Adaptation Of Cancer Cells Research Articles

Genetics of enzymatic dysfunctions in metabolic disorders and cancer.

Inherited metabolic disorders arise from mutations in genes involved in the biogenesis, assembly, or activity of metabolic enzymes, leading to enzymatic deficiency and severe metabolic impairments. Metabolic enzymes are essential for the normal functioning of cells and are involved in the production of amino acids, fatty acids and nucleotides, which are essential for cell growth, division and survival. When the activity of metabolic enzymes is disrupted due to mutations or changes in expression levels, it can result in various metabolic disorders that have also been linked to cancer development. However, there remains much to learn regarding the relationship between the dysregulation of metabolic enzymes and metabolic adaptations in cancer cells. In this review, we explore how dysregulated metabolism due to the alteration or change of metabolic enzymes in cancer cells plays a crucial role in tumor development, progression, metastasis and drug resistance. In addition, these changes in metabolism provide cancer cells with a number of advantages, including increased proliferation, resistance to apoptosis and the ability to evade the immune system. The tumor microenvironment, genetic context, and different signaling pathways further influence this interplay between cancer and metabolism. This review aims to explore how the dysregulation of metabolic enzymes in specific pathways, including the urea cycle, glycogen storage, lysosome storage, fatty acid oxidation, and mitochondrial respiration, contributes to the development of metabolic disorders and cancer. Additionally, the review seeks to shed light on why these enzymes represent crucial potential therapeutic targets and biomarkers in various cancer types.

Chronic oxidative stress adaptation in head and neck cancer cells generates slow-cyclers with decreased tumour growth in vivo

BackgroundReactive oxygen species (ROS) are implicated in cancer therapy and as drivers of microenvironmental tumour cell adaptations. Medical gas plasma is a multi-ROS generating technology that has been shown effective for palliative tumour control in head and neck cancer (HNC) patients before tumour cells adapted to the oxidative stress and growth regressed fatally.MethodsIn a bedside-to-bench approach, we sought to explore the oxidative stress adaptation in two human squamous cell carcinoma cell lines. Gas plasma was utilised as a putative therapeutic agent and chronic oxidative stress inducer.ResultsCellular responses of single and multiple treated cells were compared regarding sensitivity, cellular senescence, redox state and cytokine release. Whole transcriptome analysis revealed a strong correlation of cancer cell adaption with increased interleukin 1 receptor type 2 (IL1R2) expression. Using magnetic resonance imaging, tumour growth and gas plasma treatment responses of wild-type (WT) and repeatedly exposed (RE) A431 cells were further investigated in a xenograft model in vivo. RE cells generated significantly smaller tumours with suppressed inflammatory secretion profiles and increased epidermal growth factor receptor (EGFR) activity showing significantly lower gas plasma sensitivity until day 8.ConclusionsClinically, combination treatments together with cetuximab, an EGFR inhibitor, may overcome acquired oxidative stress resistance in HNC.

Stanniocalcin 1 promotes lung metastasis of breast cancer by enhancing EGFR–ERK–S100A4 signaling

Lung metastasis is the leading cause of breast cancer-related death. The tumor microenvironment contributes to the metastatic colonization of tumor cells in the lungs. Tumor secretory factors are important mediators for the adaptation of cancer cells to foreign microenvironments. Here, we report that tumor-secreted stanniocalcin 1 (STC1) promotes the pulmonary metastasis of breast cancer by enhancing the invasiveness of tumor cells and promoting angiogenesis and lung fibroblast activation in the metastatic microenvironment. The results show that STC1 modifies the metastatic microenvironment through its autocrine action on breast cancer cells. Specifically, STC1 upregulates the expression of S100 calcium-binding protein A4 (S100A4) by facilitating the phosphorylation of EGFR and ERK signaling in breast cancer cells. S100A4 mediates the effect of STC1 on angiogenesis and lung fibroblasts. Importantly, S100A4 knockdown diminishes STC1-induced lung metastasis of breast cancer. Moreover, activated JNK signaling upregulates STC1 expression in breast cancer cells with lung-tropism. Overall, our findings reveal that STC1 plays important role in breast cancer lung metastasis.

