Different Stages Of Tumor Progression Research Articles

Understanding the Role of Connexins in Hepatocellular Carcinoma: Molecular and Prognostic Implications.

Connexins, a family of tetraspan membrane proteins forming intercellular channels localized in gap junctions, play a pivotal role at the different stages of tumor progression presenting both pro- and anti-tumorigenic effects. Considering the potential role of connexins as tumor suppressors through multiple channel-independent mechanisms, their loss of expression may be associated with tumorigenic activity, while it is hypothesized that connexins favor the clonal expansion of tumor cells and promote cell migration, invasion, and proliferation, affecting metastasis and chemoresistance in some cases. Hepatocellular carcinoma (HCC), characterized by unfavorable prognosis and limited responsiveness to current therapeutic strategies, has been linked to gap junction proteins as tumorigenic factors with prognostic value. Notably, several members of connexins have emerged as promising markers for assessing the progression and aggressiveness of HCC, as well as the chemosensitivity and radiosensitivity of hepatocellular tumor cells. Our review sheds light on the multifaceted role of connexins in HCC pathogenesis, offering valuable insights on recent advances in determining their prognostic and therapeutic potential.

Abstract 86: Deep immuno-profiling of syngeneic tumor mouse models for preclinical studies

Abstract The identification of the major cellular players involved in the progression of a type of cancer is a key step for the success of new immunotherapies for personalized medicine. Immune cells play critical functions in cancer, and mice with intact immune systems are vital to understanding tumor immunology. It is however a daunting challenge as complex relationships interplay between tumor cells and the immune system. Each component of innate immunity or adaptive immunity, such as T lymphocytes, macrophages or neutrophils, may be directed to a pro- or anti-tumor function. In order to cope with the complexity of the tumor microenvironment, it is necessary to use an experimental approach capable of characterizing the heterogeneity of the cell types present in the tumor, the evolution of their relative proportion and their fine-tuned functional specificity. This approach leads to the identification of new cellular biomarkers of different stages of tumor progression in order to identify new targets for therapeutic time-window of and improve cancer diagnosis To decipher the impact of immunotherapy treatments involved in the anti-tumor response, cellular phenotyping of leukocytes infiltrating a tumor but also those present in peripheral organs is necessary. Essentially based on extracellular labeling, this primary screen aims to quantify the different cell populations present in a syngenic tumor models on B6/N or BalbC genetical backgrounds. In order to increase our understanding in the precise mode of action of anti-PD1 treatment at the cellular level in sensitive and unsensitive models, we investigated immunophenotypes and responses to immune checkpoint inhibitor (ICI) of several hallmark syngeneic tumor models (MC38, CT26, B16F10, B16-OVA, RENCA, EMT6) in immunocompetent mouse models by flow and mass cytometry. We compared growth kinetics and profiled the immune cell composition of tumor microenvironment (TME), draining lymph node (dLN) and blood in order to establish immune-phenotypic cell signatures that correlates with treatment efficacy. Supervised, unsupervised and integrative data analysis as well as visualization tools are used to identify significant changes across different experimental settings. Our results indicate that each model possesses a unique tumor-immune infiltrate profile that can be modulated with immunotherapies. Overall, these studies provide an important resource of highly-characterized syngeneic tumor model and highlight the importance of tumor immune landscape variance across models that will drive selecting the most appropriate model to test novel immunotherapeutic agents and enhance our translation of knowledge from syngeneic models to human tumors. Citation Format: Anais Joachim, Emilie Maturin, Marielle Mello, Lilia Hadjem, Magali Grange, Olivier Deas, Ana Zarubica, Bernard Malissen, Hervé Luche, François Romagne, Stéphanie Blanchin. Deep immuno-profiling of syngeneic tumor mouse models for preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 86.

