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Artikel ; Online: Isolation and Characterization of a Novel Mammary Adenocarcinoma, MCa-P1362, with Hormone Receptor Expression, Human Epidermal Growth Factor Receptor 2 Positivity, and Enrichment in Cancer and Mesenchymal Stem Cells.

Jana, Samir / Li, Wende / Lei, Pin-Ji / Wang, Zixiong / Kibara, Shaye / Huang, Peigen / Jones, Dennis

2024 Band 194, Heft 6, Seite(n) 1137–1153

Abstract: Preclinical models that display spontaneous metastasis are necessary to improve the therapeutic options for hormone receptor-positive breast cancers. Within this study, detailed cellular and molecular characterization was conducted on MCa-P1362, a newly ... ...

Abstract	Preclinical models that display spontaneous metastasis are necessary to improve the therapeutic options for hormone receptor-positive breast cancers. Within this study, detailed cellular and molecular characterization was conducted on MCa-P1362, a newly established mouse model of metastatic breast cancer that is syngeneic in BALB/c mice. MCa-P1362 cancer cells express estrogen receptor, progesterone receptor, and the human epidermal growth factor receptor 2. MCa-P1362 cancer cells proliferate in vitro and in vivo in response to estrogen, yet do not depend on steroid hormones for growth and tumor progression. Analysis of MCa-P1362 tumor explants revealed the tumors contained a mixture of cancer cells and mesenchymal stromal cells. Through transcriptomic and functional analyses of both cancer and stromal cells, stem cells were detected within both populations. Functional studies demonstrated that MCa-P1362 cancer stem cells drove tumor initiation, whereas stromal cells from these tumors contributed to drug resistance. MCa-P1362 may serve as a useful preclinical model to investigate the cellular and molecular basis of breast tumor progression and therapeutic resistance.
Mesh-Begriff(e)	Animals ; Mesenchymal Stem Cells/metabolism ; Mesenchymal Stem Cells/pathology ; Female ; Humans ; Receptor, ErbB-2/metabolism ; Mice, Inbred BALB C ; Mice ; Receptors, Estrogen/metabolism ; Adenocarcinoma/pathology ; Adenocarcinoma/metabolism ; Receptors, Progesterone/metabolism ; Breast Neoplasms/pathology ; Breast Neoplasms/metabolism ; Breast Neoplasms/genetics ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Cell Line, Tumor ; Mammary Neoplasms, Experimental/pathology ; Mammary Neoplasms, Experimental/metabolism
Sprache	Englisch
Erscheinungsdatum	2024-05-15
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2024.02.013
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: "Isolation and characterization of a novel hormone receptor positive mammary adenocarcinoma MCa-P1362 with stromal drivers of tumor growth, metastasis, and drug resistance".

Jana, Samir / Li, Wende / Lei, Pin-Ji / Wang, Zixiong / Huang, Peigen / Jones, Dennis

bioRxiv : the preprint server for biology

2023

Abstract: Preclinical models that display spontaneous metastasis are necessary to improve therapeutic options for hormone receptor positive breast cancers. In this study, we conducted a detailed cellular and molecular characterization of MCa-P1362, a novel ... ...

Abstract	Preclinical models that display spontaneous metastasis are necessary to improve therapeutic options for hormone receptor positive breast cancers. In this study, we conducted a detailed cellular and molecular characterization of MCa-P1362, a novel syngeneic Balb/c mouse model of metastatic breast cancer. MCa-P1362 cancer cells expressed estrogen receptors (ER), progesterone receptors (PR), and HER-2 receptors. MCa-P1362 cells proliferate in vitro and in vivo in response to estrogen, yet do not depend on steroid hormones for tumor progression. Further characterization of MCa-P1362 tumor explants shows that they contain a mixture of epithelial cancer cells and stromal cells. Based on transcriptomic and functional analyses of cancer and stromal cells, stem cells are present in both populations. Functional studies demonstrate that crosstalk between cancer and stromal cells promotes tumor growth, metastasis, and drug resistance. MCa-P1362 may serve as a useful preclinical model to investigate the cellular and molecular basis of hormone receptor positive tumor progression and therapeutic resistance.
Sprache	Englisch
Erscheinungsdatum	2023-06-06
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2023.06.02.543434
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Glycocalyx mechanotransduction mechanisms are involved in renal cancer metastasis.

