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Article ; Online: Modeling Molecular Pathogenesis of Idiopathic Pulmonary Fibrosis-Associated Lung Cancer in Mice.

Barravecchia, Ivana / Lee, Jennifer M / Manassa, Jason / Magnuson, Brian / Ferris, Sarah F / Cavanaugh, Sophia / Steele, Nina G / Espinoza, Carlos E / Galban, Craig J / Ramnath, Nithya / Frankel, Timothy L / Pasca di Magliano, Marina / Galban, Stefanie

Molecular cancer research : MCR

2023 Volume 22, Issue 3, Page(s) 295–307

Abstract: Idiopathic pulmonary fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. Patients with IPF have a sevenfold-increased risk of developing lung cancer. The COVID-19 ... ...

Abstract	Idiopathic pulmonary fibrosis (IPF) is characterized by progressive, often fatal loss of lung function due to overactive collagen production and tissue scarring. Patients with IPF have a sevenfold-increased risk of developing lung cancer. The COVID-19 pandemic has increased the number of patients with lung diseases, and infection can worsen prognoses for those with chronic lung diseases and disease-associated cancer. Understanding the molecular pathogenesis of IPF-associated lung cancer is imperative for identifying diagnostic biomarkers and targeted therapies that will facilitate prevention of IPF and progression to lung cancer. To understand how IPF-associated fibroblast activation, matrix remodeling, epithelial-to-mesenchymal transition (EMT), and immune modulation influences lung cancer predisposition, we developed a mouse model to recapitulate the molecular pathogenesis of pulmonary fibrosis-associated lung cancer using the bleomycin and Lewis lung carcinoma models. We demonstrate that development of pulmonary fibrosis-associated lung cancer is likely linked to increased abundance of tumor-associated macrophages and a unique gene signature that supports an immune-suppressive microenvironment through secreted factors. Not surprisingly, preexisting fibrosis provides a pre-metastatic niche and results in augmented tumor growth, and tumors associated with bleomycin-induced fibrosis are characterized by a dramatic loss of cytokeratin expression, indicative of EMT. Implications: This characterization of tumors associated with lung diseases provides new therapeutic targets that may aid in the development of treatment paradigms for lung cancer patients with preexisting pulmonary diseases.
MeSH term(s)	Humans ; Animals ; Mice ; Lung Neoplasms/genetics ; Pandemics ; Idiopathic Pulmonary Fibrosis/genetics ; Bleomycin/toxicity ; COVID-19 ; Tumor Microenvironment
Chemical Substances	Bleomycin (11056-06-7)
Language	English
Publishing date	2023-11-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-23-0480
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Zs.A 5744: Show issues

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Article: WITHDRAWN: Oncogenic KRAS

Lasse-Opsahl, Emily / Baliira, Rachael / Barravecchia, Ivana / McLintock, Elyse / Lee, Jennifer M / Ferris, Sarah F / Espinoza, Carlos E / Hinshaw, Rachael / Cavanaugh, Sophia / Robotti, Marzia / Brown, Kristee / Donahue, Katelyn / Abdelmalak, Kristena Y / Galban, Craig J / Frankel, Timothy L / Zhang, Yaqing / di Magliano, Marina Pasca / Galban, Stefanie

bioRxiv : the preprint server for biology

2024

Abstract: This manuscript has been withdrawn by the authors due to a dispute over co-first authorship that is currently being arbitrated by the medical school at our institution. Therefore, the authors do not wish this work to be cited as reference for the project. ...

Abstract	This manuscript has been withdrawn by the authors due to a dispute over co-first authorship that is currently being arbitrated by the medical school at our institution. Therefore, the authors do not wish this work to be cited as reference for the project. Upon completion of the arbitration process, we will take steps to revert the current withdrawn status. If you have any questions, please contact the corresponding author.
Language	English
Publishing date	2024-02-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.01.16.568090
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Targeting DNA Repair and Survival Signaling in Diffuse Intrinsic Pontine Gliomas to Prevent Tumor Recurrence.

Sharma, Monika / Barravecchia, Ivana / Teis, Robert / Cruz, Jeanette / Mumby, Rachel / Ziemke, Elizabeth K / Espinoza, Carlos E / Krishnamoorthy, Varunkumar / Magnuson, Brian / Ljungman, Mats / Koschmann, Carl / Chandra, Joya / Whitehead, Christopher E / Sebolt-Leopold, Judith S / Galban, Stefanie

Molecular cancer therapeutics

2023 Volume 23, Issue 1, Page(s) 24–34

Abstract: Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. ... ...

Abstract	Therapeutic resistance remains a major obstacle to successful clinical management of diffuse intrinsic pontine glioma (DIPG), a high-grade pediatric tumor of the brain stem. In nearly all patients, available therapies fail to prevent progression. Innovative combinatorial therapies that penetrate the blood-brain barrier and lead to long-term control of tumor growth are desperately needed. We identified mechanisms of resistance to radiotherapy, the standard of care for DIPG. On the basis of these findings, we rationally designed a brain-penetrant small molecule, MTX-241F, that is a highly selective inhibitor of EGFR and PI3 kinase family members, including the DNA repair protein DNA-PK. Preliminary studies demonstrated that micromolar levels of this inhibitor can be achieved in murine brain tissue and that MTX-241F exhibits promising single-agent efficacy and radiosensitizing activity in patient-derived DIPG neurospheres. Its physiochemical properties include high exposure in the brain, indicating excellent brain penetrance. Because radiotherapy results in double-strand breaks that are repaired by homologous recombination (HR) and non-homologous DNA end joining (NHEJ), we have tested the combination of MTX-241F with an inhibitor of Ataxia Telangiectasia Mutated to achieve blockade of HR and NHEJ, respectively, with or without radiotherapy. When HR blockers were combined with MTX-241F and radiotherapy, synthetic lethality was observed, providing impetus to explore this combination in clinically relevant models of DIPG. Our data provide proof-of-concept evidence to support advanced development of MTX-241F for the treatment of DIPG. Future studies will be designed to inform rapid clinical translation to ultimately impact patients diagnosed with this devastating disease.
MeSH term(s)	Humans ; Child ; Mice ; Animals ; Diffuse Intrinsic Pontine Glioma