Abstract 6812: Durable control of brain tumors by glioma inhibitory macrophages and IL33

Abstract Glioblastoma is the most common and deadly form of brain cancer. Even with aggressive treatment including surgery, chemotherapy, and radiotherapy, survival outcomes for newly diagnosed glioblastoma patients remains less than two years. Novel high throughput omics technologies have expanded our understanding of the role of innate immune system in brain tumors, that are generally believed to drive glioma progression and enable evasion of the adaptive immune system. However, targeting of this axis in the clinic remains an unmet opportunity. Previously, we discovered that the dual-function (secreted and nuclear) cytokine IL-33 is a crucial regulator of the inflammatory microenvironment that promotes glioma tumorigenesis through phenotypic and functional changes in the innate immune cell repertoire. Strikingly, when IL-33 is prevented from entering the nucleus, by deletion of its nuclear localization sequence (ΔNLS IL-33), but is still secreted, in vivo tumor growth is dramatically inhibited resulting in prolonged long-term survival. Using multiplex immunohistochemistry and spatial transcriptomics with temporal resolution across different stages of tumor progression, we identified a population of glioma-inhibitory macrophages (GIMs) unique to this suppressive environment. Assessment of GIMs in xenografts generated from patient brain tumor initiating cells found an enriched presence of these cells in xenografts with long-term survival (greater than 300 days) versus short-term survival (less than 100 days). The ability of GIMs to inhibit glioma progression was demonstrated when tumors established using a combination of ΔNLS IL-33 expressing cancer cells together with highly tumorigenic cells resulted in a growth inhibitory environment that significantly extended survival. A deeper molecular characterization of this phenotype and development of clinical strategies are currently underway. Citation Format: Shyam V. Menon, Xueqing Lun, Peipei Zeng, Jianbo Zhang, Bo Young Ahn, Henry Yu, Alisha Poole, Ngoc Ha Dang, Katalin Osz, Jennifer A. Chan, Daniela F. Quail, Stephen M. Robbins, Donna L. Senger. Durable control of brain tumors by glioma inhibitory macrophages and IL33 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6812.

Endolysosomal two-pore channel 2 plays opposing roles in primary and metastatic malignant melanoma cells.

The ion channel two-pore channel 2 (TPC2), localised on the membranes of acidic organelles such as endo-lysosomes and melanosomes, has been shown to play a role in pathologies including cancer, and it is differently expressed in primary versus metastatic melanoma cells. Whether TPC2 plays a pro- or anti-oncogenic role in different tumour conditions is a relevant open question which we have explored in melanoma at different stages of tumour progression. The behaviour of primary melanoma cell line B16F0 and its metastatic subline B16F10 were compared in response to TPC2 modulation by silencing (by small interfering RNA), knock-out (by CRISPR/Cas9) and overexpression (by mCherry-TPC2 transfected plasmid). TPC2 silencing increased cell migration, epithelial-to-mesenchymal transitionand autophagy in the metastatic samples, but abated them in the silenced primary ones. Interestingly, while TPC2 inactivation failed to affect markers of proliferation in both samples, it strongly enhanced the migratory behaviour of the metastatic cells, again suggesting that in the more aggressive phenotype TPC2 plays a specific antimetastatic role. In line with this, overexpression of TPC2 in B16F10 cells resulted in phenotype rescue, that is, a decrease in migratory ability, thus collectively resuming traits of the B16F0 primary cell line. Our research shows a novel role of TPC2 in melanoma cells that is intriguingly different in initial versus late stages of cancer progression.

Evolutionary proteogenomic landscape from pre-invasive to invasive lung adenocarcinoma

Lung adenocarcinoma follows a stepwise progression from pre-invasive to invasive. However, there remains a knowledge gap regarding molecular events from pre-invasive to invasive. Here, we conduct a comprehensive proteogenomic analysis comprising whole-exon sequencing, RNA sequencing, and proteomic and phosphoproteomic profiling on 98 pre-invasive and 99 invasive lung adenocarcinomas. The deletion of chr4q12 contributes to the progression from pre-invasive to invasive adenocarcinoma by downregulating SPATA18, thus suppressing mitophagy and promoting cell invasion. Proteomics reveals diverse enriched pathways in normal lung tissues and pre-invasive and invasive adenocarcinoma. Proteomic analyses identify three proteomic subtypes, which represent different stages of tumor progression. We also illustrate the molecular characterization of four immune clusters, including endothelial cells, B cells, DCs, and immune depression subtype. In conclusion, this comprehensive proteogenomic study characterizes the molecular architecture and hallmarks from pre-invasive to invasive lung adenocarcinoma, guiding the way to a deeper understanding of the tumorigenesis and progression of this disease.

