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BACKGROUND: Hypoxia-activated prodrug (HAP) is a promising candidate for highly tumor-specific chemotherapy. However, the oxygenation heterogeneity and dense extracellular matrix (ECM) of tumor, as well as the potential resistance to chemotherapy, have severely impeded the resulting overall efficacy of HAP. RESULTS: A HAP potentiating strategy is proposed based on ultrasound responsive nanodroplets (PTP@PLGA), which is composed of protoporphyrin (PpIX), perfluoropropane (PFP) and a typical HAP, tirapazamine (TPZ). The intense vaporization of PFP upon ultrasound irradiation can magnify the sonomechanical effect, which loosens the ECM to promote the penetration of TPZ into the deep hypoxic region. Meanwhile, the PpIX enabled sonodynamic effect can further reduce the oxygen level, thus activating the TPZ in the relatively normoxic region as well. Surprisingly, abovementioned ultrasound effect also results in the downregulation of the stemness of cancer cells, which is highly associated with drug-refractoriness. CONCLUSIONS: This work manifests an ideal example of ultrasound-based nanotechnology for potentiating HAP and also reveals the potential acoustic effect of intervening cancer stem-like cells.

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Intratumor heterogeneity is one of the major features of cancers, leading to aggressive disease and treatment failure. Cancer stem-like cells (CSCs) are believed to give rise to the heterogeneous cell types within tumors. Hence, understanding the regulatory mechanism underlying the recurrence process of heterogeneous tumor by CSCs could facilitate the development of CSC-targeted therapies. Here, utilizing single-cell transcriptomics, we present the molecular profile of osteosarcoma CSCs-derived heterogeneous tumors consisting of CSC clusters, osteoprogenitor and differentiated cell types, such as pre-osteoblasts, osteoblasts and chondroblasts. Furthermore, by constructing the comprehensive map of modulated genes during CSCs self-renewal and differentiation, we identify RAN exhibiting specific peak expression in osteosarcoma CSCs clusters which is transcriptionally up-regulated by MYBL2. Functionality, MYBL2-RAN pathway promotes the CSCs self-renewal by enhancing the nuclear accumulation of MYC protein, which in turn boosts the overexpression of RAN as a positive feedback. Importantly, blockage of MYBL2-RAN pathway sensitizes CSCs to cisplatin treatment and synergistically enhanced the cisplatin-induced cytotoxicity. Both MYBL2 and RAN are highly expressed in clinical osteosarcoma tissues which indicate poor prognosis. Collectively, our study provides advanced insights into the regeneration process of heterogeneous tumor originating from CSCs and highlights the MYBL2-RAN pathway as a promising target for CSC-based therapy in osteosarcoma.

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Intratumor heterogeneity (ITH) is a barrier to effective therapy. However, it is largely unknown how ITH is established at the onset of tumor progression, such as in colorectal cancer (CRC). Here, we integrate single-cell RNA-seq and functional validation to show that asymmetric division of CRC stem-like cells (CCSC) is critical for early ITH establishment. We find that CCSC-derived xenografts contain seven cell subtypes, including CCSCs, that dynamically change during CRC xenograft progression. Furthermore, three of the subtypes are generated by asymmetric division of CCSCs. They are functionally distinct and appear at the early stage of xenografts. In particular, we identify a chemoresistant and an invasive subtype, and investigate the regulators that control their generation. Finally, we show that targeting the regulators influences cell subtype composition and CRC progression. Our findings demonstrate that asymmetric division of CCSCs contributes to the early establishment of ITH. Targeting asymmetric division may alter ITH and benefit CRC therapy.

