Pub Date : 2025-02-01DOI: 10.1158/0008-5472.CAN-24-4442
Namgyu Lee, Dohoon Kim
During metastasis, cancer cells detach from the primary tumor, circulate through the bloodstream, and establish themselves at distant sites, facing increased levels of reactive oxygen species that act as significant barriers to metastatic progression. Adapting to and surviving in these high reactive oxygen species environments are thus crucial for successful metastasis. A recent study by Nease and colleagues identified FTSJ1 as the methyltransferase responsible for methylation of the U34 position wobble uridine modification of selenocysteine (Sec) tRNA. This methylation enables efficient Sec insertion, leading to increased translation of a subset of stress-responsive selenoproteins that combat the oxidative stress encountered during the metastatic process. This study establishes FTSJ1 as an essential redox regulator during metastasis through its role in enhancing Sec insertion efficiency and introduces a potential therapeutic strategy against metastasis.
{"title":"Adapt or Perish: Efficient Selenocysteine Insertion Is Critical for Metastasizing Cancer Cells.","authors":"Namgyu Lee, Dohoon Kim","doi":"10.1158/0008-5472.CAN-24-4442","DOIUrl":"10.1158/0008-5472.CAN-24-4442","url":null,"abstract":"<p><p>During metastasis, cancer cells detach from the primary tumor, circulate through the bloodstream, and establish themselves at distant sites, facing increased levels of reactive oxygen species that act as significant barriers to metastatic progression. Adapting to and surviving in these high reactive oxygen species environments are thus crucial for successful metastasis. A recent study by Nease and colleagues identified FTSJ1 as the methyltransferase responsible for methylation of the U34 position wobble uridine modification of selenocysteine (Sec) tRNA. This methylation enables efficient Sec insertion, leading to increased translation of a subset of stress-responsive selenoproteins that combat the oxidative stress encountered during the metastatic process. This study establishes FTSJ1 as an essential redox regulator during metastasis through its role in enhancing Sec insertion efficiency and introduces a potential therapeutic strategy against metastasis.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"410-412"},"PeriodicalIF":12.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1158/0008-5472.CAN-24-1609
Hazrat Bilal, Muhammad Nadeen Khan, Sabir Khan, Muhammad Shafiq, Wenjie Fang, Yuebin Zeng, Yangzhong Guo, Xiaohui Li, Bing Zhao, Qiao-Li Lv, Bin Xu
Fungal dysbiosis is increasingly recognized as a key factor in cancer, influencing tumor initiation, progression, and treatment outcomes. This review explores the role of fungi in carcinogenesis, with a focus on mechanisms such as immunomodulation, inflammation induction, tumor microenvironment remodeling, and interkingdom interactions. Fungal metabolites are involved in oncogenesis, and antifungals can interact with anticancer drugs, including eliciting potential adverse effects and influencing immune responses. Furthermore, mycobiota profiles have potential as diagnostic and prognostic biomarkers, emphasizing their clinical relevance. The interplay between fungi and cancer therapies can affect drug resistance, therapeutic efficacy, and risk of invasive fungal infections associated with targeted therapies. Finally, emerging strategies for modulating mycobiota in cancer care are promising approaches to improve patient outcomes.