A luminescent sensor for investigating serotonin metabolism in neuroendocrine cancer

BackgroundSerotonin is emerging as a promising therapeutic target in tryptophan hydroxylase 1–positive tumors, but further mechanistic studies are needed to effectively target dysregulated serotonin metabolism. One challenge is a lack of methods for studying the dynamic nature of serotonin metabolism. Here, we report the development of a genetically encoded luminescent biosensor, termed iSero-Rluc, for the real-time detection of serotonin in live cells. MethodsThe engineered serotonin binding domain (iSero) and Renilla luciferase (Rluc) reporter were cloned into yeast and mammalian expression vectors to create a fusion protein that could act as a biosensor to detect endogenous serotonin levels in live cells. The iSero-Rluc biosensor was stably expressed in the BON cell line and luciferase assays, mass spectroscopy, immunofluorescence, and Western blotting were used to study serotonin metabolism under different cell culture conditions. ResultsThe iSero-Rluc sensor detected exogenous serotonin in a yeast model. When stably expressed in the BON cell line, iSero-Rluc revealed that serotonin biosynthesis is increased in an anchorage-independent growth state and is induced upon serum starvation. ConclusionThe iSero-Rluc biosensor is a powerful tool in the study of tumor serotonin metabolism. It enabled real-time detection of alterations in serotonin synthesis in living cells under various growth conditions and has the potential to provide greater insight into serotonin metabolism in different stages of tumor progression and to identify therapeutic strategies to target cancer metastases and carcinoid crises.

Mechanisms of tumor-associated macrophages affecting the progression of hepatocellular carcinoma.

Tumor-associated macrophages (TAMs) are essential components of the immune cell stroma of hepatocellular carcinoma. TAMs originate from monocytic myeloid-derived suppressor cells, peripheral blood monocytes, and kupffer cells. The recruitment of monocytes to the HCC tumor microenvironment is facilitated by various factors, leading to their differentiation into TAMs with unique phenotypes. TAMs can directly activate or inhibit the nuclear factor-κB, interleukin-6/signal transducer and signal transducer and activator of transcription 3, Wnt/β-catenin, transforming growth factor-β1/bone morphogenetic protein, and extracellular signal-regulated kinase 1/2 signaling pathways in tumor cells and interact with other immune cells via producing cytokines and extracellular vesicles, thus affecting carcinoma cell proliferation, invasive and migratory, angiogenesis, liver fibrosis progression, and other processes to participate in different stages of tumor progression. In recent years, TAMs have received much attention as a prospective treatment target for HCC. This review describes the origin and characteristics of TAMs and their mechanism of action in the occurrence and development of HCC to offer a theoretical foundation for further clinical research of TAMs.