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Drug resistance presents one of the major causes for the failure of cancer chemotherapy. Cancer stem-like cells (CSCs), a population of self-renewal cells with high tumorigenicity and innate chemoresistance, can survive conventional chemotherapy and generate increased resistance. Here, we develop a lipid-polymer hybrid nanoparticle for co-delivery and cell-distinct release of the differentiation-inducing agent, all-trans retinoic acid and the chemotherapeutic drug, doxorubicin to overcome the CSC-associated chemoresistance. The hybrid nanoparticles achieve differential release of the combined drugs in the CSCs and bulk tumor cells by responding to their specific intracellular signal variation. In the hypoxic CSCs, ATRA is released to induce differentiation of the CSCs, and in the differentiating CSCs with decreased chemoresistance, DOX is released upon elevation of reactive oxygen species to cause subsequent cell death. In the bulk tumor cells, the drugs are released synchronously upon the hypoxic and oxidative conditions to exert potent anticancer effect. This cell-distinct drug release enhances the synergistic therapeutic efficacy of ATRA and DOX with different anticancer mechanism. We show that treatment with the hybrid nanoparticle efficiently inhibit the tumor growth and metastasis of the CSC-enriched triple negative breast cancer in the mouse models.

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Radiotherapy is widely used for cancer treatment, but paradoxically, it has been reported that surviving cancer cells can acquire resistance, leading to recurrence or metastasis. Efforts to reduce radioresistance are required to increase the effectiveness of radiotherapy. miRNAs are advantageous as therapeutic agents because it can simultaneously inhibit the expression of several target mRNAs. Therefore, this study discovered miRNA that regulated radioresistance and elucidated its signaling mechanism. Our previous study confirmed that miR-5088-5p was associated with malignancy and metastasis in breast cancer. As a study to clarify the relationship between radiation and miR-5088-5p identified as onco-miRNA, it was confirmed that radiation induced hypomethylation of the promoter of miR-5088-5p and its expression increased. On the other hand, miR-5088-5p inhibitors were confirmed to reduce radiation-induced epithelial-mesenchymal transition, stemness, and metastasis by reducing Slug. Therefore, this study showed the potential of miR-5088-5p inhibitors as therapeutic agents to suppress radioresistance.

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Pancreatic cancer is one of the most aggressive cancers and the seventh leading cause of cancer-associated death in the world. Radiation is performed as an adjuvant therapy as well as anti-cancer drugs. Because cancer stem-like cells (CSCs) are considered to be radioresistant and cause recurrence and metastasis, understanding their properties is required for the development of novel therapeutic strategies. To investigate the CSC properties of pancreatic cancer cells, we used a pancreatic CSC model, degron (++) cells, which have low proteasome activity. Degron (++) cells displayed radioresistance in comparison with control cells. Using Ribonucleic acid (RNA) sequencing, we successfully identified KRT13 as a candidate gene responsible for radioresistance. Knockdown of KRT13 sensitized the degron (++) cells to radiation. Furthermore, a database search revealed that KRT13 is upregulated in pancreatic cancer cell lines and that high expression of KRT13 is associated with poorer prognosis. These results indicate that a combination therapy of KRT13 knockdown and radiation could hold therapeutic promise in pancreatic cancer.

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While previous studies have identified cancer stem-like cells (CSCs) as a crucial driver for chemoresistance and tumor recurrence, the underlying mechanisms for populating the CSC pool remain unclear. Here, we identify hypermitophagy as a feature of human lung CSCs, promoting metabolic adaption via the Notch1-AMPK axis to drive CSC expansion. Specifically, mitophagy is highly active in CSCs, resulting in increased mitochondrial DNA (mtDNA) content in the lysosome. Lysosomal mtDNA acts as an endogenous ligand for Toll-like receptor 9 (TLR9) that promotes Notch1 activity. Notch1 interacts with AMPK to drive lysosomal AMPK activation by inducing metabolic stress and LKB1 phosphorylation. This TLR9-Notch1-AMPK axis supports mitochondrial metabolism to fuel CSC expansion. In patient-derived xenograft chimeras, targeting mitophagy and TLR9-dependent Notch1-AMPK pathway restricts tumor growth and CSC expansion. Taken together, mitochondrial hemostasis is interlinked with innate immune sensing and Notch1-AMPK activity to increase the CSC pool of human lung cancer.