Amino Acid Metabolism in Bone Metastatic Disease.

Breast and prostate tumors frequently metastasize to the bone, but the underlying mechanisms for osteotropism remain elusive. An emerging feature of metastatic progression is metabolic adaptation of cancer cells to new environments. This review will summarize the recent advances on how cancer cells utilize amino acid metabolism during metastasis, from early dissemination to interactions with the bone microenvironment. Recent studies have suggested that certain metabolic preferences for amino acids may be associated with bone metastasis. Once in the bone microenvironment, cancer cells encounter a favorable microenvironment, where a changing nutrient composition of the tumor-bone microenvironment may alter metabolic interactions with bone-resident cells to further drive metastatic outgrowth. Enhanced amino acid metabolic programs are associated with bone metastatic disease and may be further augmented by the bone microenvironment. Additional studies are necessary to fully elucidate the role of amino acid metabolism on bone metastasis.

Time-dependent effects of hypoxia on cell metabolism, signaling, and iron homeostasis in the hematopoietic progenitor model KG1a.

Lowered availability of oxygen in the micro-environment of cells perturbs metabolic and signaling pathways. It affects proliferation, tissue morphology, and differentiation. Leukemia impairs maturation of hematopoietic progenitors: the immune system, healing, and erythropoiesis are weakened, thereby perturbing iron homeostasis and further lowering oxygen provision to tissues. Here, the time-dependent molecular consequences of sudden hypoxia were studied in the KG1a model of immature hematopoietic progenitors. The oxygen tension of KG1a cells was abruptly lowered from the experimentally usual ca. 20 to 1%. Growth and key hubs of signaling, metabolism, and iron homeostasis were monitored by a combination of immunological methods and functional assays. The collapse of oxygen availability stopped proliferation after one generation. The number of cells then remained approximately constant over several days, including after anaerobic changes in the culture medium. Lowered oxygen resulted in transient increase of the hypoxia-inducible factor 1α and of its REDD1 target, inhibition of mechanistic (or mammalian) target of rapamycin, decreased autophagy, altered cap-dependent translation, and minimal repression of the already weak oxidative phosphorylation. These adjustments did not trigger important cellular iron fluxes since the cells relied on their internal iron stores to survive. In conclusion, the response of the KG1a cells to stringent hypoxia is varied, with some established hypoxia-sensitive pathways exhibiting activation whereas others were unaffected. The results draw attention to the flexibility of the environmental adaptation of cancer cells. They suggest that thorough characterization of early leukemic blasts is warranted to propose informed treatments to patients.

The role of eIF4F-driven mRNA translation in regulating the tumour microenvironment.

Cells can rapidly adjust their proteomes in dynamic environments by regulating mRNA translation. There is mounting evidence that dysregulation of mRNA translation supports the survival and adaptation of cancer cells, which has stimulated clinical interest in targeting elements of the translation machinery and, in particular, components of the eukaryotic initiation factor 4F (eIF4F) complex such as eIF4E. However, the effect of targeting mRNA translation on infiltrating immune cells and stromal cells in the tumour microenvironment (TME) has, until recently, remained unexplored. In this Perspective article, we discuss how eIF4F-sensitive mRNA translation controls the phenotypes of key non-transformed cells in the TME, with an emphasis on the underlying therapeutic implications of targeting eIF4F in cancer. As eIF4F-targeting agents are in clinical trials, we propose that a broader understanding of their effect on gene expression in the TME will reveal unappreciated therapeutic vulnerabilities that could be used to improve the efficacy of existing cancer therapies.

