Pub Date : 2024-09-14DOI: 10.1101/2024.09.10.612175
Camille Tessier, Jennifer Derrien, Aurore Dupuy, Thomas Pele, Martin Moquet, Julie Roul, Elise Douillard, Camille El Harrif, Xavier Pinson, Matthieu Le Gallo, Florence Godey, Patrick Tas, Roselyne Viel, Claude Prigent, Eric Letouze, Peggy Suzanne, Patrick Dallemagne, Mario Campone, Robert Weinberg, Jacqueline Lees, Philippe Juin, Vincent Guen
Tumor heterogeneity and plasticity, driven by Epithelial-Mesenchymal Transition (EMT), enable cancer therapeutic resistance. We previously showed that EMT promotes primary cilia formation, which enables stemness and tumorigenesis in triple-negative breast cancer (TNBC). Here, we establish a role for primary cilia in human TNBC chemotherapeutic resistance. We developed patient-derived organoids, and showed that these recapitulated the cellular heterogeneity of TNBC biopsies. Notably, one of the identified cell states bore a quasi-mesenchymal phenotype, primary cilia, and stemness signatures. We treated our TNBC organoids with chemotherapeutics and observed partial killing. The surviving cells with organoid-reconstituting capacity showed selective enrichment for the quasi-mesenchymal ciliated cell subpopulation. Genomic analyses argue that this enrichment reflects a combination of pre-existing cells and ones that arose through drug-induced cellular plasticity. We developed a family of small-molecule inhibitors of ciliogenesis and show that these, or genetic ablation of primary cilia, suppress chemoresistance. We conclude that primary cilia help TNBC to evade chemotherapy.
{"title":"Primary cilia promote EMT-induced triple-negative breast tumor heterogeneity and resistance to therapy","authors":"Camille Tessier, Jennifer Derrien, Aurore Dupuy, Thomas Pele, Martin Moquet, Julie Roul, Elise Douillard, Camille El Harrif, Xavier Pinson, Matthieu Le Gallo, Florence Godey, Patrick Tas, Roselyne Viel, Claude Prigent, Eric Letouze, Peggy Suzanne, Patrick Dallemagne, Mario Campone, Robert Weinberg, Jacqueline Lees, Philippe Juin, Vincent Guen","doi":"10.1101/2024.09.10.612175","DOIUrl":"https://doi.org/10.1101/2024.09.10.612175","url":null,"abstract":"Tumor heterogeneity and plasticity, driven by Epithelial-Mesenchymal Transition (EMT), enable cancer therapeutic resistance. We previously showed that EMT promotes primary cilia formation, which enables stemness and tumorigenesis in triple-negative breast cancer (TNBC). Here, we establish a role for primary cilia in human TNBC chemotherapeutic resistance. We developed patient-derived organoids, and showed that these recapitulated the cellular heterogeneity of TNBC biopsies. Notably, one of the identified cell states bore a quasi-mesenchymal phenotype, primary cilia, and stemness signatures. We treated our TNBC organoids with chemotherapeutics and observed partial killing. The surviving cells with organoid-reconstituting capacity showed selective enrichment for the quasi-mesenchymal ciliated cell subpopulation. Genomic analyses argue that this enrichment reflects a combination of pre-existing cells and ones that arose through drug-induced cellular plasticity. We developed a family of small-molecule inhibitors of ciliogenesis and show that these, or genetic ablation of primary cilia, suppress chemoresistance. We conclude that primary cilia help TNBC to evade chemotherapy.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.09.612065
Madeline N Hayes, Sarah Cohen-Gogo, Lynn Kee, Alex Weiss, Mehdi Layeghifard, Yagnesh Ladumor, Ivette Valencia-Sama, Anisha Rajaselvam, David R Kaplan, Anita Villani, Adam Shlien, Daniel R Morgenstern, Meredith S Irwin
Next generation sequencing of neuroblastoma (NB) tumors have revealed frequent somatic and germline genetic alterations in genes encoding proteins involved in DNA damage response (DDR) pathways. Despite being well-studied in many adult cancers, roles for DDR disruption in pediatric solid tumors remains poorly understood. To address this, patient-relevant loss-of-function mutations in DDR pathway components including Brca2, Atm, and Palb2 were incorporated into an established zebrafish MYCN transgenic model (Tg(dbh:EGFP-MYCN)). These mutations were found to enhance NB formation and metastasis in vivo, and result in upregulation of proliferation, cell cycle checkpoint and DNA damage repair transcriptional signatures, revealing potential molecular vulnerabilities in DDR-deficient NB. Zebrafish DDR-deficient NB and human NB cells with DDR protein knock-down were sensitive to the poly(ADP-ribose)-polymerase (PARP) inhibitor olaparib, and this effect was further enhanced by inhibition of the ataxia telangiectasia and rad3 related (ATR) kinase. Altogether, our data supports a functional role for DDR-deficiency in NB in vivo and therapeutic potential for combination PARP + ATR inhibition in NB patients with alterations in DDR genes.