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Drug resistance presents one of the major causes for the failure of cancer chemotherapy. Cancer stem-like cells (CSCs), a population of self-renewal cells with high tumorigenicity and innate chemoresistance, can survive conventional chemotherapy and generate increased resistance. Here, we develop a lipid-polymer hybrid nanoparticle for co-delivery and cell-distinct release of the differentiation-inducing agent, all-trans retinoic acid and the chemotherapeutic drug, doxorubicin to overcome the CSC-associated chemoresistance. The hybrid nanoparticles achieve differential release of the combined drugs in the CSCs and bulk tumor cells by responding to their specific intracellular signal variation. In the hypoxic CSCs, ATRA is released to induce differentiation of the CSCs, and in the differentiating CSCs with decreased chemoresistance, DOX is released upon elevation of reactive oxygen species to cause subsequent cell death. In the bulk tumor cells, the drugs are released synchronously upon the hypoxic and oxidative conditions to exert potent anticancer effect. This cell-distinct drug release enhances the synergistic therapeutic efficacy of ATRA and DOX with different anticancer mechanism. We show that treatment with the hybrid nanoparticle efficiently inhibit the tumor growth and metastasis of the CSC-enriched triple negative breast cancer in the mouse models.

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Many patients diagnosed with acute myeloid leukemia (AML) relapse within two years of the initial remission. The biology of AML relapse is incompletely understood, although cancer stem-like (CSL) cells have been hypothesized to be important. To test this hypothesis, we employed SORE6, a reporter designed to detect the transcriptional activity of the embryonic stem cell proteins Oct4 and Sox2, to identify/purify CSL cells in two FLT3-mutated AML cell lines. Both cell lines contained ~10% of SORE6+ cells in the steady state. Compared to SORE6- cells, SORE6+ cells exhibited more characteristics of CSL cells, with significantly higher chemoresistance and rates of spheroid formation. SORE6+ cells had substantially higher expression of Myc and FLT3 proteins, which are drivers of SORE6 activity. Using a mixture of SORE6-/SORE6+ cells that were molecularly barcoded, we generated an in vitro study model for AML relapse. Specifically, after 'in vitro remission' induced by Ara-C, both cell lines regenerated after 13 ± 3 days. Barcode analysis revealed that most of the regenerated cells were derived from the original SORE6+ cells. Regenerated cells exhibited more CSL features than did the original SORE6+ cells, even though a proportion of them lost SORE6 activity. In bone marrow samples from a patient cohort, we found that relapsed blasts expressed significantly higher levels of Myc, a surrogate marker of SORE6 activity, compared to pre-treatment blasts. To conclude, using our in vitro model, we have provided evidence that CSL cells contribute to AML relapse.

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We investigated the role of cancer stem cells (CSCs) in a population of triple-negative breast cancer (TNBC) cells that are resistant to apoptosis. A human breast cancer cell population capable of inducing p53 expression with doxycycline (Dox) was created and used as an untreated control (UT). After the addition of Dox to UT for 5 days, the cell population reconstituted with cells showing resistance to apoptosis was named RE. Fluorescence-activated cell sorting (FACS) and immunostaining revealed that after the addition of Dox, the ratio of cells in the S and G2/M phases decreased in UT as apoptosis proceeded, but did not markedly change in apoptosis-resistant RE. CSC-like cells in RE exhibited a cell morphology with a larger ratio of the major/minor axis than UT. FACS showed that RE had a higher proportion of CSC-like cells and contained more CD44+CD24- mesenchymal CSCs than ALDH1A3+ epithelial-like CSCs. In a Matrigel invasion assay, UT was more likely to form a three-dimensional cell population, whereas RE exhibited a planar population, higher migration ability, and the up-regulated expression of epithelial-mesenchymal transition-related genes. These results provide insights into the mechanisms by which TNBC cells acquire treatment resistance at the time of recurrence.

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Cancer stem-like cells (CSLC) are considered a major contributor to the development and progression of hepatocellular carcinoma (HCC). Previous studies indicated that CSLC are characterized by resistance to ferroptosis, a type of lipid peroxidation-dependent cell death. Here, we identified a set of ferroptosis-related stemness genes (FRSG) and found that these genes may be involved in immune infiltration in HCC. A four-FRSG (CDKN2A, GABARAPL1, HRAS, RPL8) risk model with prognostic prediction was constructed by a Cox analysis in HCC. Among these four genes, GABARAPL1 was downregulated in HCC tumor-repopulating cells (TRC; a type of CSLC). Its downregulation decreased the sensitivity of HCC TRC to erastin- or sorafenib-triggered ferroptosis. Together, we uncovered a molecular mechanism via which CSLC could achieve tolerance to ferroptosis. Further studies may provide potential therapeutic strategies targeting CSLC in HCC.