Moran, Heriberto / Cancel, Limary M / Huang, Peigen / Roberge, Sylvie / Xu, Tuoye / Tarbell, John M / Munn, Lance L

Matrix biology plus

2022 Band 13, Seite(n) 100100

Abstract: Mammalian cells, including cancer cells, are covered by a surface layer containing cell bound proteoglycans, glycoproteins, associated glycosaminoglycans and bound proteins that is commonly referred to as the glycocalyx. Solid tumors also have a dynamic ... ...

Abstract	Mammalian cells, including cancer cells, are covered by a surface layer containing cell bound proteoglycans, glycoproteins, associated glycosaminoglycans and bound proteins that is commonly referred to as the glycocalyx. Solid tumors also have a dynamic fluid microenvironment with elevated interstitial flow. In the present work we further investigate the hypothesis that interstitial flow is sensed by the tumor glycocalyx leading to activation of cell motility and metastasis. Using a highly metastatic renal carcinoma cell line (SN12L1) and its low metastatic counterpart (SN12C) we demonstrate in vitro that the small molecule Suberoylanilide Hydroxamic Acid (SAHA) inhibits the heparan sulfate synthesis enzyme N-deacetylase-N-sulfotransferase-1, reduces heparan sulfate in the glycocalyx and suppresses SN12L1 motility in response to interstitial flow. SN12L1 cells implanted in the kidney capsule of SCID mice formed large primary tumors and metastasized to distant organs, but when treated with SAHA metastases were not detected. In another set of experiments, the role of hyaluronic acid was investigated. Hyaluronan synthase 1, a critical enzyme in the synthetic pathway for hyaluronic acid, was knocked down in SN12L1 cells and in vitro experiments revealed inhibition of interstitial flow induced migration. Subsequently these cells were implanted in mouse kidneys and no distant metastases were detected. These findings suggest new therapeutic approaches to the treatment of kidney carcinoma metastasis.
Sprache	Englisch
Erscheinungsdatum	2022-01-06
Erscheinungsland	Netherlands
Dokumenttyp	Journal Article
ISSN	2590-0285
ISSN (online)	2590-0285
DOI	10.1016/j.mbplus.2021.100100
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Turning anecdotal irradiation-induced anticancer immune responses into reproducible in situ cancer vaccines via disulfiram/copper-mediated enhanced immunogenic cell death of breast cancer cells.

Guo, Wei / Jia, Lin / Xie, Ling / Kiang, Juliann G / Wang, Yangyang / Sun, Fengfei / Lin, Zunwen / Wang, Enwen / Zhang, Yida / Huang, Peigen / Sun, Ting / Zhang, Xiao / Bian, Zhengying / Tang, Tiejun / Guo, Jingtian / Ferrone, Soldano / Wang, Xinhui

Cell death & disease

2024 Band 15, Heft 4, Seite(n) 298

Abstract: Irradiation (IR) induces immunogenic cell death (ICD) in tumors, but it rarely leads to the abscopal effect (AE); even combining IR with immune checkpoint inhibitors has shown only anecdotal success in inducing AEs. In this study, we aimed to enhance the ...

