Pub Date : 2024-09-17DOI: 10.1101/2024.09.14.613067
Devin A King, Dakota E McCoy, Adrian Perdyan, Jakub Mieczkowski, Thierry Douki, Jennifer A Dionne, Rafael E Herrera, Ashby J Morrison
The p53 tumor suppressor is an indispensable regulator of DNA damage responses that accelerates carcinogenesis when mutated. In this report, we uncover a new mechanism by which p53 maintains genomic integrity in the absence of canonical DNA damage response activation. Specifically, loss of p53 dramatically alters chromatin structure at the nuclear periphery, allowing increased transmission of an environmental carcinogen, ultraviolet (UV) radiation, into the nucleus. Genome-wide mapping of UV-induced DNA lesions in p53-deficient primary cells reveals increased lesion abundance corresponding to regions of high mutation burden in malignant melanomas. These findings uncover a novel role of p53 in the suppression of mutations that contribute to cancer and highlight the critical influence of nuclear architecture in regulating sensitivity to carcinogens.
p53 肿瘤抑制因子是 DNA 损伤反应不可或缺的调节因子，一旦发生突变会加速癌变。在本报告中，我们发现了一种新的机制，通过这种机制，p53 可以在没有典型 DNA 损伤反应激活的情况下维持基因组的完整性。具体来说，p53 的缺失会显著改变核外围的染色质结构，从而增加环境致癌物质紫外线（UV）辐射向细胞核的传递。p53缺陷原代细胞中紫外线诱导的DNA病变的全基因组图谱显示，病变丰度增加与恶性黑色素瘤的高突变负荷区域相对应。这些发现揭示了 p53 在抑制导致癌症的突变方面的新作用，并强调了核结构在调节对致癌物质的敏感性方面的关键影响。
{"title":"p53 Regulates Nuclear Architecture to Reduce Carcinogen Sensitivity and Mutagenic Potential","authors":"Devin A King, Dakota E McCoy, Adrian Perdyan, Jakub Mieczkowski, Thierry Douki, Jennifer A Dionne, Rafael E Herrera, Ashby J Morrison","doi":"10.1101/2024.09.14.613067","DOIUrl":"https://doi.org/10.1101/2024.09.14.613067","url":null,"abstract":"The p53 tumor suppressor is an indispensable regulator of DNA damage responses that accelerates carcinogenesis when mutated. In this report, we uncover a new mechanism by which p53 maintains genomic integrity in the absence of canonical DNA damage response activation. Specifically, loss of p53 dramatically alters chromatin structure at the nuclear periphery, allowing increased transmission of an environmental carcinogen, ultraviolet (UV) radiation, into the nucleus. Genome-wide mapping of UV-induced DNA lesions in p53-deficient primary cells reveals increased lesion abundance corresponding to regions of high mutation burden in malignant melanomas. These findings uncover a novel role of p53 in the suppression of mutations that contribute to cancer and highlight the critical influence of nuclear architecture in regulating sensitivity to carcinogens.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249757","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 : 2024-09-17DOI: 10.1101/2024.09.12.612750
Andreas Zingg, Reto Ritschard, Helen Thut, Melanie Buchi, Andreas Holbro, Anton Oseledchyk, Viola Heinzelmann, Andreas Buser, Mascha Binder, Alfred Zippelius, Natalia Rodrigues Mantuano, Heinz Laubli
CAR T cell therapy has provided a significant improvement for patients with chemotherapy-resistant B cell malignancies. However, CAR T cell treatment of patients with solid cancers has been more difficult, in part because of the heterogeneous expression of tumor-specific cell surface antigens. Here, we describe the generation of a fully human CAR targeting altered glycosylation in secretory epithelial cancers. The expression of the target antigen, the truncated, sialylated O-glycan sialyl-Thomsen-Nouveau antigen (STn), was studied with a highly STn-specific antibody across various different tumor tissues. Strong expression was found in a high proportion of gastro-intestinal cancers including pancreatic cancers and in gynecological cancers, in particular ovarian and endometrial tumors. T cells expressing anti-STn CAR were tested in vitro and in vivo. Anti-STn CAR T cells showed activity in mouse models as well as in assays with primary ovarian cancer samples. No significant toxicity was observed in mouse models, although some intraluminal expression of STn was found in gastro-intestinal mouse tissue. Taken together, this fully human anti-STn CAR construct shows promising activity in preclinical tumor models supporting its further evaluation in early clinical trials.