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Cancer stem-like cells (CSCs) have been suggested to be responsible for chemoresistance and tumor recurrence owing to their self-renewal capacity and differentiation potential. Although WEE1 is a strong candidate target for anticancer therapies, its role in ovarian CSCs is yet to be elucidated. Here, we show that WEE1 plays a key role in regulating CSC properties and tumor resistance to carboplatin via a microRNA-dependent mechanism. We found that WEE1 expression is upregulated in ovarian cancer spheroids because of the decreased expression of miR-424 and miR-503, which directly target WEE1. The overexpression of miR-424/503 suppressed CSC activity by inhibiting WEE1 expression, but this effect was reversed on the restoration of WEE1 expression. Furthermore, we demonstrated that NANOG modulates the miR-424/503-WEE1 axis that regulates the properties of CSCs. We also demonstrated the pharmacological restoration of the NANOG-miR-424/503-WEE1 axis and attenuation of ovarian CSC characteristics in response to atorvastatin treatment. Lastly, miR-424/503-mediated WEE1 inhibition re-sensitized chemoresistant ovarian cancer cells to carboplatin. Additionally, combined treatment with atorvastatin and carboplatin synergistically reduced tumor growth, chemoresistance, and peritoneal seeding in the intraperitoneal mouse models of ovarian cancer. We identified a novel NANOG-miR-424/503-WEE1 pathway for regulating ovarian CSCs, which has potential therapeutic utility in ovarian cancer treatment.

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Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype for its high rates of relapse, great metastatic potential, and short overall survival. How cancer cells acquire metastatic potency through the conversion of noncancer stem-like cells into cancer cells with stem-cell properties is poorly understood. Here, we identified the long noncoding RNA (lncRNA) TGFB2-AS1 as an important regulator of the reversibility and plasticity of noncancer stem cell populations in TNBC. We revealed that TGFB2-AS1 impairs the breast cancer stem-like cell (BCSC) traits of TNBC cells in vitro and dramatically decreases tumorigenic frequency and lung metastasis in vivo. Mechanistically, TGFB2-AS1 interacts with SMARCA4, a core subunit of the SWI/SNF chromatin remodeling complex, and results in transcriptional repression of its target genes including TGFB2 and SOX2 in an in cis or in trans way, leading to inhibition of transforming growth factor ß (TGFß) signaling and BCSC characteristics. In line with this, TGFB2-AS1 overexpression in an orthotopic TNBC mouse model remarkably abrogates the enhancement of tumor growth and lung metastasis endowed by TGFß2. Furthermore, combined prognosis analysis of TGFB2-AS1 and TGFß2 in TNBC patients shows that high TGFB2-AS1 and low TGFß2 levels are correlated with better outcome. These findings demonstrate a key role of TGFB2-AS1 in inhibiting disease progression of TNBC based on switching the cancer cell fate of TNBC and also shed light on the treatment of TNBC patients.