神经母细胞瘤（NB）肿瘤的新一代测序发现，编码参与DNA损伤应答（DDR）通路的蛋白质的基因经常发生体细胞和种系遗传改变。尽管对许多成人癌症进行了深入研究，但人们对 DDR 干扰在小儿实体瘤中的作用仍知之甚少。为了解决这个问题，研究人员将与患者相关的 DDR 通路元件（包括 Brca2、Atm 和 Palb2）功能缺失突变纳入到一个已建立的斑马鱼 MYCN 转基因模型（Tg(dbh:EGFP-MYCN)）中。研究发现，这些突变会增强体内 NB 的形成和转移，并导致增殖、细胞周期检查点和 DNA 损伤修复转录特征的上调，从而揭示了 DDR 缺失型 NB 潜在的分子漏洞。斑马鱼DDR缺陷NB和敲除DDR蛋白的人类NB细胞对多（ADP-核糖）聚合酶（PARP）抑制剂奥拉帕利（olaparib）敏感，而抑制共济失调毛细血管扩张症和rad3相关（ATR）激酶可进一步增强这种效应。总之，我们的数据证明了DDR缺陷在体内NB中的功能性作用，以及PARP+ATR联合抑制DDR基因改变的NB患者的治疗潜力。
{"title":"DNA Damage Response Deficiency Enhances Neuroblastoma Progression and Sensitivity to Combination PARP and ATR Inhibition","authors":"Madeline N Hayes, Sarah Cohen-Gogo, Lynn Kee, Alex Weiss, Mehdi Layeghifard, Yagnesh Ladumor, Ivette Valencia-Sama, Anisha Rajaselvam, David R Kaplan, Anita Villani, Adam Shlien, Daniel R Morgenstern, Meredith S Irwin","doi":"10.1101/2024.09.09.612065","DOIUrl":"https://doi.org/10.1101/2024.09.09.612065","url":null,"abstract":"Next generation sequencing of neuroblastoma (NB) tumors have revealed frequent somatic and germline genetic alterations in genes encoding proteins involved in DNA damage response (DDR) pathways. Despite being well-studied in many adult cancers, roles for DDR disruption in pediatric solid tumors remains poorly understood. To address this, patient-relevant loss-of-function mutations in DDR pathway components including Brca2, Atm, and Palb2 were incorporated into an established zebrafish MYCN transgenic model (Tg(dbh:EGFP-MYCN)). These mutations were found to enhance NB formation and metastasis in vivo, and result in upregulation of proliferation, cell cycle checkpoint and DNA damage repair transcriptional signatures, revealing potential molecular vulnerabilities in DDR-deficient NB. Zebrafish DDR-deficient NB and human NB cells with DDR protein knock-down were sensitive to the poly(ADP-ribose)-polymerase (PARP) inhibitor olaparib, and this effect was further enhanced by inhibition of the ataxia telangiectasia and rad3 related (ATR) kinase. Altogether, our data supports a functional role for DDR-deficiency in NB in vivo and therapeutic potential for combination PARP + ATR inhibition in NB patients with alterations in DDR genes.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.09.611517
Gabriel F Alencar, Haroldo J Rodriguez, Thomas H Pulliam, Allison S Remington, Macy W Gilmour, Rian Alam, Austin J Jabbour, Logan J Mullen, Blair L DeBuysscher, Paul Nghiem, Justin J Taylor
While concurrent diagnoses of Merkel cell carcinoma (MCC) and other cancers, like Chronic lymphocytic leukemia (CLL), are rare, patients with MCC have a 30-fold higher incidence of CLL. While these increases have been attributed to the ability of CLL to suppress immune responses allowing for the emergence of MCC, here we found evidence that MCC could support the persistence of CLL. Using single cell sequencing approaches and computational analyses of MCC and CLL from a patient where both cancers were present in the same lymph node, we found that production of macrophage migration inhibitory factor (MIF) by MCC could promote the persistence of CLL through stimulation of CD74 and CXCR4. These results may explain why blood cell counts rapidly normalized after treatment for MCC and were maintained at normal levels despite the absence of treatment for CLL.