CAR T 细胞疗法大大改善了化疗耐药 B 细胞恶性肿瘤患者的病情。然而，CAR T 细胞治疗实体瘤患者却比较困难，部分原因是肿瘤特异性细胞表面抗原的表达不一致。在这里，我们描述了针对分泌性上皮癌糖基化改变的全人源 CAR 的产生过程。我们用一种高度 STn 特异性的抗体研究了各种不同肿瘤组织中的靶抗原--截短的、糖基化的 O-聚糖 sialyl-Thomsen-Nouveau 抗原（STn）的表达情况。在包括胰腺癌在内的高比例胃肠道癌症和妇科癌症（尤其是卵巢癌和子宫内膜癌）中发现了强表达。对表达抗 STn CAR 的 T 细胞进行了体外和体内测试。抗 STn CAR T 细胞在小鼠模型以及原发性卵巢癌样本的试验中显示出活性。虽然在小鼠胃肠道组织中发现了一些 STn 腔内表达，但在小鼠模型中没有观察到明显的毒性。综上所述，这种全人源抗 STn CAR 构建物在临床前肿瘤模型中显示出良好的活性，支持在早期临床试验中对其进行进一步评估。
{"title":"Targeting cancer-associated glycosylation for adoptive T cell therapy of gastro-intestinal and gynecological cancers","authors":"Andreas Zingg, Reto Ritschard, Helen Thut, Melanie Buchi, Andreas Holbro, Anton Oseledchyk, Viola Heinzelmann, Andreas Buser, Mascha Binder, Alfred Zippelius, Natalia Rodrigues Mantuano, Heinz Laubli","doi":"10.1101/2024.09.12.612750","DOIUrl":"https://doi.org/10.1101/2024.09.12.612750","url":null,"abstract":"CAR T cell therapy has provided a significant improvement for patients with chemotherapy-resistant B cell malignancies. However, CAR T cell treatment of patients with solid cancers has been more difficult, in part because of the heterogeneous expression of tumor-specific cell surface antigens. Here, we describe the generation of a fully human CAR targeting altered glycosylation in secretory epithelial cancers. The expression of the target antigen, the truncated, sialylated O-glycan sialyl-Thomsen-Nouveau antigen (STn), was studied with a highly STn-specific antibody across various different tumor tissues. Strong expression was found in a high proportion of gastro-intestinal cancers including pancreatic cancers and in gynecological cancers, in particular ovarian and endometrial tumors. T cells expressing anti-STn CAR were tested in vitro and in vivo. Anti-STn CAR T cells showed activity in mouse models as well as in assays with primary ovarian cancer samples. No significant toxicity was observed in mouse models, although some intraluminal expression of STn was found in gastro-intestinal mouse tissue. Taken together, this fully human anti-STn CAR construct shows promising activity in preclinical tumor models supporting its further evaluation in early clinical trials.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249841","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 : 2024-09-17DOI: 10.1101/2024.09.12.612653
Yu Liu, Zhenyu Yang, Jingya Jane Pu, Jie Zhong, Ui Soon Khoo, Yuxiong Richard Su, Gao Zhang
Oral squamous cell carcinoma (OSCC) is an increasingly prevalent malignancy worldwide. This study aims to understand molecular alterations associated with lymph node metastasis of OSCC in order to improve treatment strategies. We analyzed a cohort of 46 patients with primary OSCC, including 10 with lymph node metastasis and 36 without. Using a comprehensive multi-omics approach, encompassing genomic, transcriptomic, proteomic, epigenetic, single-cell, and spatial analyses; we integrated data to delineate the molecular landscape of OSCC in the context of lymph node metastasis. Our genomic analysis identified significant mutations in key genes within the MAPK, TGF-b, and WNT signaling pathways, which are essential for tumor development. The proteogenomic analysis highlighted pathways critical for lymph node dissemination and factors contributing to an immunosuppressive tumor microenvironment. Elevated levels of POSTN were found to reorganize the extracellular matrix (ECM), interact with TGF-b disrupt cell cycle regulation, and suppress the immune response by reducing VCAM1 activity. Integrated analyses of single-cell and spatial transcriptome data revealed that cancer-associated fibroblasts (CAFs) secrete TGF-b1/2 promoting cancer cell metastasis through epithelial-mesenchymal transition (EMT). Our integrated multi-omics analysis provides a detailed understanding of molecular mechanisms driving lymph node metastasis of OSCC. These insights could lead to more precise diagnostics and targeted treatments.
