produced by the mevalonate pathway was essential for the growth of p53-deficient tumor organoids. In contrast, inhibition of intestinal hyperproliferation by statins in an Apc/KrasG12D-mutant mouse model was independent of de novo pyrimidine synthesis. Our results highlight the importance of the mevalonate pathway for maintaining mitochondrial electron transfer and biosynthetic activity in cancer cells exposed to metabolic stress. They also demonstrate that the metabolic output of this pathway depends on both genetic and environmental context. Significance: These findings suggest that p53-deficient cancer cells activate the mevalonate pathway via SREBP2 and promote the synthesis of ubiquinone that plays an essential role in reducing oxidative stress and supports the synthesis of pyrimidine nucleotide.

Published
2020

4. Krill Protein Hydrolysate Provides High Absorption Rate for All Essential Amino Acids—A Randomized Control Cross-Over Trial

Author

Rebekka Thøgersen, Mette Hansen, Mathias T Vangsoe, and Hanne Christine Bertram

Subjects
Male, Magnetic Resonance Spectroscopy, alternative proteins, Hunger, Protein Hydrolysates, whey, protein accessibility, Whey protein isolate, soy, Reference Values, TX341-641, Food science, Soy protein, Nutrition and Dietetics, Cross-Over Studies, biology, Chemistry, Postprandial Period, Postprandial, Area Under Curve, Soybean Proteins, Digestion, Nutritive Value, amino acid, Adult, Krill, Biological Availability, Satiation, Hydrolysate, Article, Young Adult, NMR spectroscopy, postprandial absorption, Animals, Humans, human, krill protein, protein hydrolysate, marine protein, Nutrition. Foods and food supply, biology.organism_classification, Crossover study, Bioavailability, Human nutrition, Whey Proteins, Dietary Supplements, biology.protein, Amino Acids, Essential, Amino Acids, Branched-Chain, Food Science, Euphausiacea
Abstract

Background: adequate protein intake is essential to humans and, since the global demand for protein-containing foods is increasing, identifying new high-quality protein sources is needed. In this study, we investigated the acute postprandial bioavailability of amino acids (AAs) from a krill protein hydrolysate compared to a soy and a whey protein isolate. Methods: the study was a randomized, placebo-controlled crossover trial including ten healthy young males. On four non-consecutive days, volunteers consumed water or one of three protein-matched supplements: whey protein isolate, soy protein isolate or krill protein hydrolysate. Blood samples were collected prior to and until 180 min after consumption. Serum postprandial AA concentrations were determined using 1H NMR spectroscopy. Hunger and satiety were assessed using visual analogue scales (VAS). Results: whey and krill resulted in significantly higher AA concentrations compared to soy between 20–60 min and 20–40 min after consumption, respectively. Area under the curve (AUC) analyses revealed that whey resulted in the highest postprandial serum concentrations of essential AAs (EAAs) and branched chain AAs (BCAAs), followed by krill and soy, respectively. Conclusions: krill protein hydrolysate increases postprandial serum EAA and BCAA concentrations in a superior manner to soy protein isolate and thus might represent a promising future protein source in human nutrition.

Published
2021

5. MYC- and MIZ1-Dependent Vesicular Transport of Double-Strand RNA Controls Immune Evasion in Pancreatic Ductal Adenocarcinoma

Author

Lars Zender, Carsten P. Ade, Mathias T. Rosenfeldt, Emilia Vendelova, Ursula Eilers, Bastian Krenz, Elmar Wolf, Anneli Gebhardt-Wolf, Armin Wiegering, Peter Gallant, Abdallah Gaballa, Apoorva Baluapuri, Stefan Bauer, Florian Roehrig, Luana D’Artista, Georg Gasteiger, and Martin Eilers

Subjects
Cancer Research, Kruppel-Like Transcription Factors, Mice, Nude, Biology, Adenocarcinoma, Protein Serine-Threonine Kinases, Article, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Paracrine signalling, Mice, 0302 clinical medicine, Immune system, TANK-binding kinase 1, Mice, Inbred NOD, MHC class I, Animals, Humans, Autocrine signalling, 030304 developmental biology, Immune Evasion, RNA, Double-Stranded, Cell Nucleus, 0303 health sciences, Mice, Inbred BALB C, RNA, Biological Transport, Sequence Analysis, DNA, Introns, Cell biology, Mice, Inbred C57BL, Pancreatic Neoplasms, RNA silencing, HEK293 Cells, Oncology, 030220 oncology & carcinogenesis, Immune System, TLR3, biology.protein, Tumor Suppressor Protein p53, Gene Deletion, Carcinoma, Pancreatic Ductal
Abstract

Deregulated expression of the MYC oncoprotein enables tumor cells to evade immune surveillance, but the mechanisms underlying this surveillance are poorly understood. We show here that endogenous MYC protects pancreatic ductal adenocarcinoma (PDAC) driven by KRASG12D and TP53R172H from eradication by the immune system. Deletion of TANK-binding kinase 1 (TBK1) bypassed the requirement for high MYC expression. TBK1 was active due to the accumulation of double-stranded RNA (dsRNA), which was derived from inverted repetitive elements localized in introns of nuclear genes. Nuclear-derived dsRNA is packaged into extracellular vesicles and subsequently recognized by toll-like receptor 3 (TLR3) to activate TBK1 and downstream MHC class I expression in an autocrine or paracrine manner before being degraded in lysosomes. MYC suppressed loading of dsRNA onto TLR3 and its subsequent degradation via association with MIZ1. Collectively, these findings suggest that MYC and MIZ1 suppress a surveillance pathway that signals perturbances in mRNA processing to the immune system, which facilitates immune evasion in PDAC. Significance: This study identifies a TBK1-dependent pathway that links dsRNA metabolism to antitumor immunity and shows that suppression of TBK1 is a critical function of MYC in pancreatic ductal adenocarcinoma.

Published
2021

6. Loss of autophagy affects melanoma development in a manner dependent on PTEN status

Author

Sabine Roth, Owen J. Sansom, Mathias T. Rosenfeldt, Jim O'Prey, Kevin M. Ryan, Colin R Lindsay, and Colin Nixon

Subjects
Proto-Oncogene Proteins B-raf, Heterozygote, Mice, Transgenic, Autophagy-Related Protein 7, Gene Knockout Techniques, Mice, Text mining, Cell Line, Tumor, Genetics, Autophagy, Animals, PTEN, Medicine, Humans, Cancer models, Protein Kinase Inhibitors, Molecular Biology, Melanoma, Cellular Senescence, Cancer, Cell Proliferation, biology, Manchester Cancer Research Centre, business.industry, ResearchInstitutes_Networks_Beacons/mcrc, Comment, PTEN Phosphohydrolase, PTEN Phosphohydrolase/genetics, Cell Biology, medicine.disease, Gene Expression Regulation, Neoplastic, Disease Models, Animal, Oxidative Stress, Cell Transformation, Neoplastic, Mutation, biology.protein, Cancer research, business, Microtubule-Associated Proteins, Gene Deletion
Abstract

Macroautophagy (autophagy hereafter) may promote survival and growth of spontaneous tumors, including melanoma. We utilized a genetically engineered mouse model of melanoma driven by oncogenic BrafV600E and deficiency in the Pten tumor suppressor gene in melanocytes to test the functional consequences of loss of the essential autophagy gene autophagy-related-7, Atg7. Atg7 deficiency prevented melanoma development by BrafV600E and allelic Pten loss, indicating that autophagy is essential for melanomagenesis. Moreover, BrafV600E-mutant, Pten-null, Atg7-deficient melanomas displayed accumulation of autophagy substrates and growth defects, which extended animal survival. Atg7-deleted tumors showed increased oxidative stress and senescence, a known barrier to melanomagenesis. Treatment with the BRAF inhibitor dabrafenib decreased tumor growth and induced senescence that was more pronounced in tumors with Atg7 deficiency. Thus, Atg7 promotes melanoma by limiting oxidative stress and overcoming senescence, and autophagy inhibition may be of therapeutic value by augmenting the antitumor activity of BRAF inhibitors.The essential autophagy gene Atg7 promotes development of BrafV600E-mutant, Pten-null melanomas by overcoming senescence, and deleting Atg7 facilitated senescence induction and antitumor activity of BRAF inhibition. This suggests that combinatorial BRAFV600E and autophagy inhibition may improve therapeutic outcomes in patients whose tumors have BRAFV600E/K mutations, an approach currently being explored in clinical trials.