NUCLEAR DEFECTIVE IL-33 DRIVES AN ANTI-TUMORIGENIC MICROENVIRONMENT IN GLIOBLASTOMA

Abstract Despite a sophisticated treatment regimen, including surgery, chemotherapy, and radiotherapy, survival outcomes for glioblastoma remain at a dismal 14.6 months. Multi-omics profiling have established that myeloid phagocytes drive glioma progression and contribute to therapeutic resistance. However, effective targeting of this axis remains an unmet clinical opportunity. Previously, we found that the dual-function (secreted and nuclear) cytokine IL-33 is a key regulator of the inflammatory microenvironment that aids glioma tumorigenesis through phenotypic and functional changes in the innate immune cell repertoire. Strikingly, when IL-33 is prevented from entering the nucleus, by deletion of its nuclear localization signal (ΔNLS IL-33), but is still secreted, in vivo tumor growth is dramatically suppressed resulting in extended long-term survival. Using spatial transcriptomics and multiplex immunohistochemistry with temporal resolution at different stages of tumor progression, we identified a population of glioma-inhibitory macrophages (GIMs) unique to this suppressive environment. Assessment of xenografts generated from patient brain tumor initiating cells found an enrichment of GIMs in xenografts with long-term survival (>300 days) compared to short-term survivors (<100 days). The ability of GIMs to inhibit glioma progression was further highlighted when tumors established using a combination of ΔNLS IL-33 expressing cancer cells together with highly tumorigenic cells resulted in a growth inhibitory environment that significantly prolonged survival through the polarization and activation of GIMs. Additional characterization of this phenotype and development of clinical strategies to deliver ΔNLS IL-33 to brain tumors is warranted to determine if recruitment and activation of GIMs is a translatable therapeutic strategy for glioma patients.

Thymic lymphoma detection in RORγ knockout mice using 5-hydroxymethylcytosine profiling of circulating cell-free DNA

A high incidence of thymic lymphoma has been noted in mice deficient of retinoid-related orphan receptor γ2 (RORγ2), which is required for differentiation of naïve CD4+ T cells into TH17 cells. Using a RORγ homozygous knockout (KO) mouse model of thymic lymphoma, we characterized this tumor progression and investigated the utility of 5-hydroxymethylcytosine (5hmC) signatures as a non-invasive circulating biomarker for early prediction of malignancy. No evidence for malignancy was noted in the wild-type mice, while primary thymic lymphoma with multi-organ metastasis was observed microscopically in 97% of the homozygous RORγ KO mice. The severity of thymic lymphoma was not age-dependent in the KO mice of 2 to 4 months old. Differential enrichment of 5hmC in thymic DNA and plasma cell-free DNA (cfDNA) was compared across different stages of tumor progression. Random forest modeling of plasma cfDNA achieved good predictivity (AUC = 0.74) in distinguishing early non-metastatic thymic lymphoma compared to cancer-free controls, while perfect predictivity was achieved with advanced multi-organ metastatic disease (AUC = 1.00). Lymphoid-specific genes involved in thymocyte selection during T cell development (Themis, Tox) were differentially enriched in both plasma and thymic tissue. This could help in differentiating thymic lymphoma from other tumors commonly detected in rodent carcinogenicity studies used in pharmaceutical drug development to inform human malignancy risk. Overall, these results provide a proof-of-concept for using circulating cfDNA profiles in rodent carcinogenicity studies for early risk assessment of novel pharmaceutical targets.

Transfer of exosomal microRNAs confers doxorubicin resistance in osteosarcoma cells.

Osteosarcoma (OS) is the commonest primary malignant bone tumor in children and adolescents. However, chemotherapy resistance is a major challenge for the treatment of OS. Exosomes have been reported to serve an increasingly important role in different stages of tumor progression and chemotherapy resistance. The present study investigated whether exosomes derived from doxorubicin‑resistant OS cells (MG63/DXR) could be taken up in doxorubicin‑sensitive OS cells (MG63) and induce a doxorubicin‑resistant phenotype. MDR‑1, as the specific mRNA of chemoresistance, can be transferred by exosomes from MG63/DXR cells to MG63 cells. In addition, the present study identified 2,864 differentially expressed miRNAs (456 upregulated and 98 downregulated with fold‑change >2.0, P<5x10‑2, and FDR<0.05) in all three sets of exosomes from MG63/DXR cells and MG63 cells. The related miRNAs and pathways of exosomes involved in the doxorubicin resistance were identified by bioinformatic analysis. A total of 10 randomly selected exosomal miRNAs were dysregulated in exosomes from MG63/DXR cells relative to MG63 cells by reverse transcription‑quantitative PCR detection. As a result, miR‑143‑3p was found high expressed in exosomes from doxorubicin‑resistant OS cells compared with doxorubicin‑sensitive OS cells and upregulation of exosomal miR‑143‑3p abundance associated with the poor chemotherapeutic response to OS cells. Briefly, transfer of exosomal miR‑143‑3p confers doxorubicin resistance in osteosarcoma cells.