{"title":"Fungal Influences on Cancer Initiation, Progression, and Response to Treatment.","authors":"Hazrat Bilal, Muhammad Nadeen Khan, Sabir Khan, Muhammad Shafiq, Wenjie Fang, Yuebin Zeng, Yangzhong Guo, Xiaohui Li, Bing Zhao, Qiao-Li Lv, Bin Xu","doi":"10.1158/0008-5472.CAN-24-1609","DOIUrl":"10.1158/0008-5472.CAN-24-1609","url":null,"abstract":"<p><p>Fungal dysbiosis is increasingly recognized as a key factor in cancer, influencing tumor initiation, progression, and treatment outcomes. This review explores the role of fungi in carcinogenesis, with a focus on mechanisms such as immunomodulation, inflammation induction, tumor microenvironment remodeling, and interkingdom interactions. Fungal metabolites are involved in oncogenesis, and antifungals can interact with anticancer drugs, including eliciting potential adverse effects and influencing immune responses. Furthermore, mycobiota profiles have potential as diagnostic and prognostic biomarkers, emphasizing their clinical relevance. The interplay between fungi and cancer therapies can affect drug resistance, therapeutic efficacy, and risk of invasive fungal infections associated with targeted therapies. Finally, emerging strategies for modulating mycobiota in cancer care are promising approaches to improve patient outcomes.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"413-423"},"PeriodicalIF":12.5,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1158/0008-5472.can-24-0775
Florencia P. Madorsky Rowdo, Rachel Martini, Sarah E. Ackermann, Colin P. Tang, Marvel Tranquille, Adriana Irizarry, Ilkay Us, Omar Alawa, Jenna E. Moyer, Michael Sigouros, John Nguyen, Majd Al Assaad, Esther Cheng, Paula S. Ginter, Jyothi Manohar, Brian Stonaker, Richard Boateng, Joseph K. Oppong, Ernest K. Adjei, Baffour Awuah, Ishmael Kyei, Francis S. Aitpillah, Michael O. Adinku, Kwasi Ankomah, Ernest B. Osei-Bonsu, Kofi K. Gyan, Syed Hoda, Lisa Newman, Juan Miguel Mosquera, Andrea Sboner, Olivier Elemento, Lukas E. Dow, Melissa B. Davis, M. Laura Martin
Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapeutic strategies. Yet, some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. In underrepresented populations, the mutational landscape and determinants of response to existing therapies are poorly characterized because of limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture under nonphysiologic conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in three-dimensionally grown patient-derived tumor organoid (PDTO) models. A breast cancer PDTO biobank that focused on underrepresented populations, including West African patients, was established and used to conduct a negative-selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. The screen identified several previously unidentified kinase targets, and the combination of FGFR1 and EGFR inhibitors synergized to block organoid proliferation. Together, these data demonstrate the feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from underrepresented patients with cancer, and identify targets for cancer therapy. Significance: Generation of a breast cancer patient-derived tumor organoid biobank focused on underrepresented populations enabled kinome-focused CRISPR screening that identified essential kinases and potential targets for combination therapy with EGFR or MEK inhibitors. See related commentary by Trembath and Spanheimer, p. 407
{"title":"Kinome-Focused CRISPR-Cas9 Screens in African Ancestry Patient-Derived Breast Cancer Organoids Identify Essential Kinases and Synergy of EGFR and FGFR1 Inhibition","authors":"Florencia P. Madorsky Rowdo, Rachel Martini, Sarah E. Ackermann, Colin P. Tang, Marvel Tranquille, Adriana Irizarry, Ilkay Us, Omar Alawa, Jenna E. Moyer, Michael Sigouros, John Nguyen, Majd Al Assaad, Esther Cheng, Paula S. Ginter, Jyothi Manohar, Brian Stonaker, Richard Boateng, Joseph K. Oppong, Ernest K. Adjei, Baffour Awuah, Ishmael Kyei, Francis S. Aitpillah, Michael O. Adinku, Kwasi Ankomah, Ernest B. Osei-Bonsu, Kofi K. Gyan, Syed Hoda, Lisa Newman, Juan Miguel Mosquera, Andrea Sboner, Olivier Elemento, Lukas E. Dow, Melissa B. Davis, M. Laura Martin","doi":"10.1158/0008-5472.can-24-0775","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0775","url":null,"abstract":"Precision medicine approaches to cancer treatment aim to exploit genomic alterations that are specific to individual patients to tailor therapeutic strategies. Yet, some targetable genes and pathways are essential for tumor cell viability even in the absence of direct genomic alterations. In underrepresented populations, the mutational landscape and determinants of response to existing therapies are poorly characterized because of limited inclusion in clinical trials and studies. One way to reveal tumor essential genes is with genetic screens. Most screens are conducted on cell lines that bear little resemblance to patient tumors, after years of culture under nonphysiologic conditions. To address this problem, we aimed to develop a CRISPR screening pipeline in three-dimensionally grown patient-derived tumor organoid (PDTO) models. A breast cancer PDTO biobank that