{"title":"Merkel cell carcinoma-derived macrophage migration inhibitory factor (MIF) may promote persistence of Chronic Lymphocytic Leukemia","authors":"Gabriel F Alencar, Haroldo J Rodriguez, Thomas H Pulliam, Allison S Remington, Macy W Gilmour, Rian Alam, Austin J Jabbour, Logan J Mullen, Blair L DeBuysscher, Paul Nghiem, Justin J Taylor","doi":"10.1101/2024.09.09.611517","DOIUrl":"https://doi.org/10.1101/2024.09.09.611517","url":null,"abstract":"While concurrent diagnoses of Merkel cell carcinoma (MCC) and other cancers, like Chronic lymphocytic leukemia (CLL), are rare, patients with MCC have a 30-fold higher incidence of CLL. While these increases have been attributed to the ability of CLL to suppress immune responses allowing for the emergence of MCC, here we found evidence that MCC could support the persistence of CLL. Using single cell sequencing approaches and computational analyses of MCC and CLL from a patient where both cancers were present in the same lymph node, we found that production of macrophage migration inhibitory factor (MIF) by MCC could promote the persistence of CLL through stimulation of CD74 and CXCR4. These results may explain why blood cell counts rapidly normalized after treatment for MCC and were maintained at normal levels despite the absence of treatment for CLL.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.09.611959
Beatriz Bonilla-Capilla, Luis Enrique Bergues Cabrales
Different sources of noises endogenous and exogenous to the cancer are involved in its stochastic growth. The aim of this study is to propose the stochastic version of Montijano-Bergues-Bory-Gompertz equation for the unperturbed tumor growth kinetics. The maximum likelihood estimators for the intrinsic tumor growth rate and the growth decelerating factor, and their respective discrete time approximations were analytically calculated. Different simulations of the deterministic and stochastic of this equation were made for different values of their respective parameters. Limit conditions for the average diffusion coefficient and the growth decelerating factor were established. The tumor volume at the infinite was calculated for several values of parameters of the stochastic Montijano-Bergues-Bory-Gompertz equation. Furthermore, descriptive statistic for the maximum likelihood estimators of the intrinsic tumor growth rate was computed for several parameters of this equation. The results evidenced that solid tumors there are for values of the average diffusion coefficient and the growth decelerating factor less than their respective limit values. The transition between avascular and vascular phases of the unperturbed tumor growth kinetics was revealed in the plot of the discrete time approximation for the maximum likelihood estimator of the growth decelerating factor versus the discrete time approximation for the maximum likelihood estimator of the intrinsic tumor growth rate. These results were connected with different findings in the literature. In conclusion, the stochastic Montijano-Bergues-Bory-Gompertz equation may be applied in the experiment to describe the unperturbed tumor growth kinetics, as previously demonstrated for its deterministic version, in order to estimate the parameters of this equation and their connection with processes involved in the growth, progression and metastasis of unperturbed solid tumors.
{"title":"Parameter estimation in the Montijano-Bergues-Bory-Gompertz stochastic model for unperturbed tumor growth","authors":"Beatriz Bonilla-Capilla, Luis Enrique Bergues Cabrales","doi":"10.1101/2024.09.09.611959","DOIUrl":"https://doi.org/10.1101/2024.09.09.611959","url":null,"abstract":"Different sources of noises endogenous and exogenous to the cancer are involved in its stochastic growth. The aim of this study is to propose the stochastic version of Montijano-Bergues-Bory-Gompertz equation for the unperturbed tumor growth kinetics. The maximum likelihood estimators for the intrinsic tumor growth rate and the growth decelerating factor, and their respective discrete time approximations were analytically calculated. Different simulations of the deterministic and stochastic of this equation were made for different values of their respective parameters. Limit conditions for the average diffusion coefficient and the growth decelerating factor were established. The tumor volume at the infinite was calculated for several values of parameters of the stochastic Montijano-Bergues-Bory-Gompertz equation. Furthermore, descriptive statistic for the maximum likelihood estimators of the intrinsic tumor growth rate was computed for several parameters of this equation. The results evidenced that solid tumors there are for values of the average diffusion coefficient and the growth decelerating factor less than their respective limit values. The transition between avascular and vascular phases of the unperturbed tumor growth kinetics was revealed in the plot of the discrete time approximation for the maximum likelihood estimator of the growth decelerating factor versus the discrete time approximation for the maximum likelihood estimator of the intrinsic tumor growth rate. These results were connected with different findings in the literature. In conclusion, the stochastic Montijano-Bergues-Bory-Gompertz equation may be applied in the experiment to describe the unperturbed tumor growth kinetics, as previously demonstrated for its deterministic version, in order to estimate the parameters of this equation and their connection with processes involved in the growth, progression and metastasis of unperturbed solid tumors.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.10.612045
Bryce Lim, Aryan Kamal, Borja Gomez Ramos, Juan Adrian Segarra, Ignacio Ibarra, Lennart Dignas, Tim Kindinger, Kai Volz, Mohammad Rahbari, Nuh Rahbari, Eric Poisel, Kanela Kafetzopoulou, Lio Bose, Marco Breinig, Danijela Heide, Suchira Gallage, Jose Barragan Avila, Hendrik Wiethoff, Ivan Berest, Sarah Schnabellehner, Martin Schneider, Jonas Becker, Dominic Helm, Dirk Grimm, Taija Makinen, Darjus Tschaharganeh, Mathias Heikenwalder, Judith B Zaugg, Moritz Mall
Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. Regulating cell identity requires gene activation and repression. While master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether unwanted plasticity is actively suppressed by lineage-specific repressors. Here, we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that Prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternate fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and acted as a tumour suppressor in multiple liver cancer models. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo, and promoted transition of hepatocellular carcinoma to cholangiocarcinoma, conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide mechanistic evidence for PROX1 as a hepatocyte-specific safeguard and support a model where individual cell type-specific repressors actively suppress plasticity throughout life to safeguard lineage choice and prevent disease.