EDIT Software: A tool for the semi-automatic 3D reconstruction of bladder cancer and urinary bladder of animal models

Background and objectiveThis study presents the EDIT software, a tool for the visualization of the urinary bladder anatomy in the 3D space and for its semi-automatic 3D reconstruction. Methods: The inner bladder wall was computed by applying a Region of Interest (ROI) feedback-based active contour algorithm on the ultrasound images while the outer bladder wall was calculated by expanding the inner borders to approach the vascularization area on the photoacoustic images. The validation strategy of the proposed software was divided into two processes. Initially, the 3D automated reconstruction was performed on 6 phantom objects of different volume in order to compare the software computed volumes of the models with the true volumes of phantoms. Secondly, the in-vivo 3D reconstruction of the urinary bladder for 10 animals with orthotopic bladder cancer, which range in different stages of tumor progression was performed. Results: The results showed that the minimum volume similarity of the proposed 3D reconstruction method applied on phantoms is 95.59%. It is noteworthy to mention that the EDIT software enables the user to reconstruct the 3D bladder wall with high precision, even if the bladder silhouette has been significantly deformed by the tumor. Indeed, by taking into account the dataset of the 2251 in-vivo ultrasound and photoacoustic images, the presented software performs segmentation with dice similarity 96.96% and 90.91% for the inner and the outer borders of the bladder wall, respectively. Conclusions: This study delivers the EDIT software, a novel software tool that uses ultrasound and photoacoustic images to extract different 3D components of the bladder.

TGFβ Governs the Pleiotropic Activity of NDRG1 in Triple-Negative Breast Cancer Progression.

In triple-negative breast cancer (TNBC), the pleiotropic NDRG1 (N-Myc downstream regulated gene 1) promotes progression and worse survival, yet contradictory results were documented, and the mechanisms remain unknown. Phosphorylation and localization could drive NDRG1 pleiotropy, nonetheless, their role in TNBC progression and clinical outcome was not investigated. We found enhanced p-NDRG1 (Thr346) by TGFβ1 and explored whether it drives NDRG1 pleiotropy and TNBC progression. In tissue microarrays of 81 TNBC patients, we identified that staining and localization of NDRG1 and p-NDRG1 (Thr346) are biomarkers and risk factors associated with shorter overall survival. We found that TGFβ1 leads NDRG1, downstream of GSK3β, and upstream of NF-κB, to differentially regulate migration, invasion, epithelial-mesenchymal transition, tumor initiation, and maintenance of different populations of cancer stem cells (CSCs), depending on the progression stage of tumor cells, and the combination of TGFβ and GSK3β inhibitors impaired CSCs. The present study revealed the striking importance to assess both total NDRG1 and p-NDRG1 (Thr346) positiveness and subcellular localization to evaluate patient prognosis and their stratification. NDRG1 pleiotropy is driven by TGFβ to differentially promote metastasis and/or maintenance of CSCs at different stages of tumor progression, which could be abrogated by the inhibition of TGFβ and GSK3β.

In silico characterization of competing endogenous RNA network in glioblastoma multiforme with a systems biology approach.