Published
2021

7. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1

Author

Klionsky, Daniel J, Abdel-Aziz, Amal Kamal, Abdelfatah, Sara, Abdellatif, Mahmoud, Abdoli, Asghar, Abel, Steffen, Abeliovich, Hagai, Abildgaard, Marie H, Abudu, Yakubu Princely, Acevedo-Arozena, Abraham, Adamopoulos, Iannis E, Adeli, Khosrow, Adolph, Timon E, Adornetto, Annagrazia, Aflaki, Elma, Agam, Galila, Agarwal, Anupam, Aggarwal, Bharat B, Agnello, Maria, Agostinis, Patrizia, Agrewala, Javed N, Agrotis, Alexander, Aguilar, Patricia V, Ahmad, S Tariq, Ahmed, Zubair M, Ahumada-Castro, Ulises, Aits, Sonja, Aizawa, Shu, Akkoc, Yunus, Akoumianaki, Tonia, Akpinar, Hafize Aysin, Al-Abd, Ahmed M, Al-Akra, Lina, Al-Gharaibeh, Abeer, Alaoui-Jamali, Moulay A, Alberti, Simon, Alcocer-Gómez, Elísabet, Alessandri, Cristiano, Ali, Muhammad, Alim Al-Bari, M Abdul, Aliwaini, Saeb, Alizadeh, Javad, Almacellas, Eugènia, Almasan, Alexandru, Alonso, Alicia, Alonso, Guillermo D, Altan-Bonnet, Nihal, Altieri, Dario C, Álvarez, Élida MC, Alves, Sara, Alves Da Costa, Cristine, Alzaharna, Mazen M, Amadio, Marialaura, Amantini, Consuelo, Amaral, Cristina, Ambrosio, Susanna, Amer, Amal O, Ammanathan, Veena, An, Zhenyi, Andersen, Stig U, Andrabi, Shaida A, Andrade-Silva, Magaiver, Andres, Allen M, Angelini, Sabrina, Ann, David, Anozie, Uche C, Ansari, Mohammad Y, Antas, Pedro, Antebi, Adam, Antón, Zuriñe, Anwar, Tahira, Apetoh, Lionel, Apostolova, Nadezda, Araki, Toshiyuki, Araki, Yasuhiro, Arasaki, Kohei, Araújo, Wagner L, Araya, Jun, Arden, Catherine, Arévalo, Maria-Angeles, Arguelles, Sandro, Arias, Esperanza, Arikkath, Jyothi, Arimoto, Hirokazu, Ariosa, Aileen R, Armstrong-James, Darius, Arnauné-Pelloquin, Laetitia, Aroca, Angeles, Arroyo, Daniela S, Arsov, Ivica, Artero, Rubén, Asaro, Dalia Maria Lucia, Aschner, Michael, Ashrafizadeh, Milad, Ashur-Fabian, Osnat, Atanasov, Atanas G, Au, Alicia K, Auberger, Patrick, Auner, Holger W, Aurelian, Laure, Autelli, Riccardo, Avagliano, Laura, Ávalos, Yenniffer, Aveic, Sanja, Aveleira, Célia Alexandra, Avin-Wittenberg, Tamar, Aydin, Yucel, Ayton, Scott, Ayyadevara, Srinivas, Azzopardi, Maria, Baba, Misuzu, Backer, Jonathan M, Backues, Steven K, Bae, Dong-Hun, Bae, Ok-Nam, Bae, Soo Han, Baehrecke, Eric H, Baek, Ahruem, Baek, Seung-Hoon, Baek, Sung Hee, Bagetta, Giacinto, Bagniewska-Zadworna, Agnieszka, Bai, Hua, Bai, Jie, Bai, Xiyuan, Bai, Yidong, Bairagi, Nandadulal, Baksi, Shounak, Balbi, Teresa, Baldari, Cosima T, Balduini, Walter, Ballabio, Andrea, Ballester, Maria, Balazadeh, Salma, Balzan, Rena, Bandopadhyay, Rina, Banerjee, Sreeparna, Banerjee, Sulagna, Bánréti, Ágnes, Bao, Yan, Baptista, Mauricio S, Baracca, Alessandra, Barbati, Cristiana, Bargiela, Ariadna, Barilà, Daniela, Barlow, Peter G, Barmada, Sami J, Barreiro, Esther, Barreto, George E, Bartek, Jiri, Bartel, Bonnie, Bartolome, Alberto, Barve, Gaurav R, Basagoudanavar, Suresh H, Bassham, Diane C, Bast, Robert C, Basu, Alakananda, Batoko, Henri, Batten, Isabella, Baulieu, Etienne E, Baumgarner, Bradley L, Bayry, Jagadeesh, Beale, Rupert, Beau, Isabelle, Beaumatin, Florian, Bechara, Luiz RG, Beck, George R, Beers, Michael F, Begun, Jakob, Behrends, Christian, Behrens, Georg MN, Bei, Roberto, Bejarano, Eloy, Bel, Shai, Behl, Christian, Belaid, Amine, Belgareh-Touzé, Naïma, Bellarosa, Cristina, Belleudi, Francesca, Belló Pérez, Melissa, Bello-Morales, Raquel, Beltran, Jackeline Soares De Oliveira, Beltran, Sebastián, Benbrook, Doris Mangiaracina, Bendorius, Mykolas, Benitez, Bruno A, Benito-Cuesta, Irene, Bensalem, Julien, Berchtold, Martin W, Berezowska, Sabina, Bergamaschi, Daniele, Bergami, Matteo, Bergmann, Andreas, Berliocchi, Laura, Berlioz-Torrent, Clarisse, Bernard, Amélie, Berthoux, Lionel, Besirli, Cagri G, Besteiro, Sebastien, Betin, Virginie M, Beyaert, Rudi, Bezbradica, Jelena S, Bhaskar, Kiran, Bhatia-Kissova, Ingrid, Bhattacharya, Resham, Bhattacharya, Sujoy, Bhattacharyya, Shalmoli, Bhuiyan, Md Shenuarin, Bhutia, Sujit Kumar, Bi, Lanrong, Bi, Xiaolin, Biden, Trevor J, Bijian, Krikor, Billes, Viktor A, Binart, Nadine, Bincoletto, Claudia, Birgisdottir, Asa B, Bjorkoy, Geir, Blanco, Gonzalo, Blas-Garcia, Ana, Blasiak, Janusz, Blomgran, Robert, Blomgren, Klas, Blum, Janice S, Boada-Romero, Emilio, Boban, Mirta, Boesze-Battaglia, Kathleen, Boeuf, Philippe, Boland, Barry, Bomont, Pascale, Bonaldo, Paolo, Bonam, Srinivasa Reddy, Bonfili, Laura, Bonifacino, Juan S, Boone, Brian A, Bootman, Martin D, Bordi, Matteo, Borner, Christoph, Bornhauser, Beat C, Borthakur, Gautam, Bosch, Jürgen, Bose, Santanu, Botana, Luis M, Botas, Juan, Boulanger, Chantal M, Boulton, Michael E, Bourdenx, Mathieu, Bourgeois, Benjamin, Bourke, Nollaig M, Bousquet, Guilhem, Boya, Patricia, Bozhkov, Peter V, Bozi, Luiz HM, Bozkurt, Tolga O, Brackney, Doug E, Brandts, Christian H, Braun, Ralf J, Braus, Gerhard H, Bravo-Sagua, Roberto, Bravo-San Pedro, José M, Brest, Patrick, Bringer, Marie-Agnès, Briones-Herrera, Alfredo, Broaddus, V Courtney, Brodersen, Peter, Brodsky, Jeffrey L, Brody, Steven L, Bronson, Paola G, Bronstein, Jeff M, Brown, Carolyn N, Brown, Rhoderick E, Brum, Patricia C, Brumell, John H, Brunetti-Pierri, Nicola, Bruno, Daniele, Bryson-Richardson, Robert J, Bucci, Cecilia, Buchrieser, Carmen, Bueno, Marta, Buitrago-Molina, Laura Elisa, Buraschi, Simone, Buch, Shilpa, Buchan, J Ross, Buckingham, Erin M, Budak, Hikmet, Budini, Mauricio, Bultynck, Geert, Burada, Florin, Burgoyne, Joseph R, Burón, M Isabel, Bustos, Victor, Büttner, Sabrina, Butturini, Elena, Byrd, Aaron, Cabas, Isabel, Cabrera-Benitez, Sandra, Cadwell, Ken, Cai, Jingjing, Cai, Lu, Cai, Qian, Cairó, Montserrat, Calbet, Jose A, Caldwell, Guy A, Caldwell, Kim A, Call, Jarrod A, Calvani, Riccardo, Calvo, Ana C, Calvo-Rubio