A novel metabolic-related gene signature for predicting clinical prognosis and immune microenvironment in head and neck squamous cell carcinoma

ObjectivesMetabolic reprogramming is not only an essential hallmark in the progression of head and neck squamous cell carcinoma (HNSCC), but also an important regulator of cancer cell adaptation to tumor microenvironment (TME). However, the potential mechanism of metabolic reprogramming in TME of HNSCC is still unknown. MethodsThe head and neck squamous cell carcinoma with survival information were obtained the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The metabolic‐related genes were identified by differential analysis and survival analysis. Univariate and multivariate Cox regression analyses were applied to determine an overall estimate of metabolic-related risk signature and related clinical parameters. The sensitivity and specificity of the risk signature were evaluated by time-dependent receiver operation characteristic (ROC) curves. TME immune cell infiltration mediated by metabolic‐related genes was explored by gene set enrichment analysis (GSEA) and correlation analysis. ResultsSeven metabolic-related genes (SMS, MTHFD2, HPRT1, DNMT1, PYGL, ADA, and P4HA1) were identified to develop a metabolic-related risk signature. The low-risk group had a better overall survival compared to that of the high-risk group in the TCGA and GSE65858 cohorts. The AUCs for 1-, 3-, and 5-year overall survival were 0.646 vs. 0.673, 0.694 vs. 0.639, and 0.673 vs. 0.573, respectively. The AUC vale of risk score was 0.727 vs. 0.673. The low-risk group was associated with immune cell infiltration in the TME. ConclusionsThe metabolic-related risk signature were constructed and validated, which could involve in regulating the immune cell infiltration in the TME and act as an independent biomarker that predicted the prognosis of HNSCC.

Discovery of novel direct small-molecule inhibitors targeting HIF-2α using structure-based virtual screening, molecular dynamics simulation, and MM-GBSA calculations.

Hypoxia-inducible factors (HIFs) are the main regulatory factors implicated in the adaptation of cancer cells to hypoxic stress, which has provoked much interest as an attractive target for the design of promising chemotherapeutic agents. Since indirect HIF inhibitors (HIFIs) lead to the occurrence of various side effects, the need of the hour is to develop direct HIFIs, physically interacting with important functional domains within the HIF protein structure. Accordingly, in the present study, it was attempted to develop an exhaustive structure-based virtual screening (VS) process coupled with molecular docking, molecular dynamic (MD) simulation, and MM-GBSA calculations for the identification of novel direct inhibitors against the HIF-2α subunit. For this purpose, a focused library of over 200,000 compounds from the NCI database was used for VS against the PAS-B domain of the target protein, HIF-2α. This domain was suggested to be a possible ligand-binding site, which is characterized by a large internal hydrophobic cavity, unique to the HIF-2α subunit. The top-ranked compounds, NSC106416, NSC217021, NSC217026, NSC215639, and NSC277811 with the best docking scores were taken up for the subsequent in silico ADME properties and PAINS filtration. The selected drug-like hits were employed for carrying out MD simulation which was followed by MM-GBSA calculations to retrieve the candidates showing the highest in silico binding affinity towards the PAS-B domain of HIF-2α. The analysis of results indicated that all molecules, except the NSC277811, fulfilled necessary drug-likeness properties. Four selected drug-like candidates, NSC106416, NSC217021, NSC217026, and NSC215639 were found to expose the stability profiles within the cavity located inside the PAS-B domain of HIF-2α over simulation time. Finally, the results of the MM-GBSA rescoring method were indicative of the highest binding affinity of NSC217026 for the binding site of the HIF-2α PAS-B domain among selected final hits. Consequently, the hit NSC217026 could serve as a promising scaffold for further optimization toward the design of direct HIF-2α inhibitors for cancer therapy.

Tackling Osimertinib Resistance in EGFR-Mutant Non-Small Cell Lung Cancer.

The current landscape of targeted therapies directed against oncogenic driver alterations in non-small cell lung cancer (NSCLC) is expanding. Patients with EGFR-mutant NSCLC can derive significant benefit from EGFR tyrosine kinase inhibitor (TKI) therapy, including the third-generation EGFR TKI osimertinib. However, invariably, all patients will experience disease progression with this therapy mainly due to the adaptation of cancer cells through primary or secondary molecular mechanisms of resistance. The comprehension and access to tissue and cell-free DNA next-generation sequencing have fueled the development of innovative therapeutic strategies to prevent and overcome resistance to osimertinib in the clinical setting. Herein, we review the biological and clinical implications of molecular mechanisms of osimertinib resistance and the ongoing development of therapeutic strategies to overcome or prevent resistance.