Glioblastoma multiforme (GBM) is the most frequent malignant type of primary brain cancers and is a malignancy with poor prognosis. Thus, it is necessary to find novel therapeutic modalities based on molecular events occur at different stages of tumor progression. We used expression profiles of GBM tissues that contained long non-coding RNA (lncRNA), microRNA (miRNA) and mRNA signatures to make putative ceRNA networks. Our strategy led to identification of 1080 DEmRNAs, including 777 downregulated DEmRNAs (such as GJB6 and SLC12A5) and 303 upregulated DEmRNAs (such as TOP2A and RRM2), 19 DElncRNAs, including 16 downregulated DElncRNAs (such as MIR7-3HG and MIR124-2HG) and 3 upregulated DElncRNAs (such as CRNDE and XIST) and 49 DEmiRNAs, including 10 downregulated DEmiRNAs (such as hsa-miR-10b-5p and hsa-miR-1290) and 39 upregulated DEmiRNAs (such as hsa-miR-219a-2-3p and hsa-miR-338-5p). We also identified DGCR5, MIAT, hsa-miR-129-5p, XIST, hsa-miR-128-3p, PART1, hsa-miR-10b-5p, LY86-AS1, CRNDE, and DLX6-AS1 as 10 hub genes in the ceRNA network. The current study provides novel insight into molecular events during GBM pathogenesis. The identified molecules can be used as therapeutic targets for GBM.

Biomechanics of cancer stem cells.

Cancer stem cells (CSCs) have been believed to be one driving force for tumor progression and drug resistance. Despite the significance of biochemical signaling in malignancy, highly malignant tumor cells or CSCs exhibit lower cellular stiffness than weakly malignant cells or non-CSCs, which are softer than their healthy counterparts, suggesting the inverse correlation between cell stiffness and malignancy. Recent years have witnessed the rapid accumulation of evidence illustrating the reciprocity between cell cytoskeleton/mechanics and CSC functions and the potential of cellular stiffness for specific targeting of CSCs. However, a systematic understanding of tumor cell mechanics and their role in CSCs and tumor progression is still lacking. The present review summarizes the recent progress in the alterations of tumor cell cytoskeleton and stiffness at different stages of tumor progression and recapitulates the relationship between cellular stiffness and CSC functions. The altered cell mechanics may mediate the mechanoadaptive responses that possibly empower CSCs to survive and thrive during metastasis. Furthermore, we highlight the possible impact of tumor cell mechanics on CSC malignancy, which may potentiate low cell stiffness as a mechanical marker for CSC targeting.

Abstract 6081: The transcription factor SPDEF promotes the survival of mucinous pancreatic ductal adenocarcinoma of the classical subtype

Abstract Pancreatic ductal adenocarcinoma (PDA) is characterized by intra-tumoral heterogeneity. Using single-cell RNA sequencing, we reveal multiple tumor subpopulations distinguished by their differentiation state and associated with different stages of tumor progression. We identify SPDEF as a factor required for tumorigenesis in pancreatic cancer cells of epithelial and mucinous nature. SPDEF levels correlate with glandular differentiation and high secretory activity, which are characteristic features of human PDA of the classical subtype. SPDEF can drive mucus production in pancreatic cancer cells and is essential for the growth of mucus-secreting tumors by regulating endoplasmic reticulum (ER) activity. These findings offer insights into the factors controlling differentiation in PDA and may inform new therapeutic strategies with improved efficacy. Citation Format: Claudia Tonelli, Georgi N. Yordanov, Yuan Hao, Astrid Deschênes, Erin Brosnan, Abishek Doshi, Youngkyu Park, Jonathan Preall, David A. Tuveson. The transcription factor SPDEF promotes the survival of mucinous pancreatic ductal adenocarcinoma of the classical subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6081.

Abstract 6004: Surveying surface antigen expression in multiple myeloma preclinical models