Barrera, Miguel, Camara, Niels Os, Camonis, Jacques H, Camougrand, Nadine, Campanella, Michelangelo, Campbell, Edward M, Campbell-Valois, François-Xavier, Campello, Silvia, Campesi, Ilaria, Campos, Juliane C, Camuzard, Olivier, Cancino, Jorge, Candido De Almeida, Danilo, Canesi, Laura, Caniggia, Isabella, Canonico, Barbara, Cantí, Carles, Cao, Bin, Caraglia, Michele, Caramés, Beatriz, Carchman, Evie H, Cardenal-Muñoz, Elena, Cardenas, Cesar, Cardenas, Luis, Cardoso, Sandra M, Carew, Jennifer S, Carle, Georges F, Carleton, Gillian, Carloni, Silvia, Carmona-Gutierrez, Didac, Carneiro, Leticia A, Carnevali, Oliana, Carosi, Julian M, Carra, Serena, Carrier, Alice, Carrier, Lucie, Carroll, Bernadette, Carter, A Brent, Carvalho, Andreia Neves, Casanova, Magali, Casas, Caty, Casas, Josefina, Cassioli, Chiara, Castillo, Eliseo F, Castillo, Karen, Castillo-Lluva, Sonia, Castoldi, Francesca, Castori, Marco, Castro, Ariel F, Castro-Caldas, Margarida, Castro-Hernandez, Javier, Castro-Obregon, Susana, Catz, Sergio D, Cavadas, Claudia, Cavaliere, Federica, Cavallini, Gabriella, Cavinato, Maria, Cayuela, Maria L, Cebollada Rica, Paula, Cecarini, Valentina, Cecconi, Francesco, Cechowska-Pasko, Marzanna, Cenci, Simone, Ceperuelo-Mallafré, Victòria, Cerqueira, João J, Cerutti, Janete M, Cervia, Davide, Cetintas, Vildan Bozok, Cetrullo, Silvia, Chae, Han-Jung, Chagin, Andrei S, Chai, Chee-Yin, Chakrabarti, Gopal, Chakrabarti, Oishee, Chakraborty, Tapas, Chakraborty, Trinad, Chami, Mounia, Chamilos, Georgios, Chan, David W, Chan, Edmond YW, Chan, Edward D, Chan, HY Edwin, Chan, Helen H, Chan, Hung, Chan, Matthew TV, Chan, Yau Sang, Chandra, Partha K, Chang, Chih-Peng, Chang, Chunmei, Chang, Hao-Chun, Chang, Kai, Chao, Jie, Chapman, Tracey, Charlet-Berguerand, Nicolas, Chatterjee, Samrat, Chaube, Shail K, Chaudhary, Anu, Chauhan, Santosh, Chaum, Edward, Checler, Frédéric, Cheetham, Michael E, Chen, Chang-Shi, Chen, Guang-Chao, Chen, Jian-Fu, Chen, Liam L, Chen, Leilei, Chen, Lin, Chen, Mingliang, Chen, Mu-Kuan, Chen, Ning, Chen, Quan, Chen, Ruey-Hwa, Chen, Shi, Chen, Wei, Chen, Weiqiang, Chen, Xin-Ming, Chen, Xiong-Wen, Chen, Xu, Chen, Yan, Chen, Ye-Guang, Chen, Yingyu, Chen, Yongqiang, Chen, Yu-Jen, Chen, Yue-Qin, Chen, Zhefan Stephen, Chen, Zhi, Chen, Zhi-Hua, Chen, Zhijian J, Chen, Zhixiang, Cheng, Hanhua, Cheng, Jun, Cheng, Shi-Yuan, Cheng, Wei, Cheng, Xiaodong, Cheng, Xiu-Tang, Cheng, Yiyun, Cheng, Zhiyong, Chen, Zhong, Cheong, Heesun, Cheong, Jit Kong, Chernyak, Boris V, Cherry, Sara, Cheung, Chi Fai Randy, Cheung, Chun Hei Antonio, Cheung, King-Ho, Chevet, Eric, Chi, Richard J, Chiang, Alan Kwok Shing, Chiaradonna, Ferdinando, Chiarelli, Roberto, Chiariello, Mario, Chica, Nathalia, Chiocca, Susanna, Chiong, Mario, Chiou, Shih-Hwa, Chiramel, Abhilash I, Chiurchiù, Valerio, Cho, Dong-Hyung, Choe, Seong-Kyu, Choi, Augustine MK, Choi, Mary E, Choudhury, Kamalika Roy, Chow, Norman S, Chu, Charleen T, Chua, Jason P, Chua, John Jia En, Chung, Hyewon, Chung, Kin Pan, Chung, Seockhoon, Chung, So-Hyang, Chung, Yuen-Li, Cianfanelli, Valentina, Ciechomska, Iwona A, Cifuentes, Mariana, Cinque, Laura, Cirak, Sebahattin, Cirone, Mara, Clague, Michael J, Clarke, Robert, Clementi, Emilio, Coccia, Eliana M, Codogno, Patrice, Cohen, Ehud, Cohen, Mickael M, Colasanti, Tania, Colasuonno, Fiorella, Colbert, Robert A, Colell, Anna, Čolić, Miodrag, Coll, Nuria S, Collins, Mark O, Colombo, María I, Colón-Ramos, Daniel A, Combaret, Lydie, Comincini, Sergio, Cominetti, Márcia R, Consiglio, Antonella, Conte, Andrea, Conti, Fabrizio, Contu, Viorica Raluca, Cookson, Mark R, Coombs, Kevin M, Coppens, Isabelle, Corasaniti, Maria Tiziana, Corkery, Dale P, Cordes, Nils, Cortese, Katia, Costa, Maria Do Carmo, Costantino, Sarah, Costelli, Paola, Coto-Montes, Ana, Crack, Peter J, Crespo, Jose L, Criollo, Alfredo, Crippa, Valeria, Cristofani, Riccardo, Csizmadia, Tamas, Cuadrado, Antonio, Cui, Bing, Cui, Jun, Cui, Yixian, Cui, Yong, Culetto, Emmanuel, Cumino, Andrea C, Cybulsky, Andrey V, Czaja, Mark J, Czuczwar, Stanislaw J, D'Adamo, Stefania, D'Amelio, Marcello, D'Arcangelo, Daniela, D'Lugos, Andrew C, D'Orazi, Gabriella, Da Silva, James A, Dafsari, Hormos Salimi, Dagda, Ruben K, Dagdas, Yasin, Daglia, Maria, Dai, Xiaoxia, Dai, Yun, Dai, Yuyuan, Dal Col, Jessica, Dalhaimer, Paul, Dalla Valle, Luisa, Dallenga, Tobias, Dalmasso, Guillaume, Damme, Markus, Dando, Ilaria, Dantuma, Nico P, Darling, April L, Das, Hiranmoy, Dasarathy, Srinivasan, Dasari, Santosh K, Dash, Srikanta, Daumke, Oliver, Dauphinee, Adrian N, Davies, Jeffrey S, Dávila, Valeria A, Davis, Roger J, Davis, Tanja, Dayalan Naidu, Sharadha, De Amicis, Francesca, De Bosscher, Karolien, De Felice, Francesca, De Franceschi, Lucia, De Leonibus, Chiara, De Mattos Barbosa, Mayara G, De Meyer, Guido RY, De Milito, Angelo, De Nunzio, Cosimo, De Palma, Clara, De Santi, Mauro, De Virgilio, Claudio, De Zio, Daniela, Debnath, Jayanta, DeBosch, Brian J, Decuypere, Jean-Paul, Deehan, Mark A, Deflorian, Gianluca, DeGregori, James, Dehay, Benjamin, Del Rio, Gabriel, Delaney, Joe R, Delbridge, Lea MD, Delorme-Axford, Elizabeth, Delpino, M Victoria, Demarchi, Francesca, Dembitz, Vilma, Demers, Nicholas D, Deng, Hongbin, Deng, Zhiqiang, Dengjel, Joern, Dent, Paul, Denton, Donna, DePamphilis, Melvin L, Der, Channing J, 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Vega-Naredo, Ignacio, Vega-Rubin-De-Celis, Silvia, Velasco, Guillermo, Velázquez, Ariadna P, Vellai, Tibor, Vellenga, Edo, Velotti, Francesca, Verdier, Mireille, Verginis, Panayotis, Vergne, Isabelle, Verkade, Paul, Verma, Manish, Verstreken, Patrik, Vervliet, Tim, Vervoorts, Jörg, Vessoni, Alexandre T, Victor, Victor M, Vidal, Michel, Vidoni, Chiara, Vieira, Otilia V, Vierstra, Richard