Pub Date : 2024-09-07DOI: 10.1101/2024.09.04.611214
Weijian Meng, Sophia Xie, Jie Shen
Purpose: Capsaicin has previously been demonstrated to exhibit anti-tumor effect in various cancer type. However, the effect of capsaicin on gene expression and its potential mechanism on chemotherapy sensitization were still uncertain. Method: Human AGS gastric cancer cell line was treated with different concentrations of capsaicin, 5-fluorouracil and oxaliplatin. Cell viability was assessed using cell viability assay. High throughput RNA sequencing was used to screen differentially expressed genes triggered by capsaicin in AGS cells. qPCR and Western blotting were used to detect the expression of mRNAs and proteins induced by capsaicin. Result: Capsaicin could significantly inhibit cell viability at a dose-depend manner in AGS gastric cancer cell line. Through high-throughput RNA sequencing, genes regulating DNA repair, DNA replication and chromosome assemble pathways were analyzed to be down-regulated by capsaicin. qPCR and western blot assay demonstrated that capsaicin could inhibit expression of the key enzymes (FEN1, LIG1 and PARP1) which play critical roles in DNA damage response and chemotherapy resistance. In vitro assay demonstrated that capsaicin could significantly induce chemo-sensitivity of 5-FU and Oxaliplatin at low dose. Conclusion: Capsaicin could inhibit DNA repair pathway, which might contribute to cell growth inhibition and improvement of chemotherapy sensitization. These results revealed a novel function of capsaicin in DNA damage repair and provided new potential targets in cancer therapy.
{"title":"Exploring the effect of capsaicin on gene expression and chemotherapy sensitization in gastric cancer cells","authors":"Weijian Meng, Sophia Xie, Jie Shen","doi":"10.1101/2024.09.04.611214","DOIUrl":"https://doi.org/10.1101/2024.09.04.611214","url":null,"abstract":"Purpose: Capsaicin has previously been demonstrated to exhibit anti-tumor effect in various cancer type. However, the effect of capsaicin on gene expression and its potential mechanism on chemotherapy sensitization were still uncertain. Method: Human AGS gastric cancer cell line was treated with different concentrations of capsaicin, 5-fluorouracil and oxaliplatin. Cell viability was assessed using cell viability assay. High throughput RNA sequencing was used to screen differentially expressed genes triggered by capsaicin in AGS cells. qPCR and Western blotting were used to detect the expression of mRNAs and proteins induced by capsaicin. Result: Capsaicin could significantly inhibit cell viability at a dose-depend manner in AGS gastric cancer cell line. Through high-throughput RNA sequencing, genes regulating DNA repair, DNA replication and chromosome assemble pathways were analyzed to be down-regulated by capsaicin. qPCR and western blot assay demonstrated that capsaicin could inhibit expression of the key enzymes (FEN1, LIG1 and PARP1) which play critical roles in DNA damage response and chemotherapy resistance. In vitro assay demonstrated that capsaicin could significantly induce chemo-sensitivity of 5-FU and Oxaliplatin at low dose. Conclusion: Capsaicin could inhibit DNA repair pathway, which might contribute to cell growth inhibition and improvement of chemotherapy sensitization. These results revealed a novel function of capsaicin in DNA damage repair and provided new potential targets in cancer therapy.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210496","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 : 2024-09-07DOI: 10.1101/2024.09.04.611079
Zhigang Xie, Adrija Pathak, Vytas A. Bankaitis
Diffuse intrinsic pontine gliomas (DIPGs), a major type of pediatric high-grade gliomas located in the pons, are the leading cause of death in children with brain cancer. A subset (20-25%) of DIPGs harbor a lysine 27-to-methionine (K27M) mutation in HIST1H3B, which encodes histone H3.1, and an activating ACVR1 mutation. The occurrence of this pair of mutations in DIPGs, but not in pediatric gliomas in other anatomical locations, suggests the existence of a pontine-specific niche that favors DIPG gliomagenesis. Unfortunately, the identity of the underlying pontine niche remains elusive as available mouse models fail to recapitulate the anatomic specificity that characterizes DIPGs. Herein we show that the trigeminal root entry zone (TREZ), a pontine structure where several major axon tracts intersect, is enriched with proliferating oligodendrocyte-lineage cells during brainstem development. Introducing both H3.1K27M and activating Acvr1 and Pik3ca mutations (which co-occur frequently with H3.1K27M in human DIPGs) into the mouse brain leads to rapid gliomagenesis. This pathology recapitulates the pons specificity of DIPGs as glioma cells proliferate on axon tracts at the TREZ. We further show that a hyaluronan receptor important for cell stemness (HMMR) plays a key role in glioma cell proliferation at the TREZ. We propose that H3.1K27M and its co-occurring mutations drive pontine specific gliomagenesis by inducing a proliferative response of oligodendrocyte-lineage cells with enhanced stemness on large TREZ axon tracts.