{"title":"Proteogenomic Characterization of Primary Oral Squamous Cell Carcinomas Unveils the Extracellular Matrix Remodeling and Immunosuppressive Microenvironment Linked with Lymph Node Metastasis","authors":"Yu Liu, Zhenyu Yang, Jingya Jane Pu, Jie Zhong, Ui Soon Khoo, Yuxiong Richard Su, Gao Zhang","doi":"10.1101/2024.09.12.612653","DOIUrl":"https://doi.org/10.1101/2024.09.12.612653","url":null,"abstract":"Oral squamous cell carcinoma (OSCC) is an increasingly prevalent malignancy worldwide. This study aims to understand molecular alterations associated with lymph node metastasis of OSCC in order to improve treatment strategies. We analyzed a cohort of 46 patients with primary OSCC, including 10 with lymph node metastasis and 36 without. Using a comprehensive multi-omics approach, encompassing genomic, transcriptomic, proteomic, epigenetic, single-cell, and spatial analyses; we integrated data to delineate the molecular landscape of OSCC in the context of lymph node metastasis. Our genomic analysis identified significant mutations in key genes within the MAPK, TGF-b, and WNT signaling pathways, which are essential for tumor development. The proteogenomic analysis highlighted pathways critical for lymph node dissemination and factors contributing to an immunosuppressive tumor microenvironment. Elevated levels of POSTN were found to reorganize the extracellular matrix (ECM), interact with TGF-b disrupt cell cycle regulation, and suppress the immune response by reducing VCAM1 activity. Integrated analyses of single-cell and spatial transcriptome data revealed that cancer-associated fibroblasts (CAFs) secrete TGF-b1/2 promoting cancer cell metastasis through epithelial-mesenchymal transition (EMT). Our integrated multi-omics analysis provides a detailed understanding of molecular mechanisms driving lymph node metastasis of OSCC. These insights could lead to more precise diagnostics and targeted treatments.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"199 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249761","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 : 2024-09-17DOI: 10.1101/2024.09.12.612728
Justin Kim, Bryce Brunetti, Ayanesh Kumar, Ankit Mangla, Kord Honda, Akihiro Yoshida
The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular senescence. Clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent BrafV600E melanoma cells. Upregulated GLS1 expression renders BrafV600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the BrafV600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders BrafV600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced.
{"title":"Inhibition of glutaminase elicits senolysis in therapy-induced senescent melanoma cells.","authors":"Justin Kim, Bryce Brunetti, Ayanesh Kumar, Ankit Mangla, Kord Honda, Akihiro Yoshida","doi":"10.1101/2024.09.12.612728","DOIUrl":"https://doi.org/10.1101/2024.09.12.612728","url":null,"abstract":"The cyclin D1-Cyclin-Dependent Kinases 4 and 6 (CDK4/6) complex is crucial for the development of melanoma. We previously demonstrated that targeting CDK4/6 using small molecule inhibitors (CDK4/6i) suppresses BrafV600E melanoma growth in vitro and in vivo through induction of cellular senescence. Clinical trials investigating CDK4/6i in melanoma have not yielded successful outcomes, underscoring the necessity to enhance the therapeutic efficacy of CDK4/6i. Accumulated research has shown that while senescence initially suppresses cell proliferation, a prolonged state of senescence eventually leads to tumor relapse by altering the tumor microenvironment, suggesting that removal of those senescent cells (in a process referred to as senolysis) is of clinical necessity to facilitate clinical response. We demonstrate that glutaminase 1 (GLS1) expression is specifically upregulated in CDK4/6i-induced senescent BrafV600E melanoma cells. Upregulated GLS1 expression renders BrafV600E melanoma senescent cells vulnerable to GLS1 inhibitor (GLS1i). Furthermore, we demonstrate that this senolytic approach targeting upregulated GLS1 expression is applicable even though those cells developed resistance to the BrafV600E inhibitor vemurafenib, a frequently encountered substantial clinical challenge to treating patients. Thus, this novel senolytic approach may revolutionize current CDK4/6i mediated melanoma treatment if melanoma cells undergo senescence prior to developing resistance to CDK4/6i. Given that we demonstrate that a low dose of vemurafenib induced senescence, which renders BrafV600E melanoma cells susceptible to GLS1i and recent accumulated research shows many cancer cells undergo senescence in response to chemotherapy, radiation, and immunotherapy, this senolytic therapy approach may prove applicable to a wide range of cancer types once senescence and GLS1 expression are induced.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249760","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 : 2024-09-16DOI: 10.1101/2024.09.11.612412