D, Viganó, Sonia, Vihinen, Helena, Vijayan, Vinoy, Vila, Miquel, Vilar, Marçal, Villalba, José M, Villalobo, Antonio, Villarejo-Zori, Beatriz, Villarroya, Francesc, Villarroya, Joan, Vincent, Olivier, Vindis, Cecile, Viret, Christophe, Viscomi, Maria Teresa, Visnjic, Dora, Vitale, Ilio, Vocadlo, David J, Voitsekhovskaja, Olga V, Volonté, Cinzia, Volta, Mattia, Vomero, Marta, Von Haefen, Clarissa, Vooijs, Marc A, Voos, Wolfgang, Vucicevic, Ljubica, Wade-Martins, Richard, Waguri, Satoshi, Waite, Kenrick A, Wakatsuki, Shuji, Walker, David W, Walker, Mark J, Walker, Simon A, Walter, Jochen, Wandosell, Francisco G, Wang, Bo, Wang, Chao-Yung, Wang, Chen, Wang, Chenran, Wang, Chenwei, Wang, Cun-Yu, Wang, Dong, Wang, Fangyang, Wang, Feng, Wang, Fengming, Wang, Guansong, Wang, Han, Wang, Hao, Wang, Hexiang, Wang, Hong-Gang, Wang, Jianrong, Wang, Jigang, Wang, Jiou, Wang, Jundong, Wang, Kui, Wang, Lianrong, Wang, Liming, Wang, Maggie Haitian, Wang, Meiqing, Wang, Nanbu, Wang, Pengwei, Wang, Peipei, Wang, Ping, Wang, Qing Jun, Wang, Qing, Wang, Qing Kenneth, Wang, Qiong A, Wang, Wen-Tao, Wang, Wuyang, Wang, Xinnan, Wang, Xuejun, Wang, Yan, Wang, Yanchang, Wang, Yanzhuang, Wang, Yen-Yun, Wang, Yihua, Wang, Yipeng, Wang, Yu, Wang, Yuqi, Wang, Zhe, Wang, Zhenyu, Wang, Zhouguang, Warnes, Gary, Warnsmann, Verena, Watada, Hirotaka, Watanabe, Eizo, Watchon, Maxinne, Wawrzyńska, Anna, Weaver, Timothy E, Wegrzyn, Grzegorz, Wehman, Ann M, Wei, Huafeng, Wei, Lei, Wei, Taotao, Wei, Yongjie, Weiergräber, Oliver H, Weihl, Conrad C, Weindl, Günther, Weiskirchen, Ralf, Wells, Alan, Wen, Runxia H, Wen, Xin, Werner, Antonia, Weykopf, Beatrice, Wheatley, Sally P, Whitton, J Lindsay, Whitworth, Alexander J, Wiktorska, Katarzyna, Wildenberg, Manon E, Wileman, Tom, Wilkinson, Simon, Willbold, Dieter, Williams, Brett, Williams, Robin SB, Williams, Roger L, Williamson, Peter R, Wilson, Richard A, Winner, Beate, Winsor, Nathaniel J, Witkin, Steven S, Wodrich, Harald, Woehlbier, Ute, Wollert, Thomas, Wong, Esther, Wong, Jack Ho, Wong, Richard W, Wong, Vincent Kam Wai, Wong, W Wei-Lynn, Wu, An-Guo, Wu, Chengbiao, Wu, Jian, Wu, Junfang, Wu, Kenneth K, Wu, Min, Wu, Shan-Ying, Wu, Shengzhou, Wu, Shu-Yan, Wu, Shufang, Wu, William KK, Wu, Xiaohong, Wu, Xiaoqing, Wu, Yao-Wen, Wu, Yihua, Xavier, Ramnik J, Xia, Hongguang, Xia, Lixin, Xia, Zhengyuan, Xiang, Ge, Xiang, Jin, Xiang, Mingliang, Xiang, Wei, Xiao, Bin, Xiao, Guozhi, Xiao, Hengyi, Xiao, Hong-Tao, Xiao, Jian, Xiao, Lan, Xiao, Shi, Xiao, Yin, Xie, Baoming, Xie, Chuan-Ming, Xie, Min, Xie, Yuxiang, Xie, Zhiping, Xie, Zhonglin, Xilouri, Maria, Xu, Congfeng, Xu, En, Xu, Haoxing, Xu, Jing, Xu, JinRong, Xu, Liang, Xu, Wen Wen, Xu, Xiulong, Xue, Yu, Yakhine-Diop, Sokhna MS, Yamaguchi, Masamitsu, Yamaguchi, Osamu, Yamamoto, Ai, Yamashina, Shunhei, Yan, Shengmin, Yan, Shian-Jang, Yan, Zhen, Yanagi, Yasuo, Yang, Chuanbin, Yang, Dun-Sheng, Yang, Huan, Yang, Huang-Tian, Yang, Hui, Yang, Jin-Ming, Yang, Jing, Yang, Jingyu, Yang, Ling, Yang, Liu, Yang, Ming, Yang, Pei-Ming, Yang, Qian, Yang, Seungwon, Yang, Shu, Yang, Shun-Fa, Yang, Wannian, Yang, Wei Yuan, Yang, Xiaoyong, Yang, Xuesong, Yang, Yi, Yang, Ying, Yao, Honghong, Yao, Shenggen, Yao, Xiaoqiang, Yao, Yong-Gang, Yao, Yong-Ming, Yasui, Takahiro, Yazdankhah, Meysam, Yen, Paul M, Yi, Cong, Yin, Xiao-Ming, Yin, Yanhai, Yin, Zhangyuan, Yin, Ziyi, Ying, Meidan, Ying, Zheng, Yip, Calvin K, Yiu, Stephanie Pei Tung, Yoo, Young H, Yoshida, Kiyotsugu, Yoshii, Saori R, Yoshimori, Tamotsu, Yousefi, Bahman, Yu, Boxuan, Yu, Haiyang, Yu, Jun, Yu, Li, Yu, Ming-Lung, Yu, Seong-Woon, Yu, Victor C, Yu, W Haung, Yu, Zhengping, Yu, Zhou, Yuan, Junying, Yuan, Ling-Qing, Yuan, Shilin, Yuan, Shyng-Shiou F, Yuan, Yanggang, Yuan, Zengqiang, Yue, Jianbo, Yue, Zhenyu, Yun, Jeanho, Yung, Raymond L, Zacks, David N, Zaffagnini, Gabriele, Zambelli, Vanessa O, Zanella, Isabella, Zang, Qun S, Zanivan, Sara, Zappavigna, Silvia, Zaragoza, Pilar, Zarbalis, Konstantinos S, Zarebkohan, Amir, Zarrouk, Amira, Zeitlin, Scott O, Zeng, Jialiu, Zeng, Ju-Deng, Žerovnik, Eva, Zhan, Lixuan, Zhang, Bin, Zhang, Donna D, Zhang, Hanlin, Zhang, Hong, Zhang, Honghe, Zhang, Huafeng, Zhang, Huaye, Zhang, Hui, Zhang, Hui-Ling, Zhang, Jianbin, Zhang, Jianhua, Zhang, Jing-Pu, Zhang, Kalin YB, Zhang, Leshuai W, Zhang, Lin, Zhang, Lisheng, Zhang, Lu, Zhang, Luoying, Zhang, Menghuan, Zhang, Peng, Zhang, Sheng, Zhang, Wei, Zhang, Xiangnan, Zhang, Xiao-Wei, Zhang, Xiaolei, Zhang, Xiaoyan, Zhang, Xin, Zhang, Xinxin, Zhang, Xu Dong, Zhang, Yang, Zhang, Yanjin, Zhang, Yi, Zhang, Ying-Dong, Zhang, Yingmei, Zhang, Yuan-Yuan, Zhang, Yuchen, Zhang, Zhe, Zhang, Zhengguang, Zhang, Zhibing, Zhang, Zhihai, Zhang, Zhiyong, Zhang, Zili, Zhao, Haobin, Zhao, Lei, Zhao, Shuang, Zhao, Tongbiao, Zhao, Xiao-Fan, Zhao, Ying, Zhao, Yongchao, Zhao, Yongliang, Zhao, Yuting, Zheng, Guoping, Zheng, Kai, Zheng, Ling, Zheng, Shizhong, Zheng, Xi-Long, Zheng, Yi, Zheng, Zu-Guo, Zhivotovsky, Boris, Zhong, Qing, Zhou, Ao, Zhou, Ben, Zhou, Cefan, Zhou, Gang, Zhou, Hao, Zhou, Hong, Zhou, Hongbo, Zhou, Jie, Zhou, Jing, Zhou, Jiyong, Zhou, Kailiang, Zhou, Rongjia, Zhou, Xu-Jie, Zhou, Yanshuang, Zhou, Yinghong, Zhou, Yubin, Zhou, Zheng-Yu, Zhou, Zhou, Zhu, Binglin, Zhu, Changlian, Zhu, Guo-Qing, Zhu, Haining, Zhu, Hongxin, Zhu, Hua, Zhu, Wei-Guo, Zhu, Yanping, Zhu, Yushan, Zhuang, Haixia, Zhuang, Xiaohong, Zientara-Rytter, Katarzyna, Zimmermann, Christine M, Ziviani, Elena, Zoladek, Teresa, Zong, Wei-Xing, Zorov, Dmitry B, Zorzano, Antonio, Zou, Weiping, Zou, Zhen, Zou, Zhengzhi, Zuryn, Steven, Zwerschke, Werner, Brand-Saberi, Beate, Dong, X Charlie, Kenchappa, Chandra Shekar, Li, Zuguo, Lin, Yong, Oshima, Shigeru, Rong, Yueguang, Sluimer, Judith C, Stallings, Christina L, and Tong, Chun-Kit