{"title":"Active repression of cell fate plasticity by PROX1 safeguards hepatocyte identity and prevents liver tumourigenesis","authors":"Bryce Lim, Aryan Kamal, Borja Gomez Ramos, Juan Adrian Segarra, Ignacio Ibarra, Lennart Dignas, Tim Kindinger, Kai Volz, Mohammad Rahbari, Nuh Rahbari, Eric Poisel, Kanela Kafetzopoulou, Lio Bose, Marco Breinig, Danijela Heide, Suchira Gallage, Jose Barragan Avila, Hendrik Wiethoff, Ivan Berest, Sarah Schnabellehner, Martin Schneider, Jonas Becker, Dominic Helm, Dirk Grimm, Taija Makinen, Darjus Tschaharganeh, Mathias Heikenwalder, Judith B Zaugg, Moritz Mall","doi":"10.1101/2024.09.10.612045","DOIUrl":"https://doi.org/10.1101/2024.09.10.612045","url":null,"abstract":"Cell fate plasticity enables development, yet unlocked plasticity is a cancer hallmark. Regulating cell identity requires gene activation and repression. While master regulators induce lineage-specific genes to restrict plasticity, it remains unclear whether unwanted plasticity is actively suppressed by lineage-specific repressors. Here, we computationally predict so-called safeguard repressors for 18 cell types that block phenotypic plasticity lifelong. We validated hepatocyte-specific candidates using reprogramming, revealing that Prospero homeobox protein 1 (PROX1) enhanced hepatocyte identity by direct repression of alternate fate master regulators. In mice, Prox1 was required for efficient hepatocyte regeneration after injury and acted as a tumour suppressor in multiple liver cancer models. In line with patient data, Prox1 depletion caused hepatocyte fate loss in vivo, and promoted transition of hepatocellular carcinoma to cholangiocarcinoma, conversely, overexpression promoted cholangiocarcinoma to hepatocellular carcinoma transdifferentiation. Our findings provide mechanistic evidence for PROX1 as a hepatocyte-specific safeguard and support a model where individual cell type-specific repressors actively suppress plasticity throughout life to safeguard lineage choice and prevent disease.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.11.611224
Etienne Sollier, Anna Riedel, Umut H. Toprak, Justyna A. Wierzbinska, Dieter Weichenhan, Jan Philipp Schmid, Mariam Hakobyan, Aurore Touzart, Ekaterina Jahn, Binje Vick, Fiona Brown-Burke, Katherine Kelly, Simge Kelekci, Anastasija Pejkovska, Ashish Goyal, Marion Baehr, Kersten Breuer, Mei-Ju May Chen, Maria Llamazares-Prada, Mark Hartmann, Maximilian Schoenung, Nadia Correia, Andreas Trumpp, Yomn Abdullah, Ursula Klingmueller, Sadaf S. Mughal, Benedikt Brors, Frank Westermann, Matthias Schlesner, Sebastian Vosberg, Tobias Herold, Philipp A. Greif, Dietmar Pfeifer, Michael Luebbert, Thomas Fischer, Florian Heidel, Claudia Gebhard, Wencke Walter, Torsten Haferlach, Ann-Kathrin Eisfeld, Krzysztof Mrozek, Deedra Nicolet, Lars Bullinger, Leonie Smeenk, Claudia Erpelinck, Roger Mulet-Lazaro, Ruud Delwel, Aurelie Ernst, Michael Scherer, Pavlo Lutsik, Irmela Jeremias, Konstanze Doehner, Hartmut Doehner, Daniel B. Lipka, Christoph Plass
Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML.