Anna Baulies, Veronica Moncho-Amor, Diana Drago-Garcia, Anna Kucharska, Probir Chakravarty, Manuel Moreno-Valladares, Sara Cruces-Salguero, Florian Hubl, Colin Hutton, Haeun Kim, Ander Matheu, Robin Lovell-Badge, Vivian S.W. Li
Cellular plasticity plays critical roles in tissue regeneration, tumour progression and therapeutic resistance. However, the mechanism underlying this cell state transition remains elusive. Here, we show that the transcription factor SOX2 induces fetal reprogramming and reversible dormancy in colorectal cancer (CRC). SOX2 expression correlates with fetal reprogramming and poor prognosis in human primary and metastatic colorectal adenocarcinomas. In mouse CRC models, rare slow-cycling SOX2+SCA1+ cells are detected in early Apc-deleted mouse tumours that undergo slow clonal expansion over time. In contrast, the SOX2+ clones were found proliferative in advanced Apc-/-;KrasG12D/+;p53-/-;Tgfbr2-/- (AKPT) tumours, accompanied by dynamic cell state reprogramming from LGR5+ to LGR5-SCA1+ cells. Using transgenic mouse models, we demonstrate that ectopic expression of SOX2 inhibits intestinal lineage differentiation and induces fetal reprogramming. SOX2+ cells adopt dynamic cell cycle states depending on its expression level. High SOX2 expression results in hyperproliferation, whereas low SOX2 levels induce senescence-mediated dormancy. We find that loss of p53 can reverse SOX2-induced senescence, in line with the dormant cell state exit of the SOX2+ cells observed in advanced tumours. Finally, SOX2 expression is induced by 5-FU treatment in CRC. SOX2-expressing organoids exhibit increased tolerance to chemotherapy treatment, whilst deletion of SOX2 in AKPT tumour organoids sensitises drug responses. We propose that SOX2-induced plasticity and reversible dormancy promotes tumour progression and drug tolerance in CRC.
{"title":"SOX2 drives fetal reprogramming and reversible dormancy in colorectal cancer","authors":"Anna Baulies, Veronica Moncho-Amor, Diana Drago-Garcia, Anna Kucharska, Probir Chakravarty, Manuel Moreno-Valladares, Sara Cruces-Salguero, Florian Hubl, Colin Hutton, Haeun Kim, Ander Matheu, Robin Lovell-Badge, Vivian S.W. Li","doi":"10.1101/2024.09.11.612412","DOIUrl":"https://doi.org/10.1101/2024.09.11.612412","url":null,"abstract":"Cellular plasticity plays critical roles in tissue regeneration, tumour progression and therapeutic resistance. However, the mechanism underlying this cell state transition remains elusive. Here, we show that the transcription factor SOX2 induces fetal reprogramming and reversible dormancy in colorectal cancer (CRC). SOX2 expression correlates with fetal reprogramming and poor prognosis in human primary and metastatic colorectal adenocarcinomas. In mouse CRC models, rare slow-cycling SOX2+SCA1+ cells are detected in early Apc-deleted mouse tumours that undergo slow clonal expansion over time. In contrast, the SOX2+ clones were found proliferative in advanced Apc-/-;KrasG12D/+;p53-/-;Tgfbr2-/- (AKPT) tumours, accompanied by dynamic cell state reprogramming from LGR5+ to LGR5-SCA1+ cells. Using transgenic mouse models, we demonstrate that ectopic expression of SOX2 inhibits intestinal lineage differentiation and induces fetal reprogramming. SOX2+ cells adopt dynamic cell cycle states depending on its expression level. High SOX2 expression results in hyperproliferation, whereas low SOX2 levels induce senescence-mediated dormancy. We find that loss of p53 can reverse SOX2-induced senescence, in line with the dormant cell state exit of the SOX2+ cells observed in advanced tumours. Finally, SOX2 expression is induced by 5-FU treatment in CRC. SOX2-expressing organoids exhibit increased tolerance to chemotherapy treatment, whilst deletion of SOX2 in AKPT tumour organoids sensitises drug responses. We propose that SOX2-induced plasticity and reversible dormancy promotes tumour progression and drug tolerance in CRC.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249796","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 : 2024-09-16DOI: 10.1101/2024.09.11.612547
Samuel JC McCullough, Eliene Albers, Akshata Anchan, Jane Yu, Bronwen Connor, Scott Graham