Subjects
phagophore, vacuole, Autophagosome, neurodegeneration, Autophagosomes, Autophagy-Related Proteins, flux, macroautophagy, stress, LC3, lysosome, Autophagy, cancer, Animals, Humans, Biological Assay, Lysosomes, Biomarkers
Abstract

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Published
2021
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8. LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer

Author

Thales Kronenberger, Antti Poso, Liudmyla Taranets, Nikita Popov, Elias Einig, Daniel Dauch, Jule Harbig, Ramona Rudalska, Michael Forster, Sabrina Klotz, Florian Heinzmann, Werner Schmitz, Wei Cui, Lars Zender, Almut Schulze, Agata Dylawerska, Michael Bitzer, Luana D’Artista, Mathias T. Rosenfeldt, Nisar P. Malek, Marteinn Thor Snaebjornsson, Tae-Won Kang, Bernd J. Pichler, Martina Hinterleitner, Stefan Zwirner, and Stefan Laufer

Subjects
Sorafenib, Cancer Research, Carcinoma, Hepatocellular, business.industry, Fatty Acids, Liver Neoplasms, Cancer, medicine.disease, digestive system diseases, Metabolic pathway, Disease Models, Animal, Mice, Oncology, Lipotoxicity, Non-alcoholic Fatty Liver Disease, Hepatocellular carcinoma, medicine, Cancer research, Animals, Humans, Treatment resistance, Liver cancer, Liver X receptor, business, medicine.drug
Abstract

The success of molecular therapies targeting specific metabolic pathways in cancer is often limited by the plasticity and adaptability of metabolic networks. Here we show that pharmacologically induced lipotoxicity represents a promising therapeutic strategy for the treatment of hepatocellular carcinoma (HCC). LXRα-induced liponeogenesis and Raf-1 inhibition are synthetic lethal in HCC owing to a toxic accumulation of saturated fatty acids. Raf-1 was found to bind and activate SCD1, and conformation-changing DFG-out Raf inhibitors could disrupt this interaction, thereby blocking fatty acid desaturation and inducing lethal lipotoxicity. Studies in genetically engineered and nonalcoholic steatohepatitis-induced HCC mouse models and xenograft models of human HCC revealed that therapies comprising LXR agonists and Raf inhibitors were well tolerated and capable of overcoming therapy resistance in HCC. Conceptually, our study suggests pharmacologically induced lipotoxicity as a new mode for metabolic targeting of liver cancer. Zender, Dauch and colleagues demonstrate that pharmacologically induced lipotoxicity by activating LXRα and Raf-1 inhibition provides a metabolic therapeutic strategy for hepatocellular carcinoma.