focused on underrepresented populations, including West African patients, was established and used to conduct a negative-selection kinome-focused CRISPR screen to identify kinases essential for organoid growth and potential targets for combination therapy with EGFR or MEK inhibitors. The screen identified several previously unidentified kinase targets, and the combination of FGFR1 and EGFR inhibitors synergized to block organoid proliferation. Together, these data demonstrate the feasibility of CRISPR-based genetic screens in patient-derived tumor models, including PDTOs from underrepresented patients with cancer, and identify targets for cancer therapy. Significance: Generation of a breast cancer patient-derived tumor organoid biobank focused on underrepresented populations enabled kinome-focused CRISPR screening that identified essential kinases and potential targets for combination therapy with EGFR or MEK inhibitors. See related commentary by Trembath and Spanheimer, p. 407","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"17 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143072483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-31DOI: 10.1158/0008-5472.CAN-24-1954
Michael J Buckenmeyer, Elizabeth A Brooks, Madison S Taylor, Ireolu K Orenuga, Liping Yang, Ronald J Holewinski, Thomas J Meyer, Melissa Galloux, Marcial Garmendia-Cedillos, Thomas J Pohida, Thorkell Andresson, Brad St Croix, Matthew T Wolf
Three-dimensional (3D) in vitro cell culture models are invaluable tools for investigating the tumor microenvironment (TME). However, analyzing the impact of critical stromal elements, such as extracellular matrix (ECM), remains a challenge. Here, we developed a hydrogel-free self-assembly platform to establish ECM-rich 3D "MatriSpheres" to deconvolute cancer cell-ECM interactions. Mouse and human colorectal cancer (CRC) MatriSpheres actively incorporated microgram quantities of decellularized small intestine submucosa ECM, which proteomically-mimicked CRC tumor ECM compared to traditional formulations like Matrigel. Solubilized ECM, at sub-gelation concentrations, was organized by CRC cells into intercellular stroma-like regions within 5 days, displaying morphological similarity to CRC clinical pathology. MatriSpheres featured ECM-dependent transcriptional and cytokine profiles associated with malignancy, lipid metabolism, and immunoregulation. Model benchmarking with scRNA sequencing demonstrated that MatriSpheres enhanced correlation with in vivo tumor cells over traditional ECM-poor spheroids. This facile approach enables tumor-specific tissue morphogenesis, promoting cell-ECM communication to improve fidelity for disease modeling applications.
{"title":"A 3D Self-Assembly Platform Integrating Decellularized Matrix Recapitulates In Vivo Tumor Phenotypes and Heterogeneity.","authors":"Michael J Buckenmeyer, Elizabeth A Brooks, Madison S Taylor, Ireolu K Orenuga, Liping Yang, Ronald J Holewinski, Thomas J Meyer, Melissa Galloux, Marcial Garmendia-Cedillos, Thomas J Pohida, Thorkell Andresson, Brad St Croix, Matthew T Wolf","doi":"10.1158/0008-5472.CAN-24-1954","DOIUrl":"10.1158/0008-5472.CAN-24-1954","url":null,"abstract":"<p><p>Three-dimensional (3D) in vitro cell culture models are invaluable tools for investigating the tumor microenvironment (TME). However, analyzing the impact of critical stromal elements, such as extracellular matrix (ECM), remains a challenge. Here, we developed a hydrogel-free self-assembly platform to establish ECM-rich 3D \"MatriSpheres\" to deconvolute cancer cell-ECM interactions. Mouse and human colorectal cancer (CRC) MatriSpheres actively incorporated microgram quantities of decellularized small intestine submucosa ECM, which proteomically-mimicked CRC tumor ECM compared to traditional formulations like Matrigel. Solubilized ECM, at sub-gelation concentrations, was organized by CRC cells into intercellular stroma-like regions within 5 days, displaying morphological similarity to CRC clinical pathology. MatriSpheres featured ECM-dependent transcriptional and cytokine profiles associated with malignancy, lipid metabolism, and immunoregulation. Model benchmarking with scRNA sequencing demonstrated that MatriSpheres enhanced correlation with in vivo tumor cells over traditional ECM-poor spheroids. This facile approach enables tumor-specific tissue morphogenesis, promoting cell-ECM communication to improve fidelity for disease modeling applications.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":""},"PeriodicalIF":12.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-29DOI: 10.1158/0008-5472.can-24-1788
Sarah C. Van Alsten, Michael I. Love, Benjamin C. Calhoun, Eboneé N. Butler, Charles M. Perou, Katherine A. Hoadley, Melissa A. Troester
