IU Indianapolis ScholarWorks :: Browsing by Subject "Cancer"

Browsing by Subject "Cancer"

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26. The Role of Macrophages In Mediating Radiation-induced Fibrosis
(Wolters Kluwer, 2024-04-19) Vallabhapurapu, Subrahmanya D.; Pokhrel, Sabita; Granicz, Barbara; Flores Garcia, Jorge; La Ferlita, Alessandro; Beane, Joal; Kim, Alex; Sorkin, Michael; Medicine, School of Medicine
Purpose: Radiation-induced fibrosis (RIF) remains a clinically challenging problem in cancer patients without effective treatment or prevention. To elucidate the mechanisms of RIF, we investigated the role of macrophages as mediators of fibrosis, and the reciprocal signaling that occurs between macrophages and fibroblasts. Methods: Bone marrow-derived macrophages and dermal fibroblasts were isolated from C57BL/6 mice. Cells were co-cultured in a three-dimensional collagen gel system and subjected to radiation. Gel contracture was measured over time. Flow cytometry was utilized to analyze macrophage polarization towards inflammatory and anti-inflammatory phenotypes using cell surface markers such as CD38 and CD206, respectively. Macrophages from both radiated and non-radiated co-cultures were subjected to RNA sequencing to investigate radiation induced phenotypic and functional changes. Results: Co-culturing fibroblasts and macrophages led to pronounced collagen gel contraction compared to fibroblasts alone, highlighting the essential role of macrophages. In addition, radiated macrophages had a significantly increased effect on gel contracture compared to non-radiated controls indicating a changed phenotype promoting contraction. Since macrophage involvement was found to be critical for radiation-induced functional alteration in collagen gels, we investigated macrophage phenotypes in response to radiation. Flow cytometry analysis revealed that radiation-induced alternate activation (M2) of macrophages, as shown by increased CD206 expression. Similarly, RNA sequencing data showed increased expression of interferon response genes such as Ifi206 and chemokines including c-c motif chemokine ligand 7 (ccl7) suggesting a distinct inflammatory response to radiation. Furthermore, we analyzed the impact of radiation on macrophage plasticity. Interestingly, when macrophages were polarized to M2 phenotype and then radiated, their potential to repolarize to M1 was lost, as opposed to non-radiated macrophages suggesting potential loss of macrophage plasticity during radiation. Conclusion: Our study highlights the crucial role of macrophages in early RIF and their potential as a therapeutic target to mitigate the negative side effects of radiation therapy. We observed that radiation exposure induces an M2 phenotype, upregulates interferon response genes in macrophages, and impairs plasticity. These findings suggest that radiation may contribute to the pro-fibrotic environment by activating macrophages in a physiologically distinct manner. Our study offers insights into the underlying mechanisms of RIF and the role of macrophages in this process.
A Cross-Sectional Analysis of Testicular Cancer Symptom Recognition and Stage of Diagnosis
(Sage, 2022) Rovito, Michael J.; Craycraft, Mike; Adams, Wesley B.; Maresca, Michael; Saab, Mohamad M.; Cary, Clint; Gooljar, Chayna; Martinez, Sydney; Zanet, Rama Abu; Urology, School of Medicine
There is a need to further explore the relationship between atypical symptom reporting and stage diagnosis to help develop a clearer defined list of possible testicular cancer (TC) symptoms that could assist physicians diagnose the disease earlier. A cross-sectional study was employed to explore possible associations between TC symptom presentation and stage of diagnosis. An original 40-item survey was distributed among 698 TC survivors to determine the potential impact of several risk factors, experiences, and behaviors upon diagnosis. This analysis aimed to explore how certain patient-driven experiences (e.g., symptoms, perceptions, and behaviors) could serve as catalysts for seeking medical care for testicular health concerns. Experiencing hot flashes or having no symptoms had a positive association with later-stage diagnosis while change in shape had a significant negative association with later-stage diagnosis. While the logistic regression model explained relatively low variance in the data (R2 = .1415), it was statistically significant (χ2p < .001). Pain (odds ratio [OR] = 1.6524, p < .05), hot flashes (OR = 5.7893, p < .01), and no symptoms experienced (OR = 12.4836, p < .01) were all significant predictors of a more advanced stage diagnosis. The concern around uncommon/atypical symptoms are that they are indistinct and do not serve as clear signs that TC is present. However, perhaps in tandem with other more overt symptoms, their discovery can serve in a more confirmatory role for a suspect case. If observed with other uncommonly reported symptoms, these uncommon symptoms could provide another pathway in the TC diagnostic process. Clinical and patient education is warranted to increase awareness of uncommon TC symptoms.