Published
2020

9. Autophagy and cancer – insights from mouse models

Author

Mathias T. Rosenfeldt and Laura Mainz

Subjects
0301 basic medicine, Antineoplastic Agents, Bioinformatics, Biochemistry, Mice, 03 medical and health sciences, Species Specificity, Autophagy, Animals, Humans, Medicine, Tumor growth, Cancer biology, Molecular Biology, Pathological, Mice, Knockout, Clinical Trials as Topic, Cellular metabolism, Organisms, Genetically Modified, business.industry, Cancer, Neoplasms, Experimental, Cell Biology, medicine.disease, Clinical trial, 030104 developmental biology, Research Design, Drug Screening Assays, Antitumor, business
Abstract

(Macro-)autophagy is an evolutionary conserved 'self-digestion program' that serves to maintain cellular metabolism and is implicated in many pathological processes such as cancer. In recent years, an increasing number of studies in murine cancer models have provided a plethora of sometimes conflicting results about the role of autophagy in cancer biology. This review summarizes these studies and raises awareness that there are situations in which autophagy blockage might indeed reduce tumor growth, but that sometimes the exact opposite is the case. It is therefore vital to mimic patient conditions in preclinical mouse experiments as thoroughly as possible before commencing clinical trials.

Published
2017

10. A spatiotemporal comparison of length-at-age in the coral reef fish Acanthurus nigrofuscus between marine reserves and fished reefs

Author

Louis M. Penrod, Mathias T. Cramer, Ralph G. Turingan, Robert Y. Fidler, and Jessica Carroll

Subjects
0106 biological sciences, Life Cycles, Aging, Aquatic Organisms, Physiology, Philippines, Marine and Aquatic Sciences, Aquaculture, Otolith, 01 natural sciences, Geographical Locations, Larvae, Medicine and Health Sciences, Body Size, Marine Fish, Multidisciplinary, geography.geographical_feature_category, Coral Reefs, Marine reserve, Age Factors, Eukaryota, Agriculture, Age cohorts, Coral reef, Phenotype, medicine.anatomical_structure, Physiological Parameters, Vertebrates, Inner Ear, Medicine, %22">Fish , Anatomy, Research Article, Conservation of Natural Resources, Acanthurus nigrofuscus, Asia, Fish Biology, Science, Fisheries, Marine Biology, Target population, Biology, 010603 evolutionary biology, medicine, Animals, Reef, Analysis of Variance, geography, 010604 marine biology & hydrobiology, Organisms, Biology and Life Sciences, biology.organism_classification, Fishery, Fish, Ears, Perches, People and Places, Earth Sciences, Reefs, Zoology, Head, Developmental Biology
Abstract

Quantitative assessments of the capacity of marine reserves to restore historical fish body-size distributions require extensive repeated sampling to map the phenotypic responses of target populations to protection. However, the "no take" status of marine reserves oftentimes precludes repeated sampling within their borders and, as a result, our current understanding of the capacity of marine reserves to restore historical body-size distributions remains almost entirely reliant on independent, static visual surveys. To overcome this challenge, we promote the application of a traditional fisheries tool known as a "back-calculation", which allows for the estimation of fish body lengths from otolith annuli distances. This practical application was pursued in this study, using data collected in five marine reserves and adjacent fished reefs in the Philippines, to investigate spatiotemporal disparities in length-at-age of the brown surgeonfish, Acanthurus nigrofuscus. The spatial component of our analyses revealed that 1) A. nigrofuscus were phenotypically similar between marine reserves and fished reefs during their early life history; 2) marine reserve and fished reef populations diverged into significantly different length-at-age morphs between ages three and six, in which protected fish were predominantly larger than conspecifics in fished reefs; and 3) A. nigrofuscus returned to a state of general phenotypic similarity during later life. The temporal component of our analyses revealed that younger generations of A. nigrofuscus exhibited significant, positive year effects that were maintained until age eight, indicating that, within the significant age cohorts, younger generations were significantly larger than older generations.

Published
2020

11. Effects of Insect Protein Supplementation during Resistance Training on Changes in Muscle Mass and Strength in Young Men

Author

Mette Hansen, Lars-Henrik L Heckmann, Malte S Joergensen, and Mathias T Vangsoe

Subjects
0301 basic medicine, Male, buffalo larvae, Denmark, Muscle Development, Bench press, Muscle hypertrophy, 0302 clinical medicine, Absorptiometry, Photon, Larva/chemistry, Medicine, Single-Blind Method, Tenebrio, Nutrition and Dietetics, nutrition, Larva, Diet, High-Protein, Insect Proteins, Dietary Proteins, hypertrophy, lcsh:Nutrition. Foods and food supply, insect, resistance training, Adult, Dietary Carbohydrates/therapeutic use, Dietary supplement, lcsh:TX341-641, Muscle Strength Dynamometer, Muscle mass, Article, 03 medical and health sciences, Young Adult, Animal science, One-repetition maximum, Dietary Carbohydrates, Animals, Humans, Muscle Strength, Insect Proteins/therapeutic use, 030109 nutrition & dietetics, business.industry, Resistance training, Reproducibility of Results, Resistance Training, 030229 sport sciences, Protein supplementation, Confidence interval, Sports Nutritional Physiological Phenomena, Dietary Supplements, Dietary Proteins/therapeutic use, business, Tenebrio/chemistry, Food Science
Abstract

During prolonged resistance training, protein supplementation is known to promote morphological changes; however, no previous training studies have tested the effect of insect protein isolate in a human trial. The aim of this study was to investigate the potential effect of insect protein as a dietary supplement to increase muscle hypertrophy and strength gains during prolonged resistance training in young men. Eighteen healthy young men performed resistance training four day/week for eight weeks. Subjects were block randomized into two groups consuming either an insect protein isolate or isocaloric carbohydrate supplementation within 1 h after training and pre-sleep on training days. Strength and body composition were measured before and after intervention to detect adaptions to the resistance training. Three-day weighed dietary records were completed before and during intervention. Fat- and bone- free mass (FBFM) improved significantly in both groups (Mean (95% confidence interval (CI))), control group (Con): (2.5 kg (1.5, 3.5) p < 0.01), protein group (Pro): (2.7 kg (1.6, 3.8) p < 0.01) from pre- to post-. Leg and bench press one repetition maximum (1 RM) improved by Con: (42.0 kg (32.0, 52.0) p < 0.01) and (13.8 kg (10.3, 17.2) p < 0.01), Pro: (36.6 kg (27.3, 45.8) p < 0.01) and (8.1 kg (4.5, 11.8) p < 0.01), respectively. No significant differences in body composition and muscle strength improvements were found between groups. In young healthy men, insect protein supplementation did not improve adaptations to eight weeks of resistance training in comparison to carbohydrate supplementation. A high habitual protein intake in both Con and Pro may partly explain our observation of no superior effect of insect protein supplementation.