Brain cancers offer poor prognoses to patients accompanied by symptoms that drastically impact the patient and their family. Brain tumours recruit local non-transformed cells to provide trophic support and immunosuppression within the tumour microenvironment, supporting tumour progression. Given the localization and supportive role of pericytes at the brain vasculature, we explored the potential for brain pericytes to contribute to the brain cancer microenvironment. To investigate this, primary brain pericytes were treated with factors commonly upregulated in brain cancers. Changes to brain pericyte cell signalling, inflammatory secretion, and phagocytosis were investigated. The TGFβ superfamily cytokines TGFβ and GDF-15 activated SMAD2/3 and inhibited C/EBP-δ, revealing a potential mechanism behind the pleiotropic action of TGFβ on brain pericytes. IL-17 induced secretion of IL-6 without activating NFκB, STAT1, SMAD2/3, or C/EBP-δ signalling pathways. IL-27 and IFNγ induced STAT1 signalling and significantly reduced pericyte phagocytosis. The remaining brain cancer-derived factors did not induce a measured response, indicating that these factors may act on other cell types or require co-stimulation with other factors to produce significant effects. Together, these findings show potential mechanisms by which brain pericytes contribute to aspects of inflammation and starts to uncover the supportive role brain pericytes may play in brain cancers.
{"title":"Screening activity of brain cancer-derived factors on primary human brain pericytes","authors":"Samuel JC McCullough, Eliene Albers, Akshata Anchan, Jane Yu, Bronwen Connor, Scott Graham","doi":"10.1101/2024.09.11.612547","DOIUrl":"https://doi.org/10.1101/2024.09.11.612547","url":null,"abstract":"Brain cancers offer poor prognoses to patients accompanied by symptoms that drastically impact the patient and their family. Brain tumours recruit local non-transformed cells to provide trophic support and immunosuppression within the tumour microenvironment, supporting tumour progression. Given the localization and supportive role of pericytes at the brain vasculature, we explored the potential for brain pericytes to contribute to the brain cancer microenvironment. To investigate this, primary brain pericytes were treated with factors commonly upregulated in brain cancers. Changes to brain pericyte cell signalling, inflammatory secretion, and phagocytosis were investigated. The TGFβ superfamily cytokines TGFβ and GDF-15 activated SMAD2/3 and inhibited C/EBP-δ, revealing a potential mechanism behind the pleiotropic action of TGFβ on brain pericytes. IL-17 induced secretion of IL-6 without activating NFκB, STAT1, SMAD2/3, or C/EBP-δ signalling pathways. IL-27 and IFNγ induced STAT1 signalling and significantly reduced pericyte phagocytosis. The remaining brain cancer-derived factors did not induce a measured response, indicating that these factors may act on other cell types or require co-stimulation with other factors to produce significant effects. Together, these findings show potential mechanisms by which brain pericytes contribute to aspects of inflammation and starts to uncover the supportive role brain pericytes may play in brain cancers.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249798","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 : 2024-09-16DOI: 10.1101/2024.09.12.612769
Monika Dzwigonska, Patrycja Rosa, Beata Kaza, Salwador Cyranowski, Aleksandra Ellert-Miklaszewska, Agata Kominek, Tomasz Obrebski, Anna R Malik, Katarzyna Piwocka, Jakub Mieczkowski, Bozena Kaminska, Katarzyna B Leszczynska
Hypoxia rapidly alters gene expression to allow cellular adaptation to challenging conditions and support tumour growth. Hypoxia also affects the chromatin structure by modifications of histones and DNA methylation. Glioblastoma (GBM) is an aggressive, deadly primary brain tumour for which there is no effective treatment. The tumour microenvironment of GBM is highly heterogeneous, with infiltration of glioma-associated microglia and macrophages (GAMs) and the presence of necrotic, hypoxic regions. The mechanisms through which hypoxia alters the tumour microenvironment and regulates functions of infiltrating immune cells remain poorly understood. Here, we show that hypoxia modulates the expression of myeloid markers in distinct ways: upregulates the monocytic marker Lgals3 expression and downregulates the microglial markers P2ry12 and Tmem119 in microglial and monocytic GAMs in vitro and in vivo, as shown using human and mouse GBM single-cell transcriptomics datasets. The genome-wide hypoxia-dependent transcriptomic changes in microglial cells were determined in microglia-glioma co-cultures. Numerous GAM subtype markers were dysregulated in response to hypoxic stress due to associated changes in chromatin accessibility, as determined using ATACseq. While hypoxia alone drives a decrease of the overall chromatin accessibility at gene promoters, the exposure to glioma cells under hypoxic conditions leads to both increases and decreases of chromatin accessibility at promoter regions in microglial cells. Hypoxia downregulates the chromatin accessibility at the regions enriched in motifs of transcription factors regarded as master regulators of microglial cell identity and function, including SPI1 or IRF8. Overall, our data highlights the importance of hypoxic stress as a strong intratumoral regulator of myeloid cell functions, which adds complexity to the characterisation of particular GAMs subpopulations.