{"title":"A pontine-specific axonal niche supports de novo gliomagenesis","authors":"Zhigang Xie, Adrija Pathak, Vytas A. Bankaitis","doi":"10.1101/2024.09.04.611079","DOIUrl":"https://doi.org/10.1101/2024.09.04.611079","url":null,"abstract":"Diffuse intrinsic pontine gliomas (DIPGs), a major type of pediatric high-grade gliomas located in the pons, are the leading cause of death in children with brain cancer. A subset (20-25%) of DIPGs harbor a lysine 27-to-methionine (K27M) mutation in HIST1H3B, which encodes histone H3.1, and an activating ACVR1 mutation. The occurrence of this pair of mutations in DIPGs, but not in pediatric gliomas in other anatomical locations, suggests the existence of a pontine-specific niche that favors DIPG gliomagenesis. Unfortunately, the identity of the underlying pontine niche remains elusive as available mouse models fail to recapitulate the anatomic specificity that characterizes DIPGs. Herein we show that the trigeminal root entry zone (TREZ), a pontine structure where several major axon tracts intersect, is enriched with proliferating oligodendrocyte-lineage cells during brainstem development. Introducing both H3.1K27M and activating Acvr1 and Pik3ca mutations (which co-occur frequently with H3.1K27M in human DIPGs) into the mouse brain leads to rapid gliomagenesis. This pathology recapitulates the pons specificity of DIPGs as glioma cells proliferate on axon tracts at the TREZ. We further show that a hyaluronan receptor important for cell stemness (HMMR) plays a key role in glioma cell proliferation at the TREZ. We propose that H3.1K27M and its co-occurring mutations drive pontine specific gliomagenesis by inducing a proliferative response of oligodendrocyte-lineage cells with enhanced stemness on large TREZ axon tracts.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210500","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 : 2024-09-07DOI: 10.1101/2024.09.04.611275
Andrea Bilger, Ella T Ward-Shaw, Denis L Lee, Renee E King, Michael A Newton, Darya Buehler, Kristina A Matkowskyj, John P Sundberg, Hu Rong, Paul F Lambert
Development of invasive cancer in mammals is thought to require months or years after initial events such as mutation or viral infection. Rarely, invasive cancers regress spontaneously. We show that cancers can develop and regress on a timescale of weeks, not months or years. Invasive squamous cell carcinomas developed in normal adult, immune-competent mice as soon as 2 weeks after infection with mouse papillomavirus MmuPV1. Tumor development, regression or persistence was tissue- and strain-dependent. Cancers in infected mice developed rapidly at sites also prone to papillomavirus-induced tumors and cancers in humans - the throat, anus, and skin - and their frequency was increased in mice constitutively expressing the papillomavirus E5 oncogene, which MmuPV1 lacks. Cancers and dysplasia in the throat and anus regressed completely within 4-8 weeks of infection; however, skin lesions in the ear persisted. T-cell depletion in the mouse showed that regression of throat and anal tumors requires T cells. We conclude that papillomavirus infection suffices for rapid onset of invasive cancer, and persistence of lesions depends on factors including tissue type and host immunity. The speed of these events should promote rapid progress in the study of viral cancer development, persistence, and regression.