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BACKGROUND: Maintenance of cancer stem-like cell (CSC) stemness supported by aberrantly regulated cancer cell metabolism is critical for CSC self-renewal and tumor progression. As a key glycolytic enzyme, hexokinase 2 (HK2) plays an instrumental role in aerobic glycolysis and tumor progression. However, whether HK2 directly contribute to CSC stemness maintenance in small cell lung cancer (SCLC) is largely unclear. In this study, we aimed to investgate whether HK2 independent of its glycolytic activity is directly involved in stemness maintenance of CSC in SCLC. METHODS: Immunoblotting analyses were conducted to determine the expression of HK2 in SCLC CSCs and their differentiated counterparts. CSC-like properties and tumorigenesis of SCLC cells with or without HK2 depletion or overexpression were examined by sphere formation assay and xenograft mouse model. Immunoprecipitation and mass spectrometry analyses were performed to identify the binding proteins of CD133. The expression levels of CD133-associated and CSC-relevant proteins were evaluated by immunoblotting, immunoprecipitation, immunofluorescence, and immunohistochemistry assay. RNA expression levels of Nanog, POU5F1, Lin28, HK2, Prominin-1 were analyzed through quantitative reverse transcription PCR. Polyubiquitination of CD133 was examined by in vitro or in vivo ubiquitination assay. CD133+ cells were sorted by flow cytometry using an anti-CD133 antibody. RESULTS: We demonstrated that HK2 expression was much higher in CSCs of SCLC than in their differentiated counterparts. HK2 depletion inhibited CSC stemness and promoted CSC differentiation. Mechanistically, non-mitochondrial HK2 directly interacted with CD133 and enhanced CD133 expression without affecting CD133 mRNA levels. The interaction of HK2 and CD133 promoted the binding of the deubiquitinase ubiquitin-specific protease 11 (USP11) to CD133, thereby inhibiting CD133 polyubiquitylation and degradation. HK2-mediated upregulation of CD133 expression enhanced the expression of cell renewal regulators, SCLC cell stemness, and tumor growth in mice. In addition, HK2 expression was positively correlated with CD133 expression in human SCLC specimens, and their expression levels were associated with poor prognosis of SCLC patients. CONCLUSIONS: These results revealed a critical non-metabolic function of HK2 in promotion of cancer cell stemness. Our findings provided new insights into the multifaceted roles of HK2 in tumor development.

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Hyperactivation of hedgehog signaling occurs in colorectal cancer stem-like cells (CSCs), a rare subpopulation, potentially involved in metastasis, chemotherapy resistance, and cancer relapse. Garcinone C, a xanthone isolated from mangosteen (Garcinia mangostana), suppresses colorectal cancer in vivo and in vitro by inhibiting Gli1-dependent noncanonical hedgehog signaling. Herein, we investigated the effect of garcinone C on cancer stemness and invasiveness in colorectal cancer; Gli1 was noted as pivotal in maintaining stemness and invasiveness in HCT116 and HT29 CSCs. Garcinone C inhibited the proliferation and self-renewal of HCT116 and HT29 CSCs. Colon cancer stemness markers such as CD44, CD133, ALDH1, and Nanog were significantly decreased by garcinone C. Computational studies showed that garcinone C showed a high affinity with the Gli1 protein ZF domain by forming hydrogen bonds with amino acid residues of ASP244, ARG223, and ASP216. Besides, MG132 blocked the effects of garcinone C on Gli1. Thus, garcinone C suppressed colorectal CSCs by binding to Gli1 and enhancing its degradation. MMP2 and MMP9 levels, invasive-related markers, were increased in HCT116 CSCs but decreased by garcinone C. E-cadherin level was reduced in HCT116 CSCs, while the presence of garcinone C was restored. Garcinone C inhibited the proliferation and invasiveness of colorectal CSCs by targeting Gli1-dependent Hh signaling. Garcinone C may be a potent natural agent against colorectal cancer relapse.

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Antibody-based therapeutics, which induce apoptosis of malignant cells by selectively binding to their receptors, hold tremendous promise for clinical cancer therapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received considerable interest due to its favorable capability of activating apoptosis in cancer cells by interacting with death receptors (DRs). However, cancer stem-like cells (CSCs) show deficient or lower DR and are highly resistant to TRAIL-mediated apoptosis limiting the therapeutic efficacy. Here, we report a liposome-mediated acclimatization strategy to overcome the CSC-emanated TRAIL resistance. The liposomal assemblies coencapsulating plasmid DNA encoding TRAIL and salinomycin enable cancer cells as protein generators to express TRAIL, and more importantly, can acclimatize resistant CSCs to be sensitized to the TRAIL-triggered apoptosis by salinomycin-induced upregulation of DR expression on CSCs. This programmable liposome-based drug codelivery system shows the potential to efficiently eliminate CSCs and inhibit CSC-enriched tumor growth in the orthotopic colon tumor mouse model.

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While most Sonic Hedgehog-associated medulloblastomas (SHH-MBs) respond to therapeutic intervention, radiation therapy often causes deleterious long-term neurocognitive defects, especially in infants and young children. To limit neurological comorbidities, the development of a reduction-of-therapy treatment or de-escalation approach was investigated. Although retrospective analysis of MBs indicated low-dose therapy was potentially effective, clinical de-escalation trials showed poor outcomes in infant SHH-MBs and was prematurely terminated. Recent studies suggest the existence of cancer-stem-cell (CSC)-like cell populations that are more resistant to therapies and drive tumor recurrence. This review will discuss the mechanism of these CSC-like cells in SHH-MBs in resisting to p53-pathway activation, which may contribute to the disappointing outcomes of the recent de-escalation trials.