Cancer genomics consortia have identified somatic drivers of breast cancer subtypes. However, these studies have predominantly included older, non-Black women, and the related socioeconomic status (SES) data is limited. Increased representation and depth of social data are crucial for understanding how health inequity is intertwined with somatic landscapes. Here, we conducted targeted sequencing on primary tumors from the Carolina Breast Cancer Study (N = 357; 52% Black, 47% <50) and compared the results to The Cancer Genome Atlas (N = 948; 18% Black, 27% <50). Race (Black vs. non-Black), age, and SES were evaluated in association with mutations, copy number alterations, and aneuploidy using generalized linear models. Pathway dysfunction was also assessed by aggregating mutation and copy number alterations. Adjusting for age, Black participants (N =350) were significantly more likely to have TP53 and FAT1 mutations and less likely to have PIK3CA, CDH1, DDR2, and GATA3 mutations than non-Black participants. Younger participants had more GATA3 alterations and fewer KMT2C, PTEN, MAP3K1 and CDH1 alterations. Black participants had significant enrichment for MYC (8q) and PIK3CA (3q26) amplifications and higher total aneuploidy, but age was not associated with copy number variation. SES was associated with different patterns of alteration in Black versus non-Black women. Overall, Black participants showed modest differences in TP53, PIK3CA, and other alterations that further varied by SES. Race is a social construct, and varying distributions of etiologic factors across social strata may predispose Black, young, and low SES women to cancer subtypes characterized by these alterations.
{"title":"Genomic Analysis Reveals Racial and Age-Related Differences in the Somatic Landscape of Breast Cancer and the Association with Socioeconomic Factors","authors":"Sarah C. Van Alsten, Michael I. Love, Benjamin C. Calhoun, Eboneé N. Butler, Charles M. Perou, Katherine A. Hoadley, Melissa A. Troester","doi":"10.1158/0008-5472.can-24-1788","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1788","url":null,"abstract":"Cancer genomics consortia have identified somatic drivers of breast cancer subtypes. However, these studies have predominantly included older, non-Black women, and the related socioeconomic status (SES) data is limited. Increased representation and depth of social data are crucial for understanding how health inequity is intertwined with somatic landscapes. Here, we conducted targeted sequencing on primary tumors from the Carolina Breast Cancer Study (N = 357; 52% Black, 47% &lt;50) and compared the results to The Cancer Genome Atlas (N = 948; 18% Black, 27% &lt;50). Race (Black vs. non-Black), age, and SES were evaluated in association with mutations, copy number alterations, and aneuploidy using generalized linear models. Pathway dysfunction was also assessed by aggregating mutation and copy number alterations. Adjusting for age, Black participants (N =350) were significantly more likely to have TP53 and FAT1 mutations and less likely to have PIK3CA, CDH1, DDR2, and GATA3 mutations than non-Black participants. Younger participants had more GATA3 alterations and fewer KMT2C, PTEN, MAP3K1 and CDH1 alterations. Black participants had significant enrichment for MYC (8q) and PIK3CA (3q26) amplifications and higher total aneuploidy, but age was not associated with copy number variation. SES was associated with different patterns of alteration in Black versus non-Black women. Overall, Black participants showed modest differences in TP53, PIK3CA, and other alterations that further varied by SES. Race is a social construct, and varying distributions of etiologic factors across social strata may predispose Black, young, and low SES women to cancer subtypes characterized by these alterations.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"45 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-29DOI: 10.1158/0008-5472.can-24-2464
Dingchang Li, Xianqiang Liu, Wenxing Gao, Wen Zhao, Shuaifei Ji, Sizhe Wang, Jinran Yang, Dingling Li, Zhengyao Chang, Yi Chen, Xu Sun, Jingcheng Zhou, Yanan Jiao, Xiaohui Du, Guanglong Dong
Colorectal cancer (CRC) is the second leading cause of cancer-related mortality globally. While immunotherapeutic approaches are effective in a subset of CRC patients, the majority of CRC cases receive limited benefits from immunotherapy. This study developed an immune subtype classification system based on diverse immune cells and pathways. A model constructed through machine learning based on immune subtypes could accurately predict the sensitivity of CRC patients to immunotherapy. Validation of this model across public datasets and clinical samples confirmed its high precision and reliability. Furthermore, drug screening based on the immune subtypes identified the IGF1R inhibitor I-OMe-AG-538 (AG-538) as a potent enhancer of antitumor immunity. Mechanistic investigations revealed that AG-538 induced reactive oxygen species (ROS)-dependent DNA damage and downregulated the expression of multiple repair genes, triggering cGAS/STING-mediated type I IFN signaling within tumor cells. This signaling cascade increased tumor immunogenicity and refined the tumor immune microenvironment, thereby enhancing efficacy of immune checkpoint blockade treatment. In summary, these findings present a predictive model for immune response and highlight the potential of AG-538 combined with anti-PD1 antibodies as a chemoimmunotherapeutic strategy.