Abstract 4818: GCN2 eIF2 kinase and p53 coordinate amino acid homeostasis and metabolism in prostate cancer

Abstract Activation of the integrated stress response (ISR) contributes to the progression of many cancers, including prostate cancer (PCa). The ISR features a family of protein kinases that phosphorylate the eukaryotic translation initiation factor 2 (eIF2) during different stress conditions, resulting in repression of global protein synthesis. In parallel, eIF2 phosphorylation also enhances the translation of select gene transcripts, such as ATF4, which directs the transcription of ISR-target genes that are critical for cancer stress adaptation. We recently reported (Cordova et al., 2022 eLife) that the eIF2 kinase GCN2 is a driver of the ISR in PCa and is critical for the maintenance of essential amino acid (EAA) homeostasis. GCN2 is activated in PCa due to EAA limitations, resulting in increased expression of key amino acid transporters which provide for nutrient import to facilitate protein synthesis and metabolism that drive PCa proliferation. Genetic loss or pharmacological inhibition of GCN2 results in lowered expression of amino acid transporters, leading to severe depletion of intracellular essential amino acids and reduced proliferation in PCa cell lines and xenograft models. These results support the therapeutic potential of targeting GCN2 in PCa.We recently determined that loss of GCN2 in PCa triggers a G1 nutrient-sensitive cell cycle checkpoint that is dependent on p53 and its target gene CDKN1A, encoding p21 inhibitor of cell cycle. Induced G1 arrest and p53/p21 signaling by GCN2 inhibition is reversed by supplementation with EAAs, suggesting amino acid limitation is critical for activation of p53. Metabolic stresses, such as amino acid starvation, have been suggested to activate p53 in different cancers and p53 regulates metabolic pathways that are critical for cancer cells adaptation to stresses. We also showed that depletion of specific amino acids activates GCN2 and p53 in cultured PCa cells. Using transcriptomic and metabolomic analyses, we determined that loss of GCN2 or p53 in PCa cells impacted multiple metabolic pathways, specifically those involved in amino acid and nucleotide metabolism, supporting the importance of GCN2 and p53 in metabolic homeostasis. In addition, deletion of p53 in PCa cells exacerbates the activation of GCN2 and the ISR, suggesting that loss of p53 results in amino acid imbalances that further activate GCN2. Importantly, inhibition of GCN2 in combination with loss of p53 resulted in increased cell death and apoptosis in PCa. Our study suggests that GCN2 and p53 can be activated in parallel in PCa and these stress response pathways are crucial for PCa cells to maintain homeostasis and adapt to metabolic stress. We propose that GCN2 and p53 function to coordinate PCa growth and progression by regulating metabolism and cell cycle control. Targeting these stress pathways in combination may provide enhanced efficacy for the treatment of PCa. Citation Format: Ricardo A. Cordova, Noah R. Sommers, Angela J. Klunk, Haroon M. Mohiuddin, Roberto Pili, Ronald C. Wek, Kirk A. Staschke. GCN2 eIF2 kinase and p53 coordinate amino acid homeostasis and metabolism in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4818.

Abstract 2787: Targeting Nrf2 signaling pathway by Keap1-mediated degradation in acquired gemcitabine resistant pancreatic cancer cells