Published
2018

12. Loss of autophagy causes a synthetic lethal deficiency in DNA repair

Author

Jim O'Prey, Daniel R. Croft, Naihan Xu, Mathias T. Rosenfeldt, Kevin M. Ryan, Yaou Zhang, Margaret O'Prey, Emma Y. Liu, Laurence Y. Lao, David A. F. Gillespie, Jaclyn S. Long, Alice D. Baudot, Sanket Joshi, Florian Beaumatin, and Michaela Mrschtik

Subjects
Programmed cell death, Multidisciplinary, Base Sequence, DNA Repair, DNA repair, DNA damage, Autophagy, Synthetic lethality, Biological Sciences, Biology, Real-Time Polymerase Chain Reaction, Molecular biology, Cell biology, Non-homologous end joining, Mice, Animals, Genes, Lethal, CHEK1, Homologous Recombination, Homologous recombination, Cells, Cultured, DNA Primers
Abstract

(Macro)autophagy delivers cellular constituents to lysosomes for degradation. Although a cytoplasmic process, autophagy-deficient cells accumulate genomic damage, but an explanation for this effect is currently unclear. We report here that inhibition of autophagy causes elevated proteasomal activity leading to enhanced degradation of checkpoint kinase 1 (Chk1), a pivotal factor for the error-free DNA repair process, homologous recombination (HR). We show that loss of autophagy critically impairs HR and that autophagy-deficient cells accrue micronuclei and sub-G1 DNA, indicators of diminished genomic integrity. Moreover, due to impaired HR, autophagy-deficient cells are hyperdependent on nonhomologous end joining (NHEJ) for repair of DNA double-strand breaks. Consequently, inhibition of NHEJ following DNA damage in the absence of autophagy results in persistence of genomic lesions and rapid cell death. Because autophagy deficiency occurs in several diseases, these findings constitute an important link between autophagy and DNA repair and highlight a synthetic lethal strategy to kill autophagy-deficient cells.

Published
2015

13. PTEN deficiency permits the formation of pancreatic cancer in the absence of autophagy

Author

Mathias T. Rosenfeldt, Jim O'Prey, Jennifer P. Morton, Kevin M. Ryan, Colin Nixon, Owen J. Sansom, and Lucia Flossbach

Subjects
0301 basic medicine, Programmed cell death, Biology, Autophagy-Related Protein 7, 03 medical and health sciences, Mice, Pancreatic cancer, Cell Line, Tumor, Correspondence, medicine, Autophagy, PTEN, Animals, Humans, Molecular Biology, Cell growth, Neurodegeneration, PTEN Phosphohydrolase, Cancer, Cell Biology, medicine.disease, Pancreatic Neoplasms, 030104 developmental biology, Apoptosis, biology.protein, Cancer research, Tumor Suppressor Protein p53
Abstract

No abstract available.

Published
2017

14. p53 status determines the role of autophagy in pancreatic tumour development

Author

Peter D. Adams, Kurt I. Anderson, Liang Zheng, Kevin M. Ryan, Amy Au, Agata Mrowinska, Mathias T. Rosenfeldt, Gillian M. Mackay, Colin Nixon, Taranjit Singh Rai, Jim O'Prey, Jennifer P. Morton, Owen J. Sansom, Eyal Gottlieb, and Rachel A. Ridgway

Subjects
Mice, 129 Strain, ATG5, Pancreatic Intraepithelial Neoplasia, Cellular homeostasis, Oncogene Protein p21(ras), Biology, medicine.disease_cause, Autophagy-Related Protein 7, Autophagy-Related Protein 5, law.invention, Pentose Phosphate Pathway, Mice, law, Cell Line, Tumor, Autophagy, medicine, Animals, Humans, Metabolomics, Alleles, Multidisciplinary, Cancer, Genes, p53, medicine.disease, Survival Analysis, Cell biology, Mice, Inbred C57BL, Pancreatic Neoplasms, Disease Models, Animal, Glucose, Suppressor, KRAS, Tumor Suppressor Protein p53, Glycolysis, Microtubule-Associated Proteins, Precancerous Conditions, Carcinoma, Pancreatic Ductal, Hydroxychloroquine
Abstract

Macroautophagy (hereafter referred to as autophagy) is a process in which organelles termed autophagosomes deliver cytoplasmic constituents to lysosomes for degradation. Autophagy has a major role in cellular homeostasis and has been implicated in various forms of human disease. The role of autophagy in cancer seems to be complex, with reports indicating both pro-tumorigenic and tumour-suppressive roles. Here we show, in a humanized genetically-modified mouse model of pancreatic ductal adenocarcinoma (PDAC), that autophagy's role in tumour development is intrinsically connected to the status of the tumour suppressor p53. Mice with pancreases containing an activated oncogenic allele of Kras (also called Ki-Ras)--the most common mutational event in PDAC--develop a small number of pre-cancerous lesions that stochastically develop into PDAC over time. However, mice also lacking the essential autophagy genes Atg5 or Atg7 accumulate low-grade, pre-malignant pancreatic intraepithelial neoplasia lesions, but progression to high-grade pancreatic intraepithelial neoplasias and PDAC is blocked. In marked contrast, in mice containing oncogenic Kras and lacking p53, loss of autophagy no longer blocks tumour progression, but actually accelerates tumour onset, with metabolic analysis revealing enhanced glucose uptake and enrichment of anabolic pathways, which can fuel tumour growth. These findings provide considerable insight into the role of autophagy in cancer and have important implications for autophagy inhibition in cancer therapy. In this regard, we also show that treatment of mice with the autophagy inhibitor hydroxychloroquine, which is currently being used in several clinical trials, significantly accelerates tumour formation in mice containing oncogenic Kras but lacking p53.

Published
2013

15. Senescence Sensitivity of Breast Cancer Cells Is Defined by Positive Feedback Loop between CIP2A and E2F1

Author

Owen J. Sansom, Anchit Khanna, Jukka Westermarck, Gerard I. Evan, Pirkko-Liisa Kellokumpu-Lehtinen, Aleksandra Zwolinska, Mathias T. Rosenfeldt, Edward K. L. Chan, Veli-Matti Kähäri, Harri Sihto, Anni Laine, Minna Niemelä, Jean-Christophe Marine, Melissa R. Junttila, Christophe Côme, Kevin M. Ryan, and Heikki Joensuu

Subjects
Cyclin-Dependent Kinase Inhibitor p21, Senescence, Blotting, Western, Breast Neoplasms, Mammary Neoplasms, Animal, Docetaxel, Biology, Vinblastine, Vinorelbine, Autoantigens, Article, Mice, Breast cancer, Cell Line, Tumor, medicine, Animals, Humans, E2F1, Cellular Senescence, Cell Proliferation, Feedback, Physiological, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Cell growth, Antinematodal Agents, Intracellular Signaling Peptides and Proteins, Membrane Proteins, Fibroblasts, Embryo, Mammalian, HCT116 Cells, medicine.disease, Oncology, Drug Resistance, Neoplasm, Cell culture, MCF-7 Cells, Cancer research, Female, Taxoids, Tumor Suppressor Protein p53, Cell aging, E2F1 Transcription Factor, medicine.drug
Abstract