Abstract	Irradiation (IR) induces immunogenic cell death (ICD) in tumors, but it rarely leads to the abscopal effect (AE); even combining IR with immune checkpoint inhibitors has shown only anecdotal success in inducing AEs. In this study, we aimed to enhance the IR-induced immune response and generate reproducible AEs using the anti-alcoholism drug, disulfiram (DSF), complexed with copper (DSF/Cu) to induce tumor ICD. We measured ICD in vitro and in vivo. In mouse tumor models, DSF/Cu was injected intratumorally followed by localized tumor IR, creating an in situ cancer vaccine. We determined the anticancer response by primary tumor rejection and assessed systemic immune responses by tumor rechallenge and the occurrence of AEs relative to spontaneous lung metastasis. In addition, we analyzed immune cell subsets and quantified proinflammatory and immunosuppressive chemokines/cytokines in the tumor microenvironment (TME) and blood of the vaccinated mice. Immune cell depletion was investigated for its effects on the vaccine-induced anticancer response. The results showed that DSF/Cu and IR induced more potent ICD under hypoxia than normoxia in vitro. Low-dose intratumoral (i.t.) injection of DSF/Cu and IR(12Gy) demonstrated strong anti-primary and -rechallenged tumor effects and robust AEs in mouse models. These vaccinations also increased CD8
Mesh-Begriff(e)	Disulfiram/pharmacology ; Animals ; Cancer Vaccines/pharmacology ; Cancer Vaccines/immunology ; Female ; Mice ; Immunogenic Cell Death/drug effects ; Copper/pharmacology ; Humans ; Breast Neoplasms/immunology ; Breast Neoplasms/pathology ; Breast Neoplasms/drug therapy ; Cell Line, Tumor ; Tumor Microenvironment/drug effects ; Mice, Inbred BALB C
Chemische Substanzen	Disulfiram (TR3MLJ1UAI) ; Cancer Vaccines ; Copper (789U1901C5)
Sprache	Englisch
Erscheinungsdatum	2024-04-27
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-024-06644-3
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Absence of Tissue-Sparing Effects in Partial Proton FLASH Irradiation in Murine Intestine.

Zhang, Qixian / Gerweck, Leo E / Cascio, Ethan / Gu, Liqun / Yang, Qingyuan / Dong, Xinyue / Huang, Peigen / Bertolet, Alejandro / Nesteruk, Konrad Pawel / Sung, Wonmo / McNamara, Aimee L / Schuemann, Jan

Cancers

2023 Band 15, Heft 8

Abstract: Ultra-high dose rate irradiation has been reported to protect normal tissues more than conventional dose rate irradiation. This tissue sparing has been termed the FLASH effect. We investigated the FLASH effect of proton irradiation on the intestine as ... ...

Abstract	Ultra-high dose rate irradiation has been reported to protect normal tissues more than conventional dose rate irradiation. This tissue sparing has been termed the FLASH effect. We investigated the FLASH effect of proton irradiation on the intestine as well as the hypothesis that lymphocyte depletion is a cause of the FLASH effect. A 16 × 12 mm
Sprache	Englisch
Erscheinungsdatum	2023-04-13
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15082269
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Wnt inhibition alleviates resistance to immune checkpoint blockade in glioblastoma.

Jain, Rakesh / Krishnan, Shanmugarajan / Lee, Somin / Amoozgar, Zohreh / Subudhi, Sonu / Kumar, Ashwin / Posada, Jessica / Lindeman, Neal / Lei, Pinji / Duquette, Mark / Roberge, Sylvie / Huang, Peigen / Andersson, Patrik / Datta, Meenal / Munn, Lance / Fukumura, Dai

Research square

2023

Abstract: Wnt signaling plays a critical role in the progression and treatment outcome of glioblastoma (GBM). Here, we identified WNT7b as a heretofore unknown mechanism of resistance to immune checkpoint inhibition (αPD1) in GBM patients and murine models. ... ...

Abstract	Wnt signaling plays a critical role in the progression and treatment outcome of glioblastoma (GBM). Here, we identified WNT7b as a heretofore unknown mechanism of resistance to immune checkpoint inhibition (αPD1) in GBM patients and murine models. Acquired resistance to αPD1 was found to be associated with the upregulation of Wnt7b and β-catenin protein levels in GBM in patients and in a clinically relevant, stem-rich GBM model. Combining the porcupine inhibitor WNT974 with αPD1 prolonged the survival of GBM-bearing mice. However, this combination had a dichotomous response, with a subset of tumors showing refractoriness. WNT974 and αPD1 expanded a subset of DC3-like dendritic cells (DCs) and decreased the granulocytic myeloid-derived suppressor cells (gMDSCs) in the tumor microenvironment (TME). By contrast, monocytic MDSCs (mMDSCs) increased, while T-cell infiltration remained unchanged, suggesting potential TME-mediated resistance. Our preclinical findings warrant the testing of Wnt7b/β-catenin combined with αPD1 in GBM patients with elevated Wnt7b/β-catenin signaling.
Sprache	Englisch
Erscheinungsdatum	2023-12-26
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.21203/rs.3.rs-3707472/v1
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Proton FLASH effects on mouse skin at different oxygen tensions.