Abstract Redox status is a main indicator of cancer cell adaptation to chemotherapy. Nuclear factor erythroid 2-related factor 2 (Nrf2) is one of the crucial regulators of redox condition and can affected to drug resistance through redox imbalance. The incidence and mortality of pancreatic cancer (PC) have been gradually increasing globally. Although the first line treatment with anticancer agents improves the disease status, acquired drug resistance is major huddles in the treatment failure. Targeting Nrf2 has been suggested as a promising therapeutic approach for the overcoming drug resistance. In the present study, Nrf2 was found to be upregulated in tumor tissues and gemcitabine-resistant PC cells. In addition, Nrf2 knockdown exhibited to recover gemcitabine sensitivity in the gemcitabine-resistant PC cells. To further validate the role of Nrf2 in gemcitabine-resistant cells, the effects of Nrf2 inhibitor, periplocin, were employed. Periplocin exerted the antiproliferative activities by regulating Nrf2 suppression which leads to the increase of reactive oxygen species generation. Furthermore, the downregulation of Nrf2 by periplocin was correlated to Keap1-mediated protein degradation. Docking simulation also confirmed the binding interaction of Nrf2 and Keap1 by periplocin. These findings suggest that targeting the Nrf2 might be a therapeutic strategy for overcoming acquired gemcitabine PC. Keywords: Pancreatic cancer cell, Gemcitabine resistance, Nuclear factor erythroid-2-related factor 2 (Nrf2), Kelch Like ECH Associated Protein 1 (Keap1), protein degradation Acknowledgements: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2022R1I1A1A01063346). Citation Format: Sang Kook Lee, Eun Seo Bae, Woong Sub Byun, Chae Won Ock, Won Kyung Kim, Hyen Joo Park. Targeting Nrf2 signaling pathway by Keap1-mediated degradation in acquired gemcitabine resistant pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2787.

Calcium signalling pathways in prostate cancer initiation and progression.

Cancer cells proliferate, differentiate and migrate by repurposing physiological signalling mechanisms. In particular, altered calcium signalling is emerging as one of the most widespread adaptations in cancer cells. Remodelling of calcium signalling promotes the development of several malignancies, including prostate cancer. Gene expression data from in vitro, in vivo and bioinformatics studies using patient samples and xenografts have shown considerable changes in the expression of various components of the calcium signalling toolkit during the development of prostate cancer. Moreover, preclinical and clinical evidence suggests that altered calcium signalling is a crucial component of the molecular re-programming that drives prostate cancer progression. Evidence points to calcium signalling re-modelling, commonly involving crosstalk between calcium and other cellular signalling pathways, underpinning the onset and temporal progression of this disease. Discrete alterations in calcium signalling have been implicated in hormone-sensitive, castration-resistant and aggressive variant forms of prostate cancer. Hence, modulation of calcium signals and downstream effector molecules is a plausible therapeutic strategy for both early and late stages of prostate cancer. Based on this premise, clinical trials have been undertaken to establish the feasibility of targeting calcium signalling specifically for prostate cancer.

L-asparaginase anti-tumor activity in pancreatic cancer is dependent on its glutaminase activity and resistance is mediated by glutamine synthetase

l-Asparaginase is a cornerstone of acute lymphoblastic leukemia (ALL) therapy since lymphoblasts lack asparagine synthetase (ASNS) and rely on extracellular asparagine availability for survival. Resistance mechanisms are associated with increased ASNS expression in ALL. However, the association between ASNS and l-Asparaginase efficacy in solid tumors remains unclear, thus limiting clinical development. Interestingly, l-Asparaginase also has a glutaminase co-activity that is crucial in pancreatic cancer where KRAS mutations activate glutamine metabolism. By developing l-Asparaginase-resistant pancreatic cancer cells and using OMICS approaches, we identified glutamine synthetase (GS) as a marker of resistance to l-Asparaginase. GS is the only enzyme able to synthesize glutamine, and its expression also correlates with l-Asparaginase efficacy in 27 human cell lines from 11 cancer indications. Finally, we further demonstrated that GS inhibition prevents cancer cell adaptation to l-Asparaginase-induced glutamine starvation. These findings could pave the way to the development of promising drug combinations to overcome l-Asparaginase resistance.