A Mechanistic Approach to Identify Novel Therapeutic Drugs for Targeting FA-Disrupted Malignancies
(2023-07) Sheth, Aditya Sukumar; Clapp, D. Wade; Vance, Gail; Angus, Steve; Herbert, Brittney-Shea
The Fanconi anemia (FA) signaling network plays a critical role in maintaining genomic integrity during interphase and mitosis. Biallelic germline mutation of any of the 22 genes that constitute this pathway (FANCA-FANCW) results in Fanconi Anemia, a cancer predisposition syndrome characterized by congenital malformations, bone marrow failure, and pediatric acute myeloid leukemias (AMLs). Among the general population, acquired genetic disruptions of the FA pathway are found in 30% of all sporadic cancers and over 15% of sporadic pediatric AMLs underscoring the importance of this pathway in the prevention of malignant transformation. Therefore, the identification of precision therapies for FA-deficient AML is a critical need. The canonical tumor suppressive role of FA proteins in the repair of DNA damage during interphase is well established. We and others have uncovered the roles of FA proteins in mitotic regulation, suggesting additional mechanisms by which the FA pathway prevents genomic instability. Mutation of FANCA is the most common cause of FA and is one of the most frequently disrupted FA pathway genes in sporadic AML. To identify synthetic lethal targets of FANCA, we previously identified mitotic phospho-signaling pathways required for the survival of FANCA-/- patient-derived fibroblasts through a kinome-wide shRNA screen. We identified mitotic kinases CHEK1, PLK1, SLK, and TTK as potential targets, which suggests a mitosis-specific vulnerability of FA-deficient cells. These findings corroborate work by others who have identified synthetic lethal interactions between PLK1 and the FA pathway members, FANCG and BRCA1, suggesting that inactivation of the FA pathway may sensitize cancers to PLK1 inhibition. A more thorough understanding of FA pathway function in mitosis provides new insight into AML pathogenesis and suggests that genetic disruptions of the FA pathway may be predictive of sensitivity to PLK1 inhibition, providing a preclinical rationale for the development of precision therapies.
Acquisition, processing, and single-cell analysis of normal human breast tissues from a biobank
(Cell Press, 2021-12-16) Bhat-Nakshatri, Poornima; Marino, Natascia; Gao, Hongyu; Liu, Yunlong; Storniolo, Anna Maria; Nakshatri, Harikrishna; Surgery, School of Medicine
The Komen Tissue Bank is the only biorepository in the world for normal breast tissues from women. Below we report the acquisition and processing of breast tissue from volunteer donors and describe an experimental and analysis pipeline to generate a single-cell atlas. This atlas is based on single-cell RNA-seq and is useful to derive breast epithelial cell subcluster-specific gene expression signatures, which can be applied to breast cancer gene expression data to identify putative cell-of-origin. For complete details on the use and execution of this protocol, please refer to Bhat-Nakshatri et al. (2021).
Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer
(Elsevier, 2023-08-16) Ghobashi, Ahmed H.; Vuong, Truc T.; Kimani, Jane W.; Ladaika, Christopher A.; Hollenhorst, Peter C.; O’Hagan, Heather M.; Biochemistry and Molecular Biology, School of Medicine
Colorectal cancer (CRC) develops in part through the deregulation of different signaling pathways, including activation of the WNT/β-catenin and PI3K/AKT pathways. Additionally, the lysine methyltransferase enhancer of zeste homologue 2 (EZH2) is commonly overexpressed in CRC. EZH2 canonically represses gene transcription by trimethylating lysine 27 of histone H3, but also has non-histone substrates. Here, we demonstrated that in CRC, active AKT phosphorylated EZH2 on serine 21. Phosphorylation of EZH2 by AKT induced EZH2 to interact with and methylate β-catenin at lysine 49, which increased β-catenin’s binding to the chromatin. Additionally, EZH2-mediated β-catenin trimethylation induced β-catenin to interact with TCF1 and RNA polymerase II and resulted in dramatic gains in genomic regions with β-catenin occupancy. EZH2 catalytic inhibition decreased stemness but increased migratory phenotypes of CRC cells with active AKT. Overall, we demonstrated that EZH2 modulates AKT-induced changes in gene expression through the AKT/EZH2/β-catenin axis in CRC.
ADAR3 activates NF-κB signaling and promotes glioblastoma cell resistance to temozolomide
(Springer Nature, 2022-08-03) Kurup, Reshma Raghava; Oakes, Eimile K.; Vadlamani, Pranathi; Nwosu, Obi; Danthi, Pranav; Hundley, Heather A.; Medicine, School of Medicine
The RNA binding protein ADAR3 is expressed exclusively in the brain and reported to have elevated expression in tumors of patients suffering from glioblastoma compared to adjacent brain tissue. Yet, other studies have indicated that glioblastoma tumors exhibit hemizygous deletions of the genomic region encompassing ADAR3 (10p15.3). As the molecular and cellular consequences of altered ADAR3 expression are largely unknown, here we directly examined the impacts of elevated ADAR3 in a glioblastoma cell line model. Transcriptome-wide sequencing revealed 641 differentially expressed genes between control and ADAR3-expressing U87-MG glioblastoma cells. A vast majority of these genes belong to pathways involved in glioblastoma progression and are regulated by NF-κB signaling. Biochemical and molecular analysis indicated that ADAR3-expressing U87-MG cells exhibit increased NF-κB activation, and treatment with an NF-κB inhibitor abrogated the impacts of ADAR3 on gene expression. Similarly, we found that increased cell survival of ADAR3-expressing cells to temozolomide, the preferred chemotherapeutic for glioblastoma, was due to increased NF-κB activity. Aberrant constitutive NF-κB activation is a common event in glioblastoma and can impact both tumor progression and resistance to treatment. Our results suggest that elevated ADAR3 promotes NF-κB activation and a gene expression program that provides a growth advantage to glioblastoma cells.