{"title":"Pyjacker identifies enhancer hijacking events in acute myeloid leukemia including MNX1 activation via deletion 7q","authors":"Etienne Sollier, Anna Riedel, Umut H. Toprak, Justyna A. Wierzbinska, Dieter Weichenhan, Jan Philipp Schmid, Mariam Hakobyan, Aurore Touzart, Ekaterina Jahn, Binje Vick, Fiona Brown-Burke, Katherine Kelly, Simge Kelekci, Anastasija Pejkovska, Ashish Goyal, Marion Baehr, Kersten Breuer, Mei-Ju May Chen, Maria Llamazares-Prada, Mark Hartmann, Maximilian Schoenung, Nadia Correia, Andreas Trumpp, Yomn Abdullah, Ursula Klingmueller, Sadaf S. Mughal, Benedikt Brors, Frank Westermann, Matthias Schlesner, Sebastian Vosberg, Tobias Herold, Philipp A. Greif, Dietmar Pfeifer, Michael Luebbert, Thomas Fischer, Florian Heidel, Claudia Gebhard, Wencke Walter, Torsten Haferlach, Ann-Kathrin Eisfeld, Krzysztof Mrozek, Deedra Nicolet, Lars Bullinger, Leonie Smeenk, Claudia Erpelinck, Roger Mulet-Lazaro, Ruud Delwel, Aurelie Ernst, Michael Scherer, Pavlo Lutsik, Irmela Jeremias, Konstanze Doehner, Hartmut Doehner, Daniel B. Lipka, Christoph Plass","doi":"10.1101/2024.09.11.611224","DOIUrl":"https://doi.org/10.1101/2024.09.11.611224","url":null,"abstract":"Acute myeloid leukemia with complex karyotype (ckAML) is characterized by high genomic complexity, including frequent TP53 mutations and chromothripsis. We hypothesized that the numerous genomic rearrangements could reposition active enhancers near proto-oncogenes, leading to their aberrant expression. We developed pyjacker, a computational tool for the detection of enhancer hijacking events, and applied it to a cohort of 39 ckAML samples. Pyjacker identified motor neuron and pancreas homeobox 1 (MNX1), a gene aberrantly expressed in 1.4% of AML patients, often as a result of del(7)(q22q36) associated with hijacking of a CDK6 enhancer. MNX1-activated cases show significant co-occurrence with BCOR mutations and a gene signature shared with t(7;12)(q36;p13) pediatric AML. We demonstrated that MNX1 is a dependency gene, as its knockdown in a xenograft model reduces leukemia cell fitness. In conclusion, enhancer hijacking is a frequent mechanism for oncogene activation in AML.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.09.612077
Chloe S Baron, Olivia Mitchell, Serine Avagyan, Romain Menard, Song Yang, Anne L Robertson, Rajiv Potluri, Jay Shendure, Romain Madelaine, Aaron McKenna, Leonard I. Zon
Hematopoietic stem cells are regulated by endothelial and mesenchymal stromal cells in the marrow niche1-3. Leukemogenesis was long believed to be solely driven by genetic perturbations in hematopoietic cells but introduction of genetic mutations in the microenvironment demonstrated the ability of niche cells to drive disease progression4-8. The mechanisms by which the stem cell niche induces leukemia remain poorly understood. Here, using cellular barcoding in zebrafish, we found that clones of niche endothelial and stromal cells are significantly expanded in leukemic marrows. The pro-angiogenic peptide apelin secreted by leukemic cells induced sinusoidal endothelial cell clonal selection and transcriptional reprogramming towards an angiogenic state to promote leukemogenesis in vivo. Overexpression of apelin in normal hematopoietic stem cells led to clonal amplification of the niche endothelial cells and promotes clonal dominance of blood cells. Knock-out of apelin in leukemic zebrafish resulted in a significant reduction in disease progression. Our results demonstrate that leukemic cells remodel the clonal and transcriptional landscape of the marrow niche to promote leukemogenesis and provide a potential therapeutic opportunity for anti-apelin treatment.