Abstract Multiple myeloma (MM) is a progressive hematological cancer with a 5-year survival rate of 53% (1). Novel therapeutic strategies are being developed to target specific MM surface antigens. Yet, changes in antigen expression through MM progression are poorly understood in the clinic and have not been well characterized in preclinical models. Here, we were interested in understanding how BCMA, CD38, CD138 and HLA-DR surface expression patterns may be affected as MM progresses in preclinical models. To do so, ARH-77 and RPMI-8226 cells were inoculated subcutaneously while MM.1S, MM.1R, U266 and NCI-H929 cells were dosed intravenously into NSG mice. Tumor xenograft or bone marrow, whole blood and spleen were processed for flow cytometry analysis. Antigen expression was measured at different stages of tumor progression as well as in vitro. Soluble BCMA levels were assessed in the mouse serum by ELISA. ARH-77 and RPMI-8226 subcutaneous xenografts show preferential growth when inoculated in PBS and 50% growth factor-reduced Matrigel, respectively. BCMA expression was reduced in both ARH-77 and RPMI-8226 xenografts compared to in vitro culture. CD38 and HLA-DR expression increased as ARH-77/PBS and RPMI-8226/Matrigel tumor volume progressed. All 4 antigens were detected in the bone marrow from MM.1S, MM.1R and U266-bearing mice, as early as 5-6 weeks post intravenous injection. In contrast, antigens were not detected in any tissue from mice injected with NCI-H929, likely indicating failed engraftment. At 5 weeks, antigens were detected in the whole blood and spleen in MM.1S-bearing mice only, suggesting organ invasion and a more advanced disease-stage compared to MM.1R or U266. Experiments are being carried out to test antigen expression in tissue at late-stage tumor progression as well as serum BCMA levels in the intravenous MM models. These data highlight antigen expression differences in MM cells when analyzed in mouse tissue compared to in vitro culture. Like the widely variable expression observed between patients (2, 3), BCMA and CD138 were differentially expressed in the mouse bone marrow between models. Our observations suggest that commonly targeted antigens in MM vary kinetically in vivo and can be measured by flow cytometry. The present findings also support the use of RPMI-8226 and MM.1S cell lines when screening for antigen-specific immunotherapies and combinatorial studies for MM treatment.

The Role of SOD2 in Migration and Anchorage-Independent Growth of SKOV3 Ovarian Cancer Cells

The 5-year survival rates for ovarian cancer are 93%, 75%, and 30% for localized, regional, and distant tumors, respectively. These vast differences in survival rates underscore the need to identify novel therapeutic targets that are effective at different stages of tumor progression to better treat all patients diagnosed with this deadly disease. Manganese superoxide dismutase (SOD2) is a mitochondrial antioxidant enzyme responsible for eliminating superoxide and preventing oxidative damage to the mitochondria. Recent studies have implicated changes in SOD2 expression levels in multiple cancers, including breast, colorectal, prostate, and head and neck. While studies have begun to unravel the role of SOD2 in ovarian cancer, no one has looked at the specific role SOD2 plays in distinct stages of tumor progression of ovarian cancer. Here, we report SOD2 deficiency (accomplished through utilizing shRNA techniques) results in increased invasive and migratory ability of SKOV3 cells, a commonly used ovarian adenocarcinoma cell line. In contrast, SOD2-deficient SKOV3 cells display abrogated anchorage-independent growth in soft agar. These studies in SKOV3 cells indicate that SOD2 expression hampers invasion and migration critical for early tumor initiation but helps maintain anchorage-independent growth necessary for ovarian cancer metastases. In aggregate, SOD2 plays a context-dependent role in ovarian cancer progression and its utility as a therapeutic target for later-stage anchorage-independent ovarian cancer cells should be further explored. (First online: March 1, 2022)

Adapt to Persist: Glioblastoma Microenvironment and Epigenetic Regulation on Cell Plasticity.