Abstract P6-11-14: Mitochondrial structure and function adaptation in residual triple negative breast cancer cells surviving chemotherapy treatment

Abstract Background: Neoadjuvant chemotherapy (NACT) used for triple-negative breast cancer (TNBC) eradicates tumors in only 45% of patients. TNBC patients with substantial residual cancer burden have poor metastasis-free and overall survival rates. Our previous studies demonstrated mitochondrial oxidative phosphorylation (OXPHOS) was elevated, suggesting a unique therapeutic dependency of residual tumor cells that survived after NACT. However, mechanisms underlying this enhanced reliance on OXPHOS are yet unknown. Mitochondria are morphologically plastic organelles that cycle between fission and fusion to maintain mitochondrial integrity and metabolic homeostasis. Methods: We modeled residual disease in human TNBC cells by treating with chemotherapeutic agents at the IC50 of cell killing, then evaluating surviving cells after 48 hours of treatment. We modeled residual TNBC in orthotopic patient-derived xenograft (PDX) model (PIM001p) by treating with standard front-line NACT (Adriamycin + cyclophosphamide; AC), then longitudinally harvesting tumors prior to treatment, residual, and upon regrowth. We analyzed mitochondrial morphology, mtDNA content and integrity, mitochondrial oxygen consumption rate, and metabolomic flux. We developed a U-Net based deep learning model that automatically detects and quantifies mitochondrial features in transmission electron micrographs. To test the functional dependency of mitochondrial structure in TNBC, we perturbed mitochondrial fusion genetically (by knocking down the fusion-driving protein Optic Atrophy 1, OPA1) and pharmacologically (using the first-in-class small molecule OPA1 inhibitor, MYLS22). Results: Pharmacologic or genetic disruption of mitochondrial fusion and fission resulted in decreased or increased OXPHOS rate, respectively, in TNBC cells, revealing for the first time that mitochondria morphology regulates OXPHOS in TNBC. Upon comparing mitochondrial effects of conventional chemotherapies, we found that DNA-damaging agents (adriamycin, carboplatin) increased mitochondrial elongation, mitochondrial content, flux of glucose through the TCA cycle, and OXPHOS, whereas taxanes (paclitaxel, docetaxel) instead decreased mitochondrial elongation and OXPHOS rate. Increased levels of the short protein isoform of OPA1 were observed in residual cells that not killed by DNA-damaging chemotherapy treatment. Treatment of cells with adriamycin followed by MYLS22 or given concurrently with MYLS22 drastically decreased cell growth. Conversely, cells treated with adriamycin, inducing fusion, followed by the DRP1 inhibitor Mdivi-1, further inducing fusion, were less sensitive to adriamycin than were vehicle-treated cells. Further, we observed heightened OXPHOS, OPA1 protein levels, and mitochondrial elongation in residual tumors of the PDX model following AC treatment. We found that sequential treatment first with AC, thus inducing mitochondrial fusion and OXPHOS, followed by MYLS22 to inhibit OPA1 in residual tumors, was able to suppress mitochondrial fusion and OXPHOS and significantly inhibited residual tumor regrowth. Our deep-learning algorithm identified distinct changes in mitochondrial phenotypes in residual tumors of multiple PDX models. Treatment of non-chemotherapy-treated mice with the OPA1 inhibitor MYLS22 as a single agent had no effect on tumor growth, revealing that post-AC residual tumors have an enhanced dependency on mitochondrial fusion compared to treatment-naïve tumors. Taken together, our findings establish a functional role for mitochondrial structure in chemotherapeutic response and metabolic reprogramming, which may confer survival advantage to TNBC cells. These results suggest that pharmacologic perturbation of mitochondrial structure can overcome chemoresistance in TNBC cells when administered rationally based on our understanding of chemotherapy-induced mitochondrial adaptations. Citation Format: Lily Baek, Junegoo Lee, Katherine E. Pendleton, Mariah J. Berner, Emily Goff, Lin Tan, Sara Martinez, Iqbal Mahmud, Argenis Arriojas, Alexander Zhurkevich, Tao Wang, Matthew Meyer, Bora Lim, James P. Barrish, Weston Porter, Kourosh Zarringhalam, Philip L. Lorenzi, Gloria V. Echeverria. Mitochondrial structure and function adaptation in residual triple negative breast cancer cells surviving chemotherapy treatment [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-11-14.

Mitochondrial structure and function adaptation in residual triple negative breast cancer cells surviving chemotherapy treatment.