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BACKGROUND: Acquired therapeutic resistance and metastasis/recurrence remain significant challenge in advance renal cell carcinoma (RCC), thus the establishment of patient-derived cancer models may provide a clue to assess the problem. We recently characterized that neuritogenesis-related protein neuritin 1 (NRN1) functions as an oncogene in testicular germ cell tumor. This study aims to elucidate the role of NRN1 in RCC. METHODS: NRN1 expression in clinical RCC specimens was analyzed based on immunohistochemistry. NRN1-associated genes in RCC were screened by the RNA-sequencing dataset from The Cancer Genome Atlas (TCGA). RCC patient-derived cancer cell (RCC-PDC) spheroid cultures were established and their viabilities were evaluated under the condition of gene silencing/overexpression. The therapeutic effect of NRN1-specific siRNA was evaluated in RCC-PDC xenograft models. RESULTS: NRN1 immunoreactivity was positively associated with shorter overall survival in RCC patients. In TCGA RCC RNA-sequencing dataset, C-X-C chemokine receptor type 4 (CXCR4), a prognostic and stemness-related factor in RCC, is a gene whose expression is substantially correlated with NRN1 expression. Gain- and loss-of-function studies in RCC-PDC spheroid cultures revealed that NRN1 significantly promotes cell viability along with the upregulation of CXCR4. The NRN1-specific siRNA injection significantly suppressed the proliferation of RCC-PDC-derived xenograft tumors, in which CXCR4 expression is significantly repressed. CONCLUSION: NRN1 can be a potential diagnostic and therapeutic target in RCC as analyzed by preclinical patient-derived cancer models and clinicopathological studies.

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Cancer stem cells (CSCs) or cancer-initiating cells (CICs) are key factors for tumor generation and metastasis. We investigated a filtration method to enhance CSCs (CICs) from colon carcinoma HT-29 cells and primary colon carcinoma cells derived from patient colon tumors using poly(lactide-co-glycolic acid)/silk screen (PLGA/SK) filters. The colon carcinoma cell solutions were permeated via porous filters to obtain a permeation solution. Then, the cell cultivation media were permeated via the filters to obtain the recovered solution, where the colon carcinoma cells that adhered to the filters were washed off into the recovered solution. Subsequently, the filters were incubated in the culture media to obtain the migrated cells via the filters. Colon carcinoma HT-29 cells with high tumorigenicity, which might be CSCs (CICs), were enhanced in the cells in the recovered solution and in the migrated cells based on the CSC (CIC) marker expression, colony-forming unit assay, and carcinoembryonic antigen (CEA) production. Although primary colon carcinoma cells isolated from colon tumor tissues contained fibroblast-like cells, the primary colon carcinoma cells were purified from fibroblast-like cells by filtration through PLGA/SK filters, indicating that the filtration method is effective in purifying primary colon carcinoma cells.

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BMI-1, a polycomb ring finger oncogene, is highly expressed in multiple cancer cells and is involved in cancer cell proliferation, invasion, and apoptosis. BMI-1 represents a cancer stemness marker that is associated with the regulation of stem cell self-renewal. In this study, pharmacological inhibition (PTC596) or knockdown (siRNA) of BMI-1 reduced cancer stem-like cells and enhanced cancer cell death. Mechanistically, the inhibition of BMI-1 induced the downregulation of Mcl-1 protein, but not Mcl-1 mRNA. PTC596 downregulated Mcl-1 protein expression at the post-translational level through the proteasome-ubiquitin system. PTC596 and BMI-1 siRNA induced downregulation of DUB3 deubiquitinase, which was strongly linked to Mcl-1 destabilization. Furthermore, overexpression of Mcl-1 or DUB3 inhibited apoptosis by PTC596. Taken together, our findings reveal that the inhibition of BMI-1 induces Mcl-1 destabilization through downregulation of DUB3, resulting in the induction of cancer cell death.

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