{"title":"Hypoxic stress dysregulates functions of glioma-associated myeloid cells through epigenomic and transcriptional programs","authors":"Monika Dzwigonska, Patrycja Rosa, Beata Kaza, Salwador Cyranowski, Aleksandra Ellert-Miklaszewska, Agata Kominek, Tomasz Obrebski, Anna R Malik, Katarzyna Piwocka, Jakub Mieczkowski, Bozena Kaminska, Katarzyna B Leszczynska","doi":"10.1101/2024.09.12.612769","DOIUrl":"https://doi.org/10.1101/2024.09.12.612769","url":null,"abstract":"Hypoxia rapidly alters gene expression to allow cellular adaptation to challenging conditions and support tumour growth. Hypoxia also affects the chromatin structure by modifications of histones and DNA methylation. Glioblastoma (GBM) is an aggressive, deadly primary brain tumour for which there is no effective treatment. The tumour microenvironment of GBM is highly heterogeneous, with infiltration of glioma-associated microglia and macrophages (GAMs) and the presence of necrotic, hypoxic regions. The mechanisms through which hypoxia alters the tumour microenvironment and regulates functions of infiltrating immune cells remain poorly understood. Here, we show that hypoxia modulates the expression of myeloid markers in distinct ways: upregulates the monocytic marker Lgals3 expression and downregulates the microglial markers P2ry12 and Tmem119 in microglial and monocytic GAMs in vitro and in vivo, as shown using human and mouse GBM single-cell transcriptomics datasets. The genome-wide hypoxia-dependent transcriptomic changes in microglial cells were determined in microglia-glioma co-cultures. Numerous GAM subtype markers were dysregulated in response to hypoxic stress due to associated changes in chromatin accessibility, as determined using ATACseq. While hypoxia alone drives a decrease of the overall chromatin accessibility at gene promoters, the exposure to glioma cells under hypoxic conditions leads to both increases and decreases of chromatin accessibility at promoter regions in microglial cells. Hypoxia downregulates the chromatin accessibility at the regions enriched in motifs of transcription factors regarded as master regulators of microglial cell identity and function, including SPI1 or IRF8. Overall, our data highlights the importance of hypoxic stress as a strong intratumoral regulator of myeloid cell functions, which adds complexity to the characterisation of particular GAMs subpopulations.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"59 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249797","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 : 2024-09-16DOI: 10.1101/2024.09.13.612988
Jake Y. Chen, James C Gu
We introduce the Multi-level Parameterized Automata (MLPA), an innovative digital twin model that revolutionizes personalized cancer growth simulation and treatment optimization. MLPA integrates macroscopic electronic health records and microscopic genomic data, employing stochastic cellular automata to model tumor progression and treatment efficacy dynamically. This multi-scale approach enables MLPA to simulate complex cancer behaviors, including metastasis and pharmacological responses, with remarkable precision. Our validation using bioluminescent imaging from mice demonstrates MLPA's exceptional predictive power, achieving an improvement in accuracy over baseline models for tumor growth prediction. The model accurately captures tumors' characteristic S-shaped growth curve and shows high fidelity in simulating various scenarios, from natural progression to aggressive growth and drug treatment responses. MLPA's ability to simulate drug effects through gene pathway perturbation, validated through equivalence testing, underscores its potential as a powerful tool for precision oncology. The framework offers a robust platform for exploring personalized treatment strategies, potentially transforming patient outcomes by optimizing therapy based on individual biological profiles. We present the theoretical foundation, implementation, and validation of MLPA, highlighting its capacity to advance the field of computational oncology and foster more effective, tailored cancer treatment solutions. As we progress towards precision medicine, MLPA stands at the forefront, offering new possibilities in cancer modeling and treatment optimization. The code and imaging dataset used is available at https://github.com/alphamind-club/MLPA.