{"title":"An Immune Subtype Classification System Enables the Development of Strategies to Predict and Enhance Immunotherapy Responses in Colorectal Cancer","authors":"Dingchang Li, Xianqiang Liu, Wenxing Gao, Wen Zhao, Shuaifei Ji, Sizhe Wang, Jinran Yang, Dingling Li, Zhengyao Chang, Yi Chen, Xu Sun, Jingcheng Zhou, Yanan Jiao, Xiaohui Du, Guanglong Dong","doi":"10.1158/0008-5472.can-24-2464","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2464","url":null,"abstract":"Colorectal cancer (CRC) is the second leading cause of cancer-related mortality globally. While immunotherapeutic approaches are effective in a subset of CRC patients, the majority of CRC cases receive limited benefits from immunotherapy. This study developed an immune subtype classification system based on diverse immune cells and pathways. A model constructed through machine learning based on immune subtypes could accurately predict the sensitivity of CRC patients to immunotherapy. Validation of this model across public datasets and clinical samples confirmed its high precision and reliability. Furthermore, drug screening based on the immune subtypes identified the IGF1R inhibitor I-OMe-AG-538 (AG-538) as a potent enhancer of antitumor immunity. Mechanistic investigations revealed that AG-538 induced reactive oxygen species (ROS)-dependent DNA damage and downregulated the expression of multiple repair genes, triggering cGAS/STING-mediated type I IFN signaling within tumor cells. This signaling cascade increased tumor immunogenicity and refined the tumor immune microenvironment, thereby enhancing efficacy of immune checkpoint blockade treatment. In summary, these findings present a predictive model for immune response and highlight the potential of AG-538 combined with anti-PD1 antibodies as a chemoimmunotherapeutic strategy.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"16 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-29DOI: 10.1158/0008-5472.can-25-0335
Pranay Dey, Cathrin Brisken
A recent publication by Bornes and colleagues explored the impact of the estrous cycle on mammary tumor response to neoadjuvant chemotherapy (NAC). Using genetically engineered mouse models, Bornes and colleagues revealed that chemotherapy is less effective when initiated during the diestrus stage compared to during the estrus stage. A number of changes during diestrous were identified that may reduce chemosensitivity of mammary tumors: an increased mesenchymal state of breast cancer cells during diestrous, decreased blood vessel diameters, and higher numbers of macrophages in the tumor microenvironment. Macrophage depletion was sufficient to mitigate this resistance. To translate these findings to humans, retrospective analyses of premenopausal breast cancer patients were conducted. Serum progesterone levels served to determine the menstrual cycle phases, which revealed that treatment efficacy is reduced in women receiving NAC during the luteal (progesterone-high) phase compared to those treated during the follicular (progesterone-low) phase. The findings show that physiological hormone fluctuations may influence chemosensitivity through tumor cell-extrinsic mechanisms with the important implication that aligning treatment initiation with the menstrual cycle improves therapeutic outcomes and that consideration of systemic factors may improve therapy outcome.