Neoadjuvant chemotherapy (NACT) used for triple negative breast cancer (TNBC) eradicates tumors in ~45% of patients. Unfortunately, TNBC patients with substantial residual cancer burden have poor metastasis free and overall survival rates. We previously demonstrated mitochondrial oxidative phosphorylation (OXPHOS) was elevated and was a unique therapeutic dependency of residual TNBC cells surviving NACT. We sought to investigate the mechanism underlying this enhanced reliance on mitochondrial metabolism. Mitochondria are morphologically plastic organelles that cycle between fission and fusion to maintain mitochondrial integrity and metabolic homeostasis. The functional impact of mitochondrial structure on metabolic output is highly context dependent. Several chemotherapy agents are conventionally used for neoadjuvant treatment of TNBC patients. Upon comparing mitochondrial effects of conventional chemotherapies, we found that DNA-damaging agents increased mitochondrial elongation, mitochondrial content, flux of glucose through the TCA cycle, and OXPHOS, whereas taxanes instead decreased mitochondrial elongation and OXPHOS. The mitochondrial effects of DNA-damaging chemotherapies were dependent on the mitochondrial inner membrane fusion protein optic atrophy 1 (OPA1). Further, we observed heightened OXPHOS, OPA1 protein levels, and mitochondrial elongation in an orthotopic patient-derived xenograft (PDX) model of residual TNBC. Pharmacologic or genetic disruption of mitochondrial fusion and fission resulted in decreased or increased OXPHOS, respectively, revealing longer mitochondria favor oxphos in TNBC cells. Using TNBC cell lines and an in vivo PDX model of residual TNBC, we found that sequential treatment with DNA-damaging chemotherapy, thus inducing mitochondrial fusion and OXPHOS, followed by MYLS22, a specific inhibitor of OPA1, was able to suppress mitochondrial fusion and OXPHOS and significantly inhibit regrowth of residual tumor cells. Our data suggest that TNBC mitochondria can optimize OXPHOS through OPA1-mediated mitochondrial fusion. These findings may provide an opportunity to overcome mitochondrial adaptations of chemoresistant TNBC.

Transcriptomic analysis reveals differential adaptation of colorectal cancer cells to low and acute doses of cisplatin

Over the years, the landscape of cisplatin-based cancer treatment options has undergone continuous transitions. Currently, there is much debate over the optimum dose of cisplatin to be administered to cancer patients. In clinical practice, it can extend from repeated low sub-toxic doses to a few cycles of acute high drug doses. Herein, the molecular understanding of the overall cellular response to such differential doses of cisplatin becomes crucial before any decision making; and it has been a grey area of research. In this study, colorectal cancer (CRC) cells were treated with either- a low sub-toxic dose (LD; 30 µM) or a ten times higher acute dose (HD; 300 µM) of cisplatin, and thereafter, the cellular response was mapped through RNA sequencing followed by transcriptomic analysis. Interestingly, we observed that the tumor cells’ response to varying doses of cisplatin is distinctly different, and they activate unique transcriptional programs. The analysis of differentially regulated or uniquely expressed transcripts and corresponding pathways revealed a preferential enrichment of genes associated with chromatin organization, oxidative stress, senescence-associated signaling, and developmentally-active signaling pathways in HD; whereas, modulation of autophagy, protein homeostasis, or differential expression of ABC transporters was primarily enriched in LD. This study is the first of its kind to highlight cellular transcriptomic adaptations to different doses of cisplatin in CRC cells. Consequently, since, protein homeostasis was found to be deeply affected after cisplatin treatment, we further analyzed one of the primary cellular protein homeostatic mechanisms- autophagy. It was activated upon LD, but not HD, and served as a pro-survival strategy through the regulation of oxidative stress. Inhibition of autophagy improved sensitivity to LD. Overall, our study provides a holistic understanding of the distinct molecular signatures induced in CRC cells in response to differential cisplatin doses. These findings might facilitate the design of tailored therapy or appropriate drug dose for enhanced efficacy against CRCs.