{"title":"Leukemia-derived apelin selects endothelial niche clones to promote tumorigenesis","authors":"Chloe S Baron, Olivia Mitchell, Serine Avagyan, Romain Menard, Song Yang, Anne L Robertson, Rajiv Potluri, Jay Shendure, Romain Madelaine, Aaron McKenna, Leonard I. Zon","doi":"10.1101/2024.09.09.612077","DOIUrl":"https://doi.org/10.1101/2024.09.09.612077","url":null,"abstract":"Hematopoietic stem cells are regulated by endothelial and mesenchymal stromal cells in the marrow niche1-3. Leukemogenesis was long believed to be solely driven by genetic perturbations in hematopoietic cells but introduction of genetic mutations in the microenvironment demonstrated the ability of niche cells to drive disease progression4-8. The mechanisms by which the stem cell niche induces leukemia remain poorly understood. Here, using cellular barcoding in zebrafish, we found that clones of niche endothelial and stromal cells are significantly expanded in leukemic marrows. The pro-angiogenic peptide apelin secreted by leukemic cells induced sinusoidal endothelial cell clonal selection and transcriptional reprogramming towards an angiogenic state to promote leukemogenesis in vivo. Overexpression of apelin in normal hematopoietic stem cells led to clonal amplification of the niche endothelial cells and promotes clonal dominance of blood cells. Knock-out of apelin in leukemic zebrafish resulted in a significant reduction in disease progression. Our results demonstrate that leukemic cells remodel the clonal and transcriptional landscape of the marrow niche to promote leukemogenesis and provide a potential therapeutic opportunity for anti-apelin treatment.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.10.611650
Monica Roman-Trufero, Istvan T Kleijn, Kevin Blighe, Jinglin Zhou, Paula Saavedra-Garcia, Abigail Gaffar, Marilena Christoforou, Axel Bellotti, Joel Abrahams, Abdelmadjid Atrih, Douglas J Lamont, Marek Gierlinski, Pooja Jayaprakash, Audrey M Michel, Eric Aboagye, Mariia Yuneva, Glenn R Masson, Vahid Shahrezaei, Holger W Auner
The Integrated Stress Response (ISR) is a corrective physiological program to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omic approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations define an ISR-independent role of GCN2 in regulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.
{"title":"An integrated stress response-independent role of GCN2 prevents excessive ribosome biogenesis and mRNA translation","authors":"Monica Roman-Trufero, Istvan T Kleijn, Kevin Blighe, Jinglin Zhou, Paula Saavedra-Garcia, Abigail Gaffar, Marilena Christoforou, Axel Bellotti, Joel Abrahams, Abdelmadjid Atrih, Douglas J Lamont, Marek Gierlinski, Pooja Jayaprakash, Audrey M Michel, Eric Aboagye, Mariia Yuneva, Glenn R Masson, Vahid Shahrezaei, Holger W Auner","doi":"10.1101/2024.09.10.611650","DOIUrl":"https://doi.org/10.1101/2024.09.10.611650","url":null,"abstract":"The Integrated Stress Response (ISR) is a corrective physiological program to restore cellular homeostasis that is based on the attenuation of global protein synthesis and a resource-enhancing transcriptional programme. GCN2 is the oldest of four kinases that are activated by diverse cellular stresses to trigger the ISR and acts as the primary responder to amino acid shortage and ribosome collisions. Here, using a broad multi-omic approach, we uncover an ISR-independent role of GCN2. GCN2 inhibition or depletion in the absence of discernible stress causes excessive protein synthesis and ribosome biogenesis, perturbs the cellular translatome, and results in a dynamic and broad loss of metabolic homeostasis. Cancer cells that rely on GCN2 to keep protein synthesis in check under conditions of full nutrient availability depend on GCN2 for survival and unrestricted tumour growth. Our observations define an ISR-independent role of GCN2 in regulating the cellular proteome and translatome and suggest new avenues for cancer therapies based on unleashing excessive mRNA translation.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210602","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.09.612133
Paola Manara, Austin D Newsam, Venu VG Saralamma, Marco V Russo, Alicia Bilbao Martinez, Nikolai Fattakhov, Tyler A Cunningham, Abdessamad Y Alaoui, Dhanvantri Chahar, Alexandra M Carbone, Olivia B Lightfuss, Alexa M Barroso, Kyle S Hoffman, Francesco Maura, Daniel Bilbao, Jonathan H Schatz
Cancers coopt stress-response pathways to drive oncogenesis, dodge immune surveillance, and resist cytotoxic therapies. Several of these provide protection from ferroptosis, iron-mediated oxidative cell death. Here, we found dramatic sensitization to ferroptosis upon disruption of cap-dependent translation in diffuse large B-cell lymphoma (DLBCL). Specifically, rocaglate inhibitors of the eIF4A1 RNA helicase synergized with pharmacologic ferroptosis inducers, driven by a collapse of glutathione production that protects polyunsaturated fatty acids from ferroptotic oxidation. These effects occur despite initial up-regulation of specific protective factors. We find lost translation of NRF2, oncogenic master regulator of antioxidant gene-expression, is a key consequence of eIF4A1 inhibition. In vivo, combination of the clinical rocaglate zotatifin with a pharmacologically optimized ferroptosis inducer eradicated DLBCL patient derived xenografts. Moreover, we found zotatifin pre-exposure sensitized DLBCL to CD19-directed chimeric antigen receptor (CAR-19) T cells. Translational disruption therefore provides new opportunities to leverage therapeutic impacts of ferroptosis inducers including cytotoxic immunotherapies.