Adding recombinant AAVs to the cancer therapeutics mix
(Elsevier, 2022-10-02) Mulcrone, Patrick L.; Herzog, Roland W.; Xiao, Weidong; Pediatrics, School of Medicine
Gene therapy is a powerful biological tool that is reshaping therapeutic landscapes for several diseases. Researchers are using both non-viral and viral-based gene therapy methods with success in the lab and the clinic. In the cancer biology field, gene therapies are expanding treatment options and the possibility of favorable outcomes for patients. While cellular immunotherapies and oncolytic virotherapies have paved the way in cancer treatments based on genetic engineering, recombinant adeno-associated virus (rAAV), a viral-based module, is also emerging as a potential cancer therapeutic through its malleability, specificity, and broad application to common as well as rare tumor types, tumor microenvironments, and metastatic disease. A wide range of AAV serotypes, promoters, and transgenes have been successful at reducing tumor growth and burden in preclinical studies, suggesting more groundbreaking advances using rAAVs in cancer are on the horizon.
Addressing unmet needs for people with cancer cachexia: recommendations from a multistakeholder workshop
(Wiley, 2022-04) Garcia, Jose M.; Dunne, Richard F.; Santiago, Kristen; Martin, Lisa; Birnbaum, Morris J.; Crawford, Jeffrey; Hendifar, Andrew E.; Kochanczyk, Martin; Moravek, Cassadie; Piccinin, Doris; Picozzi, Vincent; Roeland, Eric J.; Selig, Wendy K.D.; Zimmers, Teresa A.; Surgery, School of Medicine
Adolescent/Young Adult Perspectives of a Therapeutic Music Video Intervention to Improve Resilience During Hematopoietic Stem Cell Transplant for Cancer
(Oxford Academic, 2020-02) Haase, Joan E.; Robb, Sheri L.; Burns, Debra S.; Stegenga, Kristin; Cherven, Brooke; Hendricks-Ferguson, Verna; Roll, Lona; Docherty, Sharron L.; Phillips, Celeste; School of Nursing
This empirical phenomenology study reports adolescents/young adults (AYA) experiences of the therapeutic music video (TMV) intervention arm of a randomized controlled clinical trial (Children's Oncology Group; COG-ANUR0631; R01 NR008583) during hospitalization for a hematopoietic stem cell transplant. A purposive subsample of 14 AYA were interviewed using a broad open-ended data-generating question about their TMV intervention experiences. At the end of each interview, we also asked AYA for suggestions on how to improve the TMV. Analysis of the narrative data resulted in four theme categories: (a) An Interwoven Experience of the Transplant and TMV Intervention; (b) TMV as a Guided Opportunity for Reflection, Self-Expression, and Meaning-Making; (c) Telling My Story: The Work of Deriving Meaning; and (d) A Way to Overcome the Bad Side of Cancer. AYA suggestions for improving the TMV are also summarized. Findings provide insight into ways the TMV supports AYA efforts to overcome distress and challenges by providing opportunities to reflect on what is meaningful, connect with others, and explore/identify personal strengths. Findings also inform our understanding about how the TMV may have functioned (i.e., mechanisms of action) to bring about significant change in AYA self-reported outcomes (i.e., positive coping, social support, and family function) for this trial.
Alteration of tumor suppressors changes the endometrial tumor spectrum
(EMBO Press, 2023) Mayo, Lindsey D.; Pediatrics, School of Medicine
The most common gynecological cancer in Europe and the United States is endometrial. Like most cancers, early-stage endometrial cancer has a more favorable prognosis, while high-grade, including endometrioid and nonendometrioid, has the worst prognosis. In endometrioid human tumors, the tumor suppressor genes PTEN and p53 (Trp53) are frequently altered or lost, as identified in datasets from The Cancer Genome Atlas. These suppressors' somatic mutations or loss of gene expression can lead to neoplastic development, tumor progression, and therapeutic resistance. In addition, somatic missense mutations are prevalent in another tumor suppressor, the F-box and WD repeats containing 7 (FBXW7). FBXW7 is part of the SCF-βTrCP ubiquitin complex that signals protein destruction. Specifically, FBXW7 is responsible for binding and facilitating the destabilization of proteins involved in proliferation and migration. Losing the function of multiple tumor suppressors could activate pathways involved in neoplastic progression, malignancy, therapeutic resistance, and formation of different tumor subtypes. The study by Brown et al in this issue of EMBO Mol Med (Brown et al, 2023) provides insight into the complexity of tumor suppressor mutations in malignant endometrial cancer.

Browsing by Subject "Cancer"

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