RBM3 suppresses stemness remodeling of prostate cancer in bone microenvironment by modulating N6-methyladenosine on CTNNB1 mRNA

Bone metastasis is the most happened metastatic event in prostate cancer (PCa) and needs a large effort in treatment. When PCa metastasizes to the bone, the new microenvironment can induce the epigenome reprogramming and stemness remodeling of cancer cells, thereby increasing the adaptability of cancer cells to the bone microenvironment, and this even leads to the occurrence of secondary tumor metastasis. Our group has previously found that RNA binding motif 3 (RBM3) affects the stem cell-like properties of PCa by interfering with alternative splicing of CD44. However, whether RBM3, as a stress-response protein, can resist microenvironmental remodeling of PCa particularly in bone metastasis remains unknown. By co-culturing PCa cells with osteoblasts to mimic PCa bone metastases, we found that RBM3 upregulates the N6-methyladenosine (m6A) methylation on the mRNA of catenin beta 1 (CTNNB1) in a manner dependent on methyltransferase 3 (METTL3), an N6-adenosine-methyltransferase complex catalytic subunit. Consequently, this modification results in a decreased stability of CTNNB1 mRNA and a followed inactivation of Wnt signaling, which ultimately inhibits the stemness remodeling of PCa cells by osteoblasts. Thus, the present study may extend our understanding of the inhibitory role of RBM3 on particularly bone metastasis of PCa.

Metabolic adaptations of cancer in extreme tumor microenvironments.

Cancer cells are highly heterogeneous to adapt to extreme tumor microenvironments (TMEs). TMEs challenge cancer cells via hypoxia, nutrition starvation, and acidic pH, promoting invasion and metastasis concomitant with genetic, epigenetic, and metabolic alterations. Metabolic adaptation to an extreme TME could allow cancer cells to evade cell death and immune responses, as well as resulting in drug resistance, recurrence, and poor patient prognosis. Therefore, elucidation of the metabolic adaptation of malignant cancer cells within TMEs is necessary, however, most are still elusive. Recently, adaptation of cancer cells within the TME can be analyzed via cell-cell interactions at the single-cell level. In addition, information into organelle-organelle interactions has recently been obtained. These cell-cell, and organelle-organelle interactions demonstrate the potential as new cancer therapy targets, as they play essential roles in the metabolic adaptation of cancer cells to the TME. In this manuscript, we review (1) metabolic adaptations within tumor microenvironments through (2) cell-to-cell, and (3) organelle-organelle metabolic interactions.

Lipid Metabolic Alterations in KRAS Mutant Tumors: Unmasking New Vulnerabilities for Cancer Therapy.

KRAS is one of the most commonly mutated genes, an event that leads to development of highly aggressive and resistant to any type of available therapy tumors. Mutated KRAS drives a complex network of lipid metabolic rearrangements to support the adaptation of cancer cells to harsh environmental conditions and ensure their survival. Because there has been only a little success in the continuous efforts of effectively targeting KRAS-driven tumors, it is of outmost importance to delineate the exact mechanisms of how they get rewired, leading to this distinctive phenotype. Therefore, the aim of this review is to summarize the available data acquired over the last years with regard to the lipid metabolic regulation of KRAS-driven tumors and elucidate their specific characteristics in an attempt to unravel novel therapeutic targets.

RNA Modifications in Cancer Stem Cell Biology.

Post-transcriptional regulation of gene expression shapes the cell state both in health and disease. RNA modifications-especially N6-methyladenosine (m6A)-have recently emerged as key players in RNA processing that depends on a sophisticated interplay between proteins of the RNA modification machinery. Importantly, the RNA epitranscriptome becomes dysregulated in cancer and promotes cancer-associated gene expression programs as well as cancer cell adaptation to the tumor microenvironment. At the top of the tumor hierarchy, cancer stem cells (CSCs) are master regulators of tumorigenesis and resistance to therapeutic intervention. Therefore, defining how RNA modifications influence the CSC state is of great importance for cancer drug development. In this chapter, we summarize the current knowledge of the roles of RNA modifications in shaping the CSC state and driving gene expression programs that confer stem-like properties to CSCs, promote CSC adaptation to the local microenvironment, and endow CSCs with metastatic potential and drug resistance.