癌症利用应激反应途径驱动肿瘤发生，躲避免疫监视，抵制细胞毒疗法。其中有几种途径能保护细胞免受铁中毒（铁介导的氧化性细胞死亡）的伤害。在这里，我们发现在弥漫大 B 细胞淋巴瘤（DLBCL）中，当帽子依赖性翻译被破坏时，细胞会对铁氧化反应产生极大的敏感性。具体来说，eIF4A1 RNA 螺旋酶的洛卡格雷特抑制剂与药物性铁氧化诱导剂协同作用，谷胱甘肽的产生会崩溃，而谷胱甘肽能保护多不饱和脂肪酸不被铁氧化。尽管最初上调了特定的保护因子，但这些影响还是发生了。我们发现，抗氧化基因表达的致癌主调节因子 NRF2 的翻译丢失是 eIF4A1 抑制的一个关键后果。在体内，将临床罗卡酯佐他替芬与药理上优化的铁变态反应诱导剂结合使用，可根除DLBCL患者衍生的异种移植物。此外，我们还发现佐他替芬的预暴露可使DLBCL对CD19导向的嵌合抗原受体（CAR-19）T细胞敏感。因此，转化干扰为利用铁变态反应诱导剂（包括细胞毒性免疫疗法）的治疗效果提供了新的机会。
{"title":"NRF2 translation block by inhibition of cap-dependent initiation sensitizes lymphoma cells to ferroptosis and CAR-T immunotherapy","authors":"Paola Manara, Austin D Newsam, Venu VG Saralamma, Marco V Russo, Alicia Bilbao Martinez, Nikolai Fattakhov, Tyler A Cunningham, Abdessamad Y Alaoui, Dhanvantri Chahar, Alexandra M Carbone, Olivia B Lightfuss, Alexa M Barroso, Kyle S Hoffman, Francesco Maura, Daniel Bilbao, Jonathan H Schatz","doi":"10.1101/2024.09.09.612133","DOIUrl":"https://doi.org/10.1101/2024.09.09.612133","url":null,"abstract":"Cancers coopt stress-response pathways to drive oncogenesis, dodge immune surveillance, and resist cytotoxic therapies. Several of these provide protection from ferroptosis, iron-mediated oxidative cell death. Here, we found dramatic sensitization to ferroptosis upon disruption of cap-dependent translation in diffuse large B-cell lymphoma (DLBCL). Specifically, rocaglate inhibitors of the eIF4A1 RNA helicase synergized with pharmacologic ferroptosis inducers, driven by a collapse of glutathione production that protects polyunsaturated fatty acids from ferroptotic oxidation. These effects occur despite initial up-regulation of specific protective factors. We find lost translation of NRF2, oncogenic master regulator of antioxidant gene-expression, is a key consequence of eIF4A1 inhibition. In vivo, combination of the clinical rocaglate zotatifin with a pharmacologically optimized ferroptosis inducer eradicated DLBCL patient derived xenografts. Moreover, we found zotatifin pre-exposure sensitized DLBCL to CD19-directed chimeric antigen receptor (CAR-19) T cells. Translational disruption therefore provides new opportunities to leverage therapeutic impacts of ferroptosis inducers including cytotoxic immunotherapies.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.09.609499
Katharine J Herbert, Rosie Upstill-Goddard, Stephan B Dreyer, Selma Rebus, Australian Pancreatic Cancer Genome Initiative, Christian Pilarsky, Debabrata Mukhopadhyay, Christopher J. Lord, Genomics Innovation Alliance, Andrew V Biankin, Fieke E.M. Froeling, David K Chang
Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer and will soon be the second most common cause of cancer related death. While regimens containing DNA damaging agents such as FOLFIRINOX and PARP inhibitors have derived clinical benefits for some patients, their efficacy invariably fails over time. This presents a significant clinical challenge, and thus there is an urgent need for novel therapeutic strategies which are able to overcome the acquisition of resistance in PDAC. Clinically relevant models of treatment resistance were generated from patient-derived cell lines by extended exposure to chemotherapy agents. Synergy scoring, clonogenicity assays, flow cytometry, immunofluorescence and transcriptomic analysis were used to investigate the efficacy of combined ATR and PARP inhibition in re-sensitising resistant PDAC to treatment. Acquisition of resistance was associated with transcriptomic shifts in cell cycle checkpoint regulation, metabolic control, DNA damage response (DDR), programmed cell death and the replication stress response. Additionally, combined treatment with the ATR inhibitor (ceralasertib), and the PARP inhibitor (olaparib) was synergistic in all models of acquired resistance. Sequential treatment using ceralasertib prior to olaparib was highly effective at low dose for DDR proficient cell lines, whereas DDR deficient models responded better when treated with olaparib first. We provide in vitro evidence of a novel therapeutic strategy to overcome acquired PARP inhibitor and platinum resistance in PDAC by using sequential exposure to ceralasertib and olaparib. A sequential regimen may be more tolerable and should be investigated clinically to circumvent dose limiting toxicity in concurrent combinations.