Simple SummaryGlioblastoma stem-like cells (GSCs) drive the progression and therapeutic resistance of glioblastoma. GSC plasticity allows them to adapt to different microenvironments and to persist after treatments. GSCs can reside in hypoxic, invasive and perivascular niches, which shape their phenotype through the induction of transitions involving metabolic and epigenetic changes. Therefore, the targeting of molecules that dynamically regulate the transcriptional programs of GSCs, and consequently their plasticity, has emerged as a novel therapeutic alternative. In this review, we described the intratumoral heterogeneity of GBM, discussing the role of GSCs niches and epigenetic modifications on the cell plasticity.Glioblastoma (GBM) is the most frequent and aggressive brain tumor, characterized by great resistance to treatments, as well as inter- and intra-tumoral heterogeneity. GBM exhibits infiltration, vascularization and hypoxia-associated necrosis, characteristics that shape a unique microenvironment in which diverse cell types are integrated. A subpopulation of cells denominated GBM stem-like cells (GSCs) exhibits multipotency and self-renewal capacity. GSCs are considered the conductors of tumor progression due to their high tumorigenic capacity, enhanced proliferation, invasion and therapeutic resistance compared to non-GSCs cells. GSCs have been classified into two molecular subtypes: proneural and mesenchymal, the latter showing a more aggressive phenotype. Tumor microenvironment and therapy can induce a proneural-to-mesenchymal transition, as a mechanism of adaptation and resistance to treatments. In addition, GSCs can transition between quiescent and proliferative substates, allowing them to persist in different niches and adapt to different stages of tumor progression. Three niches have been described for GSCs: hypoxic/necrotic, invasive and perivascular, enhancing metabolic changes and cellular interactions shaping GSCs phenotype through metabolic changes and cellular interactions that favor their stemness. The phenotypic flexibility of GSCs to adapt to each niche is modulated by dynamic epigenetic modifications. Methylases, demethylases and histone deacetylase are deregulated in GSCs, allowing them to unlock transcriptional programs that are necessary for cell survival and plasticity. In this review, we described the effects of GSCs plasticity on GBM progression, discussing the role of GSCs niches on modulating their phenotype. Finally, we described epigenetic alterations in GSCs that are important for stemness, cell fate and therapeutic resistance.

Anti-tumor Effects of Curcuminoids in Glioblastoma Multiforme: An Updated Literature Review.

Glioblastoma Multiforme (GBM) is a poorly curable brain tumor because of its extremely invasive nature. Curcuminoids, as potential phytochemicals extracted from Curcuma Longa L., have been documented for their chemopreventive and antitumor activities against several types of malignancies. These compounds exert these effects via modulation of multiple signaling pathways and molecular targets at different stages of tumor progression, proliferation, and metastasis. In experimental studies, curcuminoids have demonstrated promising therapeutic benefits to overcome GBM. Curcuminoids have been shown to exert their anti-GBM effects through regulation of angiogenesis, apoptosis, autophagy, metastasis, invasion, as well as potential molecular targets, including receptor tyrosine kinases, Sonic Hedgehog, and NF-κB. This study reviews the observations regarding the impact of curcumin and its derivatives on GBM and the potential of translating the research findings into the clinic.

Suppressing MDSC Recruitment to the Tumor Microenvironment by Antagonizing CXCR2 to Enhance the Efficacy of Immunotherapy.

Simple SummaryWhile the development of immunotherapy has greatly advanced cancer treatment, many patients do not benefit from immunotherapy. Numerous strategies have been developed to improve response to immunotherapy across cancer types, including blocking the activity of immunosuppressive immune cells, cytokines, and signaling pathways that are linked to poor responses. Myeloid-derived suppressor cells (MDSCs) are associated with poor responses to immunotherapy, and the chemokine receptor, CXCR2, is involved in recruiting MDSCs to the tumor. In this review, we present studies that explore the potential of inhibiting MDSCs through blocking CXCR2 as a strategy to enhance response to existing and novel immunotherapies. Myeloid-derived suppressor cells (MDSCs) are a heterogenous population of cells derived from immature myeloid cells. These cells are often associated with poor responses to cancer therapy, including immunotherapy, in a variety of tumor types. The C-X-C chemokine receptor 2 (CXCR2) signaling axis plays a key role in the migration of immunosuppressive MDSCs into the tumor microenvironment (TME) and the pre-metastatic niche. MDSCs impede the efficacy of immunotherapy through a variety of mechanisms. Efforts to target MDSCs by blocking CXCR2 is an active area of research as a method for improving existing and novel immunotherapy strategies. As immunotherapies gain approval for a wider array of clinical indications, it will become even more important to understand the efficacy of CXCR2 inhibition in combating immunotherapy resistance at different stages of tumor progression.