在哺乳动物中，浸润性癌症的发生被认为需要在突变或病毒感染等初始事件发生后数月或数年。罕见的是，浸润性癌症会自然消退。我们的研究表明，癌症的发展和消退只需要几周时间，而不是几个月或几年。正常成年免疫功能健全的小鼠在感染小鼠乳头状瘤病毒 MmuPV1 两周后就会出现浸润性鳞状细胞癌。肿瘤的发展、消退或持续存在与组织和品系有关。受感染小鼠的癌症在人类乳头瘤病毒诱发肿瘤和癌症的易发部位--咽喉、肛门和皮肤--迅速发展，而且在组成型表达乳头瘤病毒 E5 致癌基因（MmuPV1 缺乏这种基因）的小鼠中，癌症发生的频率增加。咽喉和肛门的癌症和发育不良在感染后 4-8 周内完全消退；但耳部皮肤的病变仍然存在。小鼠的 T 细胞耗竭表明，喉咙和肛门肿瘤的消退需要 T 细胞。我们的结论是，乳头瘤病毒感染足以导致浸润性癌症的快速发生，而病变的持续则取决于组织类型和宿主免疫等因素。这些事件的发生速度应能促进病毒性癌症的发展、持续和消退研究取得快速进展。
{"title":"Invasive cancer and spontaneous regression two weeks after papillomavirus infection","authors":"Andrea Bilger, Ella T Ward-Shaw, Denis L Lee, Renee E King, Michael A Newton, Darya Buehler, Kristina A Matkowskyj, John P Sundberg, Hu Rong, Paul F Lambert","doi":"10.1101/2024.09.04.611275","DOIUrl":"https://doi.org/10.1101/2024.09.04.611275","url":null,"abstract":"Development of invasive cancer in mammals is thought to require months or years after initial events such as mutation or viral infection. Rarely, invasive cancers regress spontaneously. We show that cancers can develop and regress on a timescale of weeks, not months or years. Invasive squamous cell carcinomas developed in normal adult, immune-competent mice as soon as 2 weeks after infection with mouse papillomavirus MmuPV1. Tumor development, regression or persistence was tissue- and strain-dependent. Cancers in infected mice developed rapidly at sites also prone to papillomavirus-induced tumors and cancers in humans - the throat, anus, and skin - and their frequency was increased in mice constitutively expressing the papillomavirus E5 oncogene, which MmuPV1 lacks. Cancers and dysplasia in the throat and anus regressed completely within 4-8 weeks of infection; however, skin lesions in the ear persisted. T-cell depletion in the mouse showed that regression of throat and anal tumors requires T cells. We conclude that papillomavirus infection suffices for rapid onset of invasive cancer, and persistence of lesions depends on factors including tissue type and host immunity. The speed of these events should promote rapid progress in the study of viral cancer development, persistence, and regression.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210495","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 : 2024-09-07DOI: 10.1101/2024.09.03.610529
Annie Li, Bianca L Gonda, Adam von Paternos, Elizabeth M Codd, Dawn R Mitchell, Markuss D Herrman, Thuc Q Dzu, Prinjali Kalyan, Chengzhuo Gao, Edwin Zhang, Julia J Mendel, Julia C Thierauf, Peter M Sadow, Thomas Denize, Diane Yang, Jong C Park, Florian J Fintelmann, Xin Gao, Ross D Merkin, Atul K Bhan, William C Faquin, Lori J Wirth, Daniel L Wirth, Stefan T Kaluziak, Anthony John Iafrate
Purpose Adenoid cystic carcinoma (ACC), a rare and lethal cancer, has shown low response rates to systemic therapies, such as cytotoxic chemotherapy and immune-checkpoint inhibitors (ICIs). Despite numerous clinical trials, some employing aggressive ICI combinations, no effective treatments for patients with recurrent or metastatic adenoid cystic carcinoma have emerged, and ACC mortality rates remain stagnant. Therefore, we aimed to characterize the ACC immune landscape to understand the poor response rates to ICIs. Experimental Design We leveraged automated multiplex immunofluorescence (mIF), RNA in-situ hybridization, and scRNAseq Gene Expression analysis to identify pathways supporting the cold ACC immune environment and molecularly characterize ACC tumors, adjacent normal tissues, and normal tissues from regions where ACCs arise. In vitro, we treated freshly resected ACCs with interferon-gamma or a STING agonist. Results mIF demonstrated that ACC tumors are immunologically cold, with few tumor-infiltrating T-lymphocytes (TILs) and low PD-L1 expression. The most striking finding, however, was a very low HLA/B2M class I expression in almost all ACCs, which was reversible through treatment with interferon-gamma, or a STING agonist. mIF and RNAseq analyses of normal tissues revealed a p63+, NFIB+, basal duct cell population with similarly low HLA/B2M class I expression. Conclusions Low/absent HLA/B2M expression may explain the immunologically cold status of ACC tumors and their lack of response to ICIs. Our findings suggest that the normal cell of ACC origin exists in an HLA-low state, and that pharmacologic manipulation with immune activators, such as STING agonists, can restore HLA/B2M in ACCs, creating a path to urgently needed, effective immunotherapies.