胰腺导管腺癌（PDAC）仍然是致死率最高的癌症，很快将成为癌症相关死亡的第二大常见原因。虽然含有 DNA 损伤剂（如 FOLFIRINOX 和 PARP 抑制剂）的治疗方案为一些患者带来了临床疗效，但随着时间的推移，这些方案的疗效总会出现衰退。这给临床治疗带来了巨大挑战，因此迫切需要能够克服 PDAC 耐药性的新型治疗策略。通过协同作用评分、克隆生成测定、流式细胞术、免疫荧光和转录组学分析，研究了联合抑制ATR和PARP对耐药PDAC治疗再敏感的疗效。耐药性的获得与细胞周期检查点调控、代谢控制、DNA损伤反应（DDR）、程序性细胞死亡和复制应激反应的转录组学转变有关。此外，在所有获得性耐药模型中，ATR抑制剂（ceralasertib）和PARP抑制剂（olaparib）的联合治疗具有协同作用。我们通过体外实验证明了一种新的治疗策略，即通过连续暴露于ceralasertib和奥拉帕利来克服PDAC中获得性PARP抑制剂和铂类耐药性。序贯疗法可能更耐受，应在临床上进行研究，以规避同时联合用药时的剂量限制毒性。
{"title":"Sequential ATR and PARP Inhibition Overcomes Acquired DNA Damaging Agent Resistance in Pancreatic Ductal Adenocarcinoma","authors":"Katharine J Herbert, Rosie Upstill-Goddard, Stephan B Dreyer, Selma Rebus, Australian Pancreatic Cancer Genome Initiative, Christian Pilarsky, Debabrata Mukhopadhyay, Christopher J. Lord, Genomics Innovation Alliance, Andrew V Biankin, Fieke E.M. Froeling, David K Chang","doi":"10.1101/2024.09.09.609499","DOIUrl":"https://doi.org/10.1101/2024.09.09.609499","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) remains the most lethal cancer and will soon be the second most common cause of cancer related death. While regimens containing DNA damaging agents such as FOLFIRINOX and PARP inhibitors have derived clinical benefits for some patients, their efficacy invariably fails over time. This presents a significant clinical challenge, and thus there is an urgent need for novel therapeutic strategies which are able to overcome the acquisition of resistance in PDAC.\u0000Clinically relevant models of treatment resistance were generated from patient-derived cell lines by extended exposure to chemotherapy agents. Synergy scoring, clonogenicity assays, flow cytometry, immunofluorescence and transcriptomic analysis were used to investigate the efficacy of combined ATR and PARP inhibition in re-sensitising resistant PDAC to treatment.\u0000Acquisition of resistance was associated with transcriptomic shifts in cell cycle checkpoint regulation, metabolic control, DNA damage response (DDR), programmed cell death and the replication stress response. Additionally, combined treatment with the ATR inhibitor (ceralasertib), and the PARP inhibitor (olaparib) was synergistic in all models of acquired resistance. Sequential treatment using ceralasertib prior to olaparib was highly effective at low dose for DDR proficient cell lines, whereas DDR deficient models responded better when treated with olaparib first.\u0000We provide in vitro evidence of a novel therapeutic strategy to overcome acquired PARP inhibitor and platinum resistance in PDAC by using sequential exposure to ceralasertib and olaparib. A sequential regimen may be more tolerable and should be investigated clinically to circumvent dose limiting toxicity in concurrent combinations.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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