Senescence induction contributes to cancer therapy responses and is crucial for p53-mediated tumor suppression. However, whether p53 inactivation actively suppresses senescence induction has been unclear. Here, we show that E2F1 overexpression, due to p53 or p21 inactivation, promotes expression of human oncoprotein CIP2A, which in turn, by inhibiting PP2A activity, increases stabilizing serine 364 phosphorylation of E2F1. Several lines of evidence show that increased activity of E2F1-CIP2A feedback renders breast cancer cells resistant to senescence induction. Importantly, mammary tumorigenesis is impaired in a CIP2A-deficient mouse model, and CIP2A-deficient tumors display markers of senescence induction. Moreover, high CIP2A expression predicts for poor prognosis in a subgroup of patients with breast cancer treated with senescence-inducing chemotherapy. Together, these results implicate the E2F1-CIP2A feedback loop as a key determinant of breast cancer cell sensitivity to senescence induction. This feedback loop also constitutes a promising prosenescence target for therapy of cancers with an inactivated p53–p21 pathway. Significance: It has been recently realized that most currently used chemotherapies exert their therapeutic effect at least partly by induction of terminal cell arrest, senescence. However, the mechanisms by which cell-intrinsic senescence sensitivity is determined are poorly understood. Results of this study identify the E2F1-CIP2A positive feedback loop as a key determinant of breast cancer cell sensitivity to senescence and growth arrest induction. Our data also indicate that this newly characterized interplay between 2 frequently overexpressed oncoproteins constitutes a promising prosenescence target for therapy of cancers with inactivated p53 and p21. Finally, these results may also facilitate novel stratification strategies for selection of patients to receive senescence-inducing cancer therapies. Cancer Discov; 3(2); 182–97. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 125

Published
2013

16. Immunohistochemical detection of cytoplasmic LC3 puncta in human cancer specimens

Author

Mickaël Michaud, Vichnou Poirier-Colame, Mathias T. Rosenfeldt, Abdul Qader Sukkurwala, Sandy Adjemian, Lorenzo Galluzzi, Sylvain Ladoire, Felipe Andreiuolo, Kevin M. Ryan, Isabelle Martins, Guido Kroemer, Eileen White, Laurence Zitvogel, and Kariman Chaba

Subjects
Cytoplasm, Pathology, medicine.medical_specialty, ATG5, Cell, Biology, Mice, Cell Line, Tumor, Neoplasms, medicine, Animals, Humans, Molecular Biology, Gene knockdown, Tissue microarray, Staining and Labeling, Cancer, Cell Biology, medicine.disease, Immunohistochemistry, Basic Research Paper, Staining, Cell biology, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, Tissue Array Analysis, Cell culture, embryonic structures, biological phenomena, cell phenomena, and immunity, Microtubule-Associated Proteins
Abstract

Autophagy is an evolutionarily conserved catabolic process that involves the entrapment of cytoplasmic components within characteristic vesicles for their delivery to and degradation within lysosomes. Alterations in autophagic signaling are found in several human diseases including cancer. Here, we describe a validated immunohistochemical protocol for the detection of LC3 puncta in human formalin-fixed, paraffin-embedded cancer specimens that can also be applied to mouse tissues. In response to systemic chemotherapy, autophagy-competent mouse tumors exhibited LC3 puncta, which did not appear in mouse cancers that had been rendered autophagy-deficient by the knockdown of Atg5 or Atg7. As compared with normal tissues, LC3 staining was moderately to highly elevated in the large majority of human cancers studied, albeit tumors of the same histological type tended to be highly heterogeneous in the number and intensity of LC3 puncta per cell. Moreover, tumor-infiltrating immune cells often were highly positive for LC3. Altogether, this protocol for LC3 staining appears suitable for the specific detection of LC3 puncta in human specimens, including tissue microarrays. We surmise that this technique can be employed for retrospective or prospective studies involving large series of human tumor samples.

Published
2012

17. Analysis of macroautophagy by immunohistochemistry

Author

Mathias T. Rosenfeldt, Li Yen Mah, Colin Nixon, Kevin M. Ryan, and Emma Y. Liu

Subjects
Autophagosome, autophagy, Microtubule-associated protein, Cellular homeostasis, Biology, Immunoglobulin light chain, Autophagy-Related Protein 7, Mice, 03 medical and health sciences, 0302 clinical medicine, Protocol, LC3, Animals, Humans, Pancreas, Molecular Biology, 030304 developmental biology, 0303 health sciences, Staining and Labeling, Autophagy, tissue sections, Cell Biology, Fibroblasts, Embryo, Mammalian, Immunohistochemistry, Cell biology, Cytoplasm, 030220 oncology & carcinogenesis, Microtubule-Associated Proteins, MAP1LC3B, Ex vivo
Abstract

(Macro)Autophagy is a phylogenetically conserved membrane-trafficking process that functions to deliver cytoplasmic cargoes to lysosomes for digestion. The process is a major mechanism for turnover of cellular constituents and is therefore critical for maintaining cellular homeostasis. Macroautophagy is characteristically distinct from other forms of autophagy due to the formation of double-membraned vesicles termed autophagosomes which encapsulate cargoes prior to fusion with lysosomes. Autophagosomes contain an integral membrane-bound form (LC3-II) of the microtubule-associated protein 1 light chain 3 β (MAP1LC3B), which has become a gold-standard marker to detect accumulation of autophagosomes and thereby changes in macroautophagy. Due to the role played by macroautophagy in various diseases, the detection of autophagosomes in tissue sections is frequently desired. To date, however, the detection of endogenous LC3-II on paraffin-embedded tissue sections has proved problematic. We report here a simple, optimized and validated method for the detection of LC3-II by immunohistochemistry in human and mouse tissue samples that we believe will be a useful resource for those wishing to study macroautophagy ex vivo.

Published
2012

18. E2F1 drives chemotherapeutic drug resistance via ABCG2

Author

Christine Dufès, Laura Bell, Mathias T. Rosenfeldt, Jaclyn S. Long, Kevin M. Ryan, Jim O'Prey, Fiona Roberts, and Colin Nixon

Subjects
Cancer Research, endocrine system, animal structures, Abcg2, Mice, Nude, Antineoplastic Agents, ATP-binding cassette transporter, Drug resistance, Biology, RC0254, Mice, Cell Line, Tumor, Genetics, medicine, ATP Binding Cassette Transporter, Subfamily G, Member 2, Animals, Humans, E2F1, Molecular Biology, Transcription factor, Oligonucleotide Array Sequence Analysis, Cancer, medicine.disease, Drug Resistance, Multiple, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Multiple drug resistance, Drug Resistance, Neoplasm, Immunology, embryonic structures, Cancer research, biology.protein, ATP-Binding Cassette Transporters, Efflux, sense organs, biological phenomena, cell phenomena, and immunity, E2F1 Transcription Factor, Neoplasm Transplantation
Abstract

Multidrug resistance is a major barrier against successful chemotherapy, and this has been shown in vitro to be often caused by ATP-binding cassette (ABC) transporters. These transporters are frequently overexpressed in human cancers and confer an adverse prognosis in many common malignancies. The genetic factors, however, that initiate their expression in cancer are largely unknown. Here we report that the major multidrug transporter ABCG2 (BCRP/MXR) is directly and specifically activated by the transcription factor E2F1--a factor perturbed in the majority of human cancers. E2F1 regulates ABCG2 expression in multiple cell systems, and, importantly, we have identified a significant correlation between elevated E2F1 and ABCG2 expression in human lung cancers. We show that E2F1 causes chemotherapeutic drug efflux both in vitro and in vivo via ABCG2. Furthermore, the E2F1-ABCG2 axis suppresses chemotherapy-induced cell death that can be restored by the inhibition of ABCG2. These findings therefore identify a new axis in multidrug resistance and highlight a radical new function of E2F1 that is relevant to tumor therapy.

Published
2014

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