{"title":"Reversible Downregulation of HLA Class I in Adenoid Cystic Carcinoma","authors":"Annie Li, Bianca L Gonda, Adam von Paternos, Elizabeth M Codd, Dawn R Mitchell, Markuss D Herrman, Thuc Q Dzu, Prinjali Kalyan, Chengzhuo Gao, Edwin Zhang, Julia J Mendel, Julia C Thierauf, Peter M Sadow, Thomas Denize, Diane Yang, Jong C Park, Florian J Fintelmann, Xin Gao, Ross D Merkin, Atul K Bhan, William C Faquin, Lori J Wirth, Daniel L Wirth, Stefan T Kaluziak, Anthony John Iafrate","doi":"10.1101/2024.09.03.610529","DOIUrl":"https://doi.org/10.1101/2024.09.03.610529","url":null,"abstract":"Purpose\u0000Adenoid cystic carcinoma (ACC), a rare and lethal cancer, has shown low response rates to systemic therapies, such as cytotoxic chemotherapy and immune-checkpoint inhibitors (ICIs). Despite numerous clinical trials, some employing aggressive ICI combinations, no effective treatments for patients with recurrent or metastatic adenoid cystic carcinoma have emerged, and ACC mortality rates remain stagnant. Therefore, we aimed to characterize the ACC immune landscape to understand the poor response rates to ICIs.\u0000Experimental Design\u0000We leveraged automated multiplex immunofluorescence (mIF), RNA in-situ hybridization, and scRNAseq Gene Expression analysis to identify pathways supporting the cold ACC immune environment and molecularly characterize ACC tumors, adjacent normal tissues, and normal tissues from regions where ACCs arise. In vitro, we treated freshly resected ACCs with interferon-gamma or a STING agonist.\u0000Results\u0000mIF demonstrated that ACC tumors are immunologically cold, with few tumor-infiltrating T-lymphocytes (TILs) and low PD-L1 expression. The most striking finding, however, was a very low HLA/B2M class I expression in almost all ACCs, which was reversible through treatment with interferon-gamma, or a STING agonist. mIF and RNAseq analyses of normal tissues revealed a p63+, NFIB+, basal duct cell population with similarly low HLA/B2M class I expression.\u0000Conclusions\u0000Low/absent HLA/B2M expression may explain the immunologically cold status of ACC tumors and their lack of response to ICIs. Our findings suggest that the normal cell of ACC origin exists in an HLA-low state, and that pharmacologic manipulation with immune activators, such as STING agonists, can restore HLA/B2M in ACCs, creating a path to urgently needed, effective immunotherapies.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"498 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210499","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 : 2024-09-07DOI: 10.1101/2024.09.05.611241
Gabriele Casagrande Raffi, Jian Chen, XueZhao Feng, Zhen Chen, Cor Lieftink, Shuang Deng, Jinzhe Mo, Chuting Zeng, Marit Steur, Jing Wang, Onno Bleijerveld, Liesbeth Hoekman, Nicole van der Wel, Feng Wang, Roderick Beijersbergen, Jian Zheng, Rene R Bernards, Liqin Wang
Drugs that eliminate senescent cells, senolytics, can be powerful when combined with pro-senescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a PANoptosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via JNK pathway activation. We show that a combination of a DR5 agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent NK and CD8+ T cell mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine IL18.
消除衰老细胞的药物（即衰老剂）与促进衰老的癌症疗法相结合，可以发挥强大的作用。通过基于CRISPR/Cas9的基因筛选，我们发现SLC25A23是衰老癌细胞的一个弱点。抑制 SLC25A23 会破坏细胞钙平衡、损害氧化磷酸化并干扰氧化还原信号转导，从而导致衰老细胞死亡。盐霉素是一种阳离子抗生素。盐霉素可促使衰老细胞发生泛凋亡样细胞死亡，包括细胞凋亡和两种免疫原性细胞死亡形式：坏死和热凋亡。值得注意的是，我们观察到盐霉素处理或 SLC25A23 抑制会增加活性氧，通过 JNK 通路激活上调死亡受体 5。我们发现，DR5 激动抗体和盐霉素的组合是一种强效的衰老溶解鸡尾酒。我们提供的证据表明，这种药物组合能在嗜热细胞因子 IL18 的介导下，引发 NK 和 CD8+ T 细胞介导的对衰老癌细胞的强效免疫破坏。
{"title":"An antibiotic that mediates immune destruction of senescent cancer cells","authors":"Gabriele Casagrande Raffi, Jian Chen, XueZhao Feng, Zhen Chen, Cor Lieftink, Shuang Deng, Jinzhe Mo, Chuting Zeng, Marit Steur, Jing Wang, Onno Bleijerveld, Liesbeth Hoekman, Nicole van der Wel, Feng Wang, Roderick Beijersbergen, Jian Zheng, Rene R Bernards, Liqin Wang","doi":"10.1101/2024.09.05.611241","DOIUrl":"https://doi.org/10.1101/2024.09.05.611241","url":null,"abstract":"Drugs that eliminate senescent cells, senolytics, can be powerful when combined with pro-senescence cancer therapies. Using a CRISPR/Cas9-based genetic screen, we identify here SLC25A23 as a vulnerability of senescent cancer cells. Suppressing SLC25A23 disrupts cellular calcium homeostasis, impairs oxidative phosphorylation and interferes with redox signaling, leading to death of senescent cells. These effects can be replicated by salinomycin, a cation ionophore antibiotic. Salinomycin prompts a PANoptosis-like cell death in senescent cells, including apoptosis and two forms of immunogenic cell death: necroptosis and pyroptosis. Notably, we observed that salinomycin treatment or SLC25A23 suppression elevates reactive oxygen species, upregulating death receptor 5 via JNK pathway activation. We show that a combination of a DR5 agonistic antibody and salinomycin is a robust senolytic cocktail. We provide evidence that this drug combination provokes a potent NK and CD8+ T cell mediated immune destruction of senescent cancer cells, mediated by the pyroptotic cytokine IL18.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210493","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 : 2024-09-06DOI: 10.1101/2024.09.05.611431