{"title":"Breaking the Rhythm: Harnessing the Menstrual Cycle for Better Chemotherapy.","authors":"Pranay Dey, Cathrin Brisken","doi":"10.1158/0008-5472.can-25-0335","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0335","url":null,"abstract":"A recent publication by Bornes and colleagues explored the impact of the estrous cycle on mammary tumor response to neoadjuvant chemotherapy (NAC). Using genetically engineered mouse models, Bornes and colleagues revealed that chemotherapy is less effective when initiated during the diestrus stage compared to during the estrus stage. A number of changes during diestrous were identified that may reduce chemosensitivity of mammary tumors: an increased mesenchymal state of breast cancer cells during diestrous, decreased blood vessel diameters, and higher numbers of macrophages in the tumor microenvironment. Macrophage depletion was sufficient to mitigate this resistance. To translate these findings to humans, retrospective analyses of premenopausal breast cancer patients were conducted. Serum progesterone levels served to determine the menstrual cycle phases, which revealed that treatment efficacy is reduced in women receiving NAC during the luteal (progesterone-high) phase compared to those treated during the follicular (progesterone-low) phase. The findings show that physiological hormone fluctuations may influence chemosensitivity through tumor cell-extrinsic mechanisms with the important implication that aligning treatment initiation with the menstrual cycle improves therapeutic outcomes and that consideration of systemic factors may improve therapy outcome.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"27 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-29DOI: 10.1158/0008-5472.can-24-1404
Imene Tabet, Esin Orhan, Ermes Candiello, Lise Fenou, Carolina Velázquez, Beatrice Orsetti, Geneviéve Rodier, William Jacot, Cyril Ribeyre, Claude Sardet, Charles Theillet
BRCA1 deficiency is observed in approximately 25% of triple-negative breast cancer (TNBC). BRCA1, a key player of homologous recombination (HR) repair, is also involved in stalled DNA replication fork protection and repair. Here, we investigated the sensitivity of BRCA1-deficient TNBC models to the frequently used replication chain terminator gemcitabine, which does not directly induce DNA breaks. A large fraction of BRCA1-deficient cells was sensitive to gemcitabine, in contrast to their isogenic BRCA1-proficient counterparts. Gemcitabine treated BRCA1-deficient cells accumulated massive levels of single strand DNA (ssDNA) and presented no RPA or RAD51 nuclear foci. The gemcitabine-induced accumulation of ssDNA in BRCA1-deficient cells was strongly diminished by targeting MRE11 with inhibitors and by siRNA attenuation. In contrast, treatment with the PARP1/2 inhibitor olaparib did not result in MRE11 dependent over-resection. Furthermore, a fraction of gemcitabine treated BRCA1-deficient cells that showed massive ssDNA accumulation slipped into mitosis, producing mitotic bridges and strongly stained BrdU and γH2AX micronuclei (MN). The BrdU-positive MN and DNA bridges also stained positively for cGAS. In conclusion, these data suggest that gemcitabine treatment in BRCA1-deficient TNBC exposes unprotected nascent DNA linked to replication fork reversal, which leads to MRE11 over-resection and ssDNA accumulation. Therefore, the observed hypersensitivity to gemcitabine indicates that it could be a beneficial addition to BRCA1-deficient TNBC treatment.