Zhang, Qixian / Gerweck, Leo E / Cascio, Ethan / Yang, Qingyuan / Huang, Peigen / Niemierko, Andrzej / Bertolet, Alejandro / Nesteruk, Konrad Pawel / McNamara, Aimee / Schuemann, Jan

Physics in medicine and biology

2023 Band 68, Heft 5

Abstract: ... ...

Abstract	Objective
Mesh-Begriff(e)	Mice ; Animals ; Protons ; Proton Therapy/methods ; Oxygen ; Skin ; Photons ; Radiotherapy Dosage
Chemische Substanzen	Protons ; Oxygen (S88TT14065)
Sprache	Englisch
Erscheinungsdatum	2023-02-27
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	208857-5
ISSN	1361-6560 ; 0031-9155
ISSN (online)	1361-6560
ISSN	0031-9155
DOI	10.1088/1361-6560/acb888
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Reprogramming the Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD-1 Therapy.

Cancer immunology research

2024 Band 12, Heft 4, Seite(n) 400–412

Abstract: Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the anti-programmed cell death protein (PD)-1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract ... ...

Abstract	Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Adding blockade of the anti-programmed cell death protein (PD)-1 pathway to gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers but with low response rates. Here, we studied the effects of anti-cytotoxic T lymphocyte antigen (CTLA)-4 when combined with anti-PD-1 and gemcitabine/cisplatin in orthotopic murine models of ICC. This combination therapy led to substantial survival benefits and reduction of morbidity in two aggressive ICC models that were resistant to immunotherapy alone. Gemcitabine/cisplatin treatment increased tumor-infiltrating lymphocytes and normalized the ICC vessels and, when combined with dual CTLA-4/PD-1 blockade, increased the number of activated CD8+Cxcr3+IFNγ+ T cells. CD8+ T cells were necessary for the therapeutic benefit because the efficacy was compromised when CD8+ T cells were depleted. Expression of Cxcr3 on CD8+ T cells is necessary and sufficient because CD8+ T cells from Cxcr3+/+ but not Cxcr3-/- mice rescued efficacy in T cell‒deficient mice. Finally, rational scheduling of anti-CTLA-4 "priming" with chemotherapy followed by anti-PD-1 therapy achieved equivalent efficacy with reduced overall drug exposure. These data suggest that this combination approach should be clinically tested to overcome resistance to current therapies in ICC patients.
Mesh-Begriff(e)	Animals ; Humans ; Mice ; CD8-Positive T-Lymphocytes ; Cholangiocarcinoma/drug therapy ; Cholangiocarcinoma/metabolism ; Cisplatin/therapeutic use ; CTLA-4 Antigen/antagonists & inhibitors ; Gemcitabine/therapeutic use ; Tumor Microenvironment
Chemische Substanzen	Cisplatin (Q20Q21Q62J) ; CTLA-4 Antigen ; Gemcitabine
Sprache	Englisch
Erscheinungsdatum	2024-01-22
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-23-0486
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Preventing NK cell activation in the damaged liver induced by cabozantinib/PD-1 blockade increases survival in hepatocellular carcinoma models.