Jimin Tan, Hortense Le, Jiehui Deng, Yingzhuo Liu, Yuan Hao, Michelle Hollenberg, Wenke Liu, Joshua M Wang, Bo Xia, Sitharam Ramaswami, Valeria Mezzano, Cynthia Loomis, Nina Murrell, Andre L Moreira, Kyunghyun Cho, Harvey I Pass, Kwok-Kin Wong, Yi Ban, Benjamin G Neel, Aristotelis Tsirigos, David Fenyo
The interaction between tumors and their microenvironment is complex and heterogeneous. Recent developments in high-dimensional multiplexed imaging have revealed the spatial organization of tumor tissues at the molecular level. However, the discovery and thorough characterization of the tumor microenvironment (TME) remains challenging due to the scale and complexity of the images. Here, we propose a self-supervised representation learning framework, CANVAS, that enables discovery of novel types of TMEs. CANVAS is a vision transformer that directly takes high-dimensional multiplexed images and is trained using self-supervised masked image modeling. In contrast to traditional spatial analysis approaches which rely on cell segmentations, CANVAS is segmentation-free, utilizes pixel-level information, and retains local morphology and biomarker distribution information. This approach allows the model to distinguish subtle morphological differences, leading to precise separation and characterization of distinct TME signatures. We applied CANVAS to a lung tumor dataset and identified and validated a monocytic signature that is associated with poor prognosis.
{"title":"Characterization of tumor heterogeneity through segmentation-free representation learning","authors":"Jimin Tan, Hortense Le, Jiehui Deng, Yingzhuo Liu, Yuan Hao, Michelle Hollenberg, Wenke Liu, Joshua M Wang, Bo Xia, Sitharam Ramaswami, Valeria Mezzano, Cynthia Loomis, Nina Murrell, Andre L Moreira, Kyunghyun Cho, Harvey I Pass, Kwok-Kin Wong, Yi Ban, Benjamin G Neel, Aristotelis Tsirigos, David Fenyo","doi":"10.1101/2024.09.05.611431","DOIUrl":"https://doi.org/10.1101/2024.09.05.611431","url":null,"abstract":"The interaction between tumors and their microenvironment is complex and heterogeneous. Recent developments in high-dimensional multiplexed imaging have revealed the spatial organization of tumor tissues at the molecular level. However, the discovery and thorough characterization of the tumor microenvironment (TME) remains challenging due to the scale and complexity of the images. Here, we propose a self-supervised representation learning framework, CANVAS, that enables discovery of novel types of TMEs. CANVAS is a vision transformer that directly takes high-dimensional multiplexed images and is trained using self-supervised masked image modeling. In contrast to traditional spatial analysis approaches which rely on cell segmentations, CANVAS is segmentation-free, utilizes pixel-level information, and retains local morphology and biomarker distribution information. This approach allows the model to distinguish subtle morphological differences, leading to precise separation and characterization of distinct TME signatures. We applied CANVAS to a lung tumor dataset and identified and validated a monocytic signature that is associated with poor prognosis.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210525","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 : 2024-09-06DOI: 10.1101/2024.09.03.611032
Rena Emond, Jeffrey West, Vince Grolmusz, Patrick Cosgrove, Aritro Nath, Alexander R. A. Anderson, Andrea H. Bild
Chemotherapy remains a commonly used and important treatment option for metastatic breast cancer. A majority of ER+ metastatic breast cancer patients ultimately develop resistance to chemotherapy, resulting in disease progression. We hypothesized that an "evolutionary double-bind", where treatment with one drug improves the response to a different agent, would improve the effectiveness and durability of responses to chemotherapy. This approach exploits vulnerabilities in acquired resistance mechanisms. Evolutionary models can be used in refractory cancer to identify alternative treatment strategies that capitalize on acquired vulnerabilities and resistance traits for improved outcomes. To develop and test these models, ER+ breast cancer cell lineages sensitive and resistant to chemotherapy are grown in spheroids with varied initial population frequencies to measure cross-sensitivity and efficacy of chemotherapy and add-on treatments such as disulfiram combination treatment. Different treatment schedules then assessed the best strategy for reducing the selection of resistant populations. We developed and parameterized a game-theoretic mathematical model from this in vitro experimental data, and used it to predict the existence of a double-bind where selection for resistance to chemotherapy induces sensitivity to disulfiram. The model predicts a dose-dependent re-sensitization (a double-bind) to chemotherapy for monotherapy disulfiram.