{"title":"Replication-Poison Treatment in BRCA1-Deficient Breast Cancer Causes MRE11 Over-Resection that Induces Single-Stranded DNA Accumulation and Mitotic Catastrophe","authors":"Imene Tabet, Esin Orhan, Ermes Candiello, Lise Fenou, Carolina Velázquez, Beatrice Orsetti, Geneviéve Rodier, William Jacot, Cyril Ribeyre, Claude Sardet, Charles Theillet","doi":"10.1158/0008-5472.can-24-1404","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1404","url":null,"abstract":"BRCA1 deficiency is observed in approximately 25% of triple-negative breast cancer (TNBC). BRCA1, a key player of homologous recombination (HR) repair, is also involved in stalled DNA replication fork protection and repair. Here, we investigated the sensitivity of BRCA1-deficient TNBC models to the frequently used replication chain terminator gemcitabine, which does not directly induce DNA breaks. A large fraction of BRCA1-deficient cells was sensitive to gemcitabine, in contrast to their isogenic BRCA1-proficient counterparts. Gemcitabine treated BRCA1-deficient cells accumulated massive levels of single strand DNA (ssDNA) and presented no RPA or RAD51 nuclear foci. The gemcitabine-induced accumulation of ssDNA in BRCA1-deficient cells was strongly diminished by targeting MRE11 with inhibitors and by siRNA attenuation. In contrast, treatment with the PARP1/2 inhibitor olaparib did not result in MRE11 dependent over-resection. Furthermore, a fraction of gemcitabine treated BRCA1-deficient cells that showed massive ssDNA accumulation slipped into mitosis, producing mitotic bridges and strongly stained BrdU and γH2AX micronuclei (MN). The BrdU-positive MN and DNA bridges also stained positively for cGAS. In conclusion, these data suggest that gemcitabine treatment in BRCA1-deficient TNBC exposes unprotected nascent DNA linked to replication fork reversal, which leads to MRE11 over-resection and ssDNA accumulation. Therefore, the observed hypersensitivity to gemcitabine indicates that it could be a beneficial addition to BRCA1-deficient TNBC treatment.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"59 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056486","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-29DOI: 10.1158/0008-5472.can-25-0357
Xiaolei Su
Biomolecular condensation has emerged as a general principle in organizing biological processes, including immune response. Xu and colleagues recently reported that the cytoplasmic tail of the CD3ɛ subunit of TCR complex, when fused to CAR, can promote CAR condensation by liquid-liquid phase separation. Through sequence engineering, the authors identified modified CD3ɛ sequences that enhance the maturation of the immunological synapse and co-receptor signaling, leading to an improvement of cytotoxicity in vitro and anti-tumor effects in mouse xenograft models. These results demonstrated that biomolecular condensation could be exploited to improve the function of CAR-T cells, highlighting an exciting strategy for developing next-generation cell therapies.
{"title":"CAR-T entering a new “phase”: Improving CAR-T function by harnessing phase separation","authors":"Xiaolei Su","doi":"10.1158/0008-5472.can-25-0357","DOIUrl":"https://doi.org/10.1158/0008-5472.can-25-0357","url":null,"abstract":"Biomolecular condensation has emerged as a general principle in organizing biological processes, including immune response. Xu and colleagues recently reported that the cytoplasmic tail of the CD3ɛ subunit of TCR complex, when fused to CAR, can promote CAR condensation by liquid-liquid phase separation. Through sequence engineering, the authors identified modified CD3ɛ sequences that enhance the maturation of the immunological synapse and co-receptor signaling, leading to an improvement of cytotoxicity in vitro and anti-tumor effects in mouse xenograft models. These results demonstrated that biomolecular condensation could be exploited to improve the function of CAR-T cells, highlighting an exciting strategy for developing next-generation cell therapies.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"69 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-24DOI: 10.1158/0008-5472.can-24-2563
Ziwei Guo, Junran Huang, Zhi J. Lu, Yongsheng Shi, Charles J. David, Mo Chen
Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and lacks effective therapeutic options. Cancer cells frequently become more dependent on splicing factors than normal cells due to increased rates of transcription. Terminal uridylyltransferase 1 (TUT1) is a specific terminal uridylyltransferase for U6 small nuclear RNA (snRNA), which plays a catalytic role in the spliceosome. Here, we found that TUT1 was required for the survival of PDAC cells but not for normal pancreatic cells. In PDAC cells, the uridylylation activity of TUT1 promoted tri-snRNP assembly by facilitating the binding of LSM proteins to U6 snRNA and subsequent tri-snRNP assembly. PDAC cells required higher amounts of tri-snRNP to efficiently splice pre-mRNA with weak splice sites to support the high transcriptional output. Depletion of TUT1 in PDAC cells resulted in inefficient splicing of exons in a group of highly expressed RNAs containing weak splice sites, thereby resulting in the collapse of an mRNA processing circuit and consequently dysregulating splicing required by PDAC cells. Overall, this study unveiled an interesting function of TUT1 in regulating splicing by modulating tri-snRNP levels and demonstrated a distinct mechanism underlying splicing addiction in pancreatic cancer cells.
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