{"title":"MLPA: A Multi-scale Digital Twin Framework for Personalized Cancer Simulation and Treatment Optimization","authors":"Jake Y. Chen, James C Gu","doi":"10.1101/2024.09.13.612988","DOIUrl":"https://doi.org/10.1101/2024.09.13.612988","url":null,"abstract":"We introduce the Multi-level Parameterized Automata (MLPA), an innovative digital twin model that revolutionizes personalized cancer growth simulation and treatment optimization. MLPA integrates macroscopic electronic health records and microscopic genomic data, employing stochastic cellular automata to model tumor progression and treatment efficacy dynamically. This multi-scale approach enables MLPA to simulate complex cancer behaviors, including metastasis and pharmacological responses, with remarkable precision. Our validation using bioluminescent imaging from mice demonstrates MLPA's exceptional predictive power, achieving an improvement in accuracy over baseline models for tumor growth prediction. The model accurately captures tumors' characteristic S-shaped growth curve and shows high fidelity in simulating various scenarios, from natural progression to aggressive growth and drug treatment responses. MLPA's ability to simulate drug effects through gene pathway perturbation, validated through equivalence testing, underscores its potential as a powerful tool for precision oncology. The framework offers a robust platform for exploring personalized treatment strategies, potentially transforming patient outcomes by optimizing therapy based on individual biological profiles. We present the theoretical foundation, implementation, and validation of MLPA, highlighting its capacity to advance the field of computational oncology and foster more effective, tailored cancer treatment solutions. As we progress towards precision medicine, MLPA stands at the forefront, offering new possibilities in cancer modeling and treatment optimization. The code and imaging dataset used is available at https://github.com/alphamind-club/MLPA.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249799","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 : 2024-09-15DOI: 10.1101/2024.09.10.612253
Elizabeth Proaño-Pérez, Eva Serrano-Candelas, Mario Guerrero, David Gómez-Peregrina, Carlos Llorens, Beatriz Soriano, Ana Gámez-Valero, Marina Herrero-Lorenzo, Eulalia Marti, Cesar Serrano, Margarita Martin
Previous studies have identified Microphthalmia-associated Transcription Factor (MITF) involvement in regulating Gastrointestinal Stromal Tumors (GIST) growth and cell cycle progression. This study uses Chromatin Immunoprecipitation combined with high-throughput sequencing (ChIP-seq) and RNA sequencing to explore MITF-modulated genes in GIST. Our findings reveal that MITF regulates genes involved in lysosome biogenesis, vesicle generation, autophagy, and mTOR signaling pathways. Comparative transcriptome analysis following MITF silencing in GIST cells shows differential enrichment in mTOR signaling, impacting tumor growth and autophagy. In the context of cancer, the interplay between autophagy and extracellular vesicle release can influence tumor progression and metastasis. We examined MITF's role in autophagy and extracellular vesicle (EV) production in GIST, finding that MITF overexpression increases autophagy, as shown by elevated LC3II levels while silencing MITF disrupts autophagosome and autolysosome formation. Despite no significant changes in EV size or number, MITF silencing notably reduces KIT expression in EV content. KIT secretion in EVs has been linked to GIST metastasis, suggesting that MITF is a crucial target for managing tumor growth and metastasis in GIST.