{"title":"A novel combination therapy for ER+ breast cancer suppresses drug resistance via an evolutionary double-bind","authors":"Rena Emond, Jeffrey West, Vince Grolmusz, Patrick Cosgrove, Aritro Nath, Alexander R. A. Anderson, Andrea H. Bild","doi":"10.1101/2024.09.03.611032","DOIUrl":"https://doi.org/10.1101/2024.09.03.611032","url":null,"abstract":"Chemotherapy remains a commonly used and important treatment option for metastatic breast cancer. A majority of ER+ metastatic breast cancer patients ultimately develop resistance to chemotherapy, resulting in disease progression. We hypothesized that an \"evolutionary double-bind\", where treatment with one drug improves the response to a different agent, would improve the effectiveness and durability of responses to chemotherapy. This approach exploits vulnerabilities in acquired resistance mechanisms. Evolutionary models can be used in refractory cancer to identify alternative treatment strategies that capitalize on acquired vulnerabilities and resistance traits for improved outcomes. To develop and test these models, ER+ breast cancer cell lineages sensitive and resistant to chemotherapy are grown in spheroids with varied initial population frequencies to measure cross-sensitivity and efficacy of chemotherapy and add-on treatments such as disulfiram combination treatment. Different treatment schedules then assessed the best strategy for reducing the selection of resistant populations. We developed and parameterized a game-theoretic mathematical model from this in vitro experimental data, and used it to predict the existence of a double-bind where selection for resistance to chemotherapy induces sensitivity to disulfiram. The model predicts a dose-dependent re-sensitization (a double-bind) to chemotherapy for monotherapy disulfiram.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210524","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 : 2024-09-06DOI: 10.1101/2024.09.05.611476
Maxime Janin
Diffuse intrinsic pontine glioma (DIPG) is a very aggressive brainstem tumor with poor survival and a lack of effective treatments. In this study, I observed the differential overexpression of the stress-related protein NAD(P)H Quinone Dehydrogenase 1 (NQO1) in some patient-derived DIPG cell lines and tumors. I sought to understand how this protein is regulated in DIPG and to investigate the therapeutic potential of the NQO1-bioactivatable drug Isobutyl-deoxynyboquinone (IB-DNQ). Interestingly, the study of the mutational profiles of the cell lines indicated that truncation of PPM1D correlated with NQO1 overexpression. From a functional standpoint, cellular models were utilized to unravel the link between PPM1D phosphatase and NQO1 expression in DIPG by dephosphorylating MDM2 serine 395, leading to NQO1 protein stabilization. From a therapeutic perspective, IB-DNQ treatment showed an NQO1-dependent growth inhibition sensitivity in vitro and induced an extended survival in vivo. Overall, my results reveal a new regulation of NQO1 at the protein level in PPM1D-mutated DIPG indicating a promising therapeutic approach.