Morita, Satoru / Kikuchi, Hiroto / Birch, Grace / Matsui, Aya / Morita, Atsuyo / Kobayashi, Tatsuya / Ruan, Zhiping / Huang, Peigen / Hernandez, Alexei / Coyne, Erin M / Shin, Sarah M / Yarchoan, Mark / Mino-Kenudson, Mari / Romee, Rizwan / Ho, Won Jin / Duda, Dan G

bioRxiv : the preprint server for biology

2023

Abstract: The addition of anti-VEGF antibody treatment to immune checkpoint blockade (ICB) has increased the efficacy of immunotherapy in advanced hepatocellular carcinoma (HCC). Despite an initial promise, adding multitargeted kinase inhibitors of VEGFR with ICB ... ...

Abstract	The addition of anti-VEGF antibody treatment to immune checkpoint blockade (ICB) has increased the efficacy of immunotherapy in advanced hepatocellular carcinoma (HCC). Despite an initial promise, adding multitargeted kinase inhibitors of VEGFR with ICB has failed to increase survival in HCC. To reveal the mechanisms underlying treatment failure, we studied the effects of cabozantinib/ICB using orthotopic murine HCC models with or without liver damage. We monitored tumor growth and liver function, recorded survival outcomes, and performed immune profiling studies for intra-tumoral and surrounding liver. Cabozantinib/ICB treatment led to tumor regression and significantly improved survival in mice with normal livers. However, consistent with the clinical findings, combination therapy failed to show survival benefits despite similar tumor control when tested in the same models but in mice with liver fibrosis. Moreover, preclinical and clinical data converged, showing that activating immune responses by cabozantinib/ICB treatment induced hepatoxicity. Immune profiling revealed that combination therapy effectively reprogrammed the tumor immune microenvironment and increased NK cell infiltration and activation in the damaged liver tissue. Surprisingly, systemic depletion of NK reduced hepatotoxicity elicited by the combination therapy without compromising its anti-cancer effect, and significantly enhanced the survival benefit even in mice with HCC and underlying liver fibrosis. These findings demonstrate that preventing NK activation allowed for maintaining a favorable therapeutic ratio when combining ICB with cabozantinib in advanced HCC models.
Sprache	Englisch
Erscheinungsdatum	2023-10-23
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2023.10.20.563378
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Inhibition of CXCR4 Enhances the Efficacy of Radiotherapy in Metastatic Prostate Cancer Models.

Gupta, Nisha / Ochiai, Hiroki / Hoshino, Yoshinori / Klein, Sebastian / Zustin, Jozef / Ramjiawan, Rakesh R / Kitahara, Shuji / Maimon, Nir / Bazou, Despina / Chiang, Sarah / Li, Sen / Schanne, Daniel H / Jain, Rakesh K / Munn, Lance L / Huang, Peigen / Kozin, Sergey V / Duda, Dan G

Cancers

2023 Band 15, Heft 4

Abstract: Radiotherapy (RT) is a standard treatment for patients with advanced prostate cancer (PCa). Previous preclinical studies showed that SDF1α/CXCR4 axis could mediate PCa metastasis (most often to the bones) and cancer resistance to RT. We found high levels ...

Abstract	Radiotherapy (RT) is a standard treatment for patients with advanced prostate cancer (PCa). Previous preclinical studies showed that SDF1α/CXCR4 axis could mediate PCa metastasis (most often to the bones) and cancer resistance to RT. We found high levels of expression for both SDF1α and its receptor CXCR4 in primary and metastatic PCa tissue samples. In vitro analyses using PCa cells revealed an important role of CXCR4 in cell invasion but not radiotolerance. Pharmacologic inhibition of CXCR4 using AMD3100 showed no efficacy in orthotopic primary and bone metastatic PCa models. However, when combined with RT, AMD3100 potentiated the effect of local single-dose RT (12 Gy) in both models. Moreover, CXCR4 inhibition also reduced lymph node metastasis from primary PCa. Notably, CXCR4 inhibition promoted the normalization of bone metastatic PCa vasculature and reduced tissue hypoxia. In conclusion, the SDF1α/CXCR4 axis is a potential therapeutic target in metastatic PCa patients treated with RT.
Sprache	Englisch
Erscheinungsdatum	2023-02-06
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15041021
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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