{"title":"MITF Targets in Gastrointestinal Stromal Tumors: Implication in Autophagy and Extracellular Vesicle Secretion","authors":"Elizabeth Proaño-Pérez, Eva Serrano-Candelas, Mario Guerrero, David Gómez-Peregrina, Carlos Llorens, Beatriz Soriano, Ana Gámez-Valero, Marina Herrero-Lorenzo, Eulalia Marti, Cesar Serrano, Margarita Martin","doi":"10.1101/2024.09.10.612253","DOIUrl":"https://doi.org/10.1101/2024.09.10.612253","url":null,"abstract":"Previous studies have identified Microphthalmia-associated Transcription Factor (MITF) involvement in regulating Gastrointestinal Stromal Tumors (GIST) growth and cell cycle progression. This study uses Chromatin Immunoprecipitation combined with high-throughput sequencing (ChIP-seq) and RNA sequencing to explore MITF-modulated genes in GIST. Our findings reveal that MITF regulates genes involved in lysosome biogenesis, vesicle generation, autophagy, and mTOR signaling pathways. Comparative transcriptome analysis following MITF silencing in GIST cells shows differential enrichment in mTOR signaling, impacting tumor growth and autophagy. In the context of cancer, the interplay between autophagy and extracellular vesicle release can influence tumor progression and metastasis. We examined MITF's role in autophagy and extracellular vesicle (EV) production in GIST, finding that MITF overexpression increases autophagy, as shown by elevated LC3II levels while silencing MITF disrupts autophagosome and autolysosome formation. Despite no significant changes in EV size or number, MITF silencing notably reduces KIT expression in EV content. KIT secretion in EVs has been linked to GIST metastasis, suggesting that MITF is a crucial target for managing tumor growth and metastasis in GIST.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"113 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249802","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 : 2024-09-15DOI: 10.1101/2024.09.11.612492
Cindy E Liang, Eva Hrabeta-Robinson, Amit Behera, Carlos Arevalo, Isobel J Fetter, Cameron M Soulette, Alexis M Thornton, Shaheen Sikandar, Angela N Brooks
Although U2AF1S34F is a recurrent splicing factor mutation in lung adenocarcinoma (ADC), U2AF1S34F alone is insufficient for producing tumors in previous models. Because lung ADCs with U2AF1S34F frequently have co-occurring KRAS mutations and smoking histories, we hypothesized that tumor-forming potential arises from U2AF1S34F interacting with oncogenic KRAS and environmental stress. To elucidate the effect of U2AF1S34F co-occurring with a second mutation, we generated human bronchial epithelial cells (HBEC3kt) with co-occurring U2AF1S34F and KRASG12V. Transcriptome analysis revealed that co-occurring U2AF1S34F and KRASG12V differentially impacts inflammatory, cell cycle, and KRAS pathways. Subsequent phenotyping found associated suppressed cytokine production, increased proliferation, anchorage-independent growth, and tumors in mouse xenografts. Interestingly, HBEC3kts harboring only U2AF1S34F display increased splicing in stress granule protein genes and viability in cigarette smoke concentrate. Our results suggest that U2AF1S34F may potentiate transformation by granting precancerous cells survival advantage in environmental stress, permitting accumulation of additional mutations like KRASG12V, which synergize with U2AF1S34F to transform the cell.
{"title":"U2AF1 S34F enhances tumorigenic potential of lung cells by exhibiting synergy with KRAS mutation and altering response to environmental stress","authors":"Cindy E Liang, Eva Hrabeta-Robinson, Amit Behera, Carlos Arevalo, Isobel J Fetter, Cameron M Soulette, Alexis M Thornton, Shaheen Sikandar, Angela N Brooks","doi":"10.1101/2024.09.11.612492","DOIUrl":"https://doi.org/10.1101/2024.09.11.612492","url":null,"abstract":"Although U2AF1<sup>S34F</sup> is a recurrent splicing factor mutation in lung adenocarcinoma (ADC), U2AF1<sup>S34F</sup> alone is insufficient for producing tumors in previous models. Because lung ADCs with U2AF1<sup>S34F</sup> frequently have co-occurring KRAS mutations and smoking histories, we hypothesized that tumor-forming potential arises from U2AF1<sup>S34F</sup> interacting with oncogenic KRAS and environmental stress. To elucidate the effect of U2AF1<sup>S34F</sup> co-occurring with a second mutation, we generated human bronchial epithelial cells (HBEC3kt) with co-occurring U2AF1<sup>S34F</sup> and KRAS<sup>G12V</sup>. Transcriptome analysis revealed that co-occurring U2AF1<sup>S34F</sup> and KRAS<sup>G12V</sup> differentially impacts inflammatory, cell cycle, and KRAS pathways. Subsequent phenotyping found associated suppressed cytokine production, increased proliferation, anchorage-independent growth, and tumors in mouse xenografts. Interestingly, HBEC3kts harboring only U2AF1<sup>S34F</sup> display increased splicing in stress granule protein genes and viability in cigarette smoke concentrate. Our results suggest that U2AF1<sup>S34F</sup> may potentiate transformation by granting precancerous cells survival advantage in environmental stress, permitting accumulation of additional mutations like KRAS<sup>G12V</sup>, which synergize with U2AF1<sup>S34F</sup> to transform the cell.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249801","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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