{"title":"PPM1D truncation-associated overexpression of the stress-related protein NQO1 confers sensitivity to the bioactivatable drug IB-DNQ in diffuse intrinsic pontine glioma","authors":"Maxime Janin","doi":"10.1101/2024.09.05.611476","DOIUrl":"https://doi.org/10.1101/2024.09.05.611476","url":null,"abstract":"Diffuse intrinsic pontine glioma (DIPG) is a very aggressive brainstem tumor with poor survival and a lack of effective treatments. In this study, I observed the differential overexpression of the stress-related protein NAD(P)H Quinone Dehydrogenase 1 (NQO1) in some patient-derived DIPG cell lines and tumors. I sought to understand how this protein is regulated in DIPG and to investigate the therapeutic potential of the NQO1-bioactivatable drug Isobutyl-deoxynyboquinone (IB-DNQ). Interestingly, the study of the mutational profiles of the cell lines indicated that truncation of PPM1D correlated with NQO1 overexpression. From a functional standpoint, cellular models were utilized to unravel the link between PPM1D phosphatase and NQO1 expression in DIPG by dephosphorylating MDM2 serine 395, leading to NQO1 protein stabilization. From a therapeutic perspective, IB-DNQ treatment showed an NQO1-dependent growth inhibition sensitivity in vitro and induced an extended survival in vivo. Overall, my results reveal a new regulation of NQO1 at the protein level in PPM1D-mutated DIPG indicating a promising therapeutic approach.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"50 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210523","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 : 2024-09-06DOI: 10.1101/2024.09.05.611458
Susmita Ghosh, Fan Fan, Reid T Powell, Yong Park, Clifford C Stephan, Scott Kopetz, Lee Ellis, Rajat Bhattacharya
Background: KRAS is frequently mutated in the tumors of patients with metastatic colorectal cancer (mCRC) and thus represents a valid target for therapy. However, the strategies of targeting KRAS directly and targeting the downstream effector mitogen-activated protein kinase kinase (MEK) via monotherapies have shown limited efficacy. Thus, there is a strong need for novel, effective combination therapies to improve MEK-inhibitor efficacy in patients with KRAS-mutated mCRC. Objective: Our objective was to identify novel drug combinations that enhance MEK-inhibitor efficacy in patients with KRAS-mutated mCRC. Design: In this study, we performed unbiased high-throughput screening (HTS) to identify drugs that enhance the efficacy of MEK inhibitors in vitro, and we validated the efficacy of the drugs in vivo. Methods: HTS was performed using 3-dimensional CRC spheroids. Trametinib, the anchor drug, was probed with 2 clinically ready libraries of 252 drugs to identify effective drug combinations. The effects of the drug combinations on CRC cell proliferation and apoptosis were further validated using cell growth assays, flow cytometry, and biochemical assays. Proteomic and immunostaining studies were performed to determine the effects of the drugs on molecular signaling and cell division. The effects of the drug combinations were examined in vivo using CRC patient-derived xenografts. Results: HTS identified paclitaxel as being synergistic with trametinib. In vitro validation showed that, compared with monotherapies, this drug combination demonstrated strong inhibition of cell growth, reduced colony formation, and enhanced apoptosis in multiple KRAS-mutated CRC cell lines. Mechanistically, combining trametinib with paclitaxel led to alterations in signaling mediators that block cell cycle progression and increases in microtubule stability that resulted in significantly higher defects in the mitosis. Finally, the combination of trametinib with paclitaxel exhibited significant inhibition of tumor growth in several KRAS-mutant patient-derived xenograft mouse models. Conclusion: Our data provide evidence supporting clinical trials of trametinib with paclitaxel as a novel therapeutic option for patients with KRAS-mutated, metastatic CRC.
{"title":"Enhancing efficacy of the MEK inhibitor trametinib with paclitaxel in KRAS-mutated colorectal cancer","authors":"Susmita Ghosh, Fan Fan, Reid T Powell, Yong Park, Clifford C Stephan, Scott Kopetz, Lee Ellis, Rajat Bhattacharya","doi":"10.1101/2024.09.05.611458","DOIUrl":"https://doi.org/10.1101/2024.09.05.611458","url":null,"abstract":"Background: KRAS is frequently mutated in the tumors of patients with metastatic colorectal cancer (mCRC) and thus represents a valid target for therapy. However, the strategies of targeting KRAS directly and targeting the downstream effector mitogen-activated protein kinase kinase (MEK) via monotherapies have shown limited efficacy. Thus, there is a strong need for novel, effective combination therapies to improve MEK-inhibitor efficacy in patients with KRAS-mutated mCRC. Objective: Our objective was to identify novel drug combinations that enhance MEK-inhibitor efficacy in patients with KRAS-mutated mCRC. Design: In this study, we performed unbiased high-throughput screening (HTS) to identify drugs that enhance the efficacy of MEK inhibitors in vitro, and we validated the efficacy of the drugs in vivo. Methods: HTS was performed using 3-dimensional CRC spheroids. Trametinib, the anchor drug, was probed with 2 clinically ready libraries of 252 drugs to identify effective drug combinations. The effects of the drug combinations on CRC cell proliferation and apoptosis were further validated using cell growth assays, flow cytometry, and biochemical assays. Proteomic and immunostaining studies were performed to determine the effects of the drugs on molecular signaling and cell division. The effects of the drug combinations were examined in vivo using CRC patient-derived xenografts. Results: HTS identified paclitaxel as being synergistic with trametinib. In vitro validation showed that, compared with monotherapies, this drug combination demonstrated strong inhibition of cell growth, reduced colony formation, and enhanced apoptosis in multiple KRAS-mutated CRC cell lines. Mechanistically, combining trametinib with paclitaxel led to alterations in signaling mediators that block cell cycle progression and increases in microtubule stability that resulted in significantly higher defects in the mitosis. Finally, the combination of trametinib with paclitaxel exhibited significant inhibition of tumor growth in several KRAS-mutant patient-derived xenograft mouse models. Conclusion: Our data provide evidence supporting clinical trials of trametinib with paclitaxel as a novel therapeutic option for patients with KRAS-mutated, metastatic CRC.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210528","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 : 2024-09-06DOI: 10.1101/2024.08.30.610515
Ifeanyichukwu O Nwosu, Stephen R Piccolo
Background: Triple-negative breast cancers (TNBC) occur more frequently in African Americans and are associated with worse outcomes when compared to other subtypes of breast cancer. These cancers lack expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) and have limited treatment options. To shed light on mechanisms behind these differences and suggest novel treatments, we used a meta-analytic approach to identify gene expression differences in breast tumors for people with self-reported African or European ancestry; additionally, we compared gene expression levels based on ER, PR, HER2 and TNBC status. Methods: After gathering and standardizing gene expression data and metadata from 106 datasets (representing 27,000 samples), we identified genes that were expressed differently between these groups via random-effects meta-analyses. To evaluate the robustness of these gene lists, we devised a novel computational methodology that uses cross validation and classification. We also computed overlaps between the most significant genes and known signaling pathways. Results: Using a false discovery rate threshold of 0.05, we identified genes that are known to play a significant role in their respective breast cancer subtypes (e.g., ESR1 for ER status and ERBB2 for HER2 status), thus confirming the validity of our findings. We also discovered genes that have not been reported previously and may be new targets for breast cancer therapy. GATA3, CA12, TBC1D9, XBP1 and FOXA1 were among the most significant genes for ER, PR, and TNBC. However, none of these genes overlapped with HER2 status, supporting prior research that HER2 tumors are mechanistically different from endocrine breast cancers. The genes identified from the race meta-analysis-including DNAJC15, HLA-DPA1, STAP2, CEP68, MOGS-have not been associated previously with race-specific breast-cancer outcomes, highlighting a potential area of further research. Conclusions: We have carried out a large meta-analysis of breast cancer gene expression data, identifying novel genes that may serve as potential biomarkers for breast cancer in diverse populations. We have also developed a computational method that identifies gene sets small enough to be analyzed and explored in future studies. This method has the potential to be applied to other cancers.
{"title":"A Comprehensive Meta-Analysis of Breast Cancer Gene Expression","authors":"Ifeanyichukwu O Nwosu, Stephen R Piccolo","doi":"10.1101/2024.08.30.610515","DOIUrl":"https://doi.org/10.1101/2024.08.30.610515","url":null,"abstract":"Background: Triple-negative breast cancers (TNBC) occur more frequently in African Americans and are associated with worse outcomes when compared to other subtypes of breast cancer. These cancers lack expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) and have limited treatment options. To shed light on mechanisms behind these differences and suggest novel treatments, we used a meta-analytic approach to identify gene expression differences in breast tumors for people with self-reported African or European ancestry; additionally, we compared gene expression levels based on ER, PR, HER2 and TNBC status. Methods: After gathering and standardizing gene expression data and metadata from 106 datasets (representing 27,000 samples), we identified genes that were expressed differently between these groups via random-effects meta-analyses. To evaluate the robustness of these gene lists, we devised a novel computational methodology that uses cross validation and classification. We also computed overlaps between the most significant genes and known signaling pathways. Results: Using a false discovery rate threshold of 0.05, we identified genes that are known to play a significant role in their respective breast cancer subtypes (e.g., ESR1 for ER status and ERBB2 for HER2 status), thus confirming the validity of our findings. We also discovered genes that have not been reported previously and may be new targets for breast cancer therapy. GATA3, CA12, TBC1D9, XBP1 and FOXA1 were among the most significant genes for ER, PR, and TNBC. However, none of these genes overlapped with HER2 status, supporting prior research that HER2 tumors are mechanistically different from endocrine breast cancers. The genes identified from the race meta-analysis-including DNAJC15, HLA-DPA1, STAP2, CEP68, MOGS-have not been associated previously with race-specific breast-cancer outcomes, highlighting a potential area of further research. Conclusions: We have carried out a large meta-analysis of breast cancer gene expression data, identifying novel genes that may serve as potential biomarkers for breast cancer in diverse populations. We have also developed a computational method that identifies gene sets small enough to be analyzed and explored in future studies. This method has the potential to be applied to other cancers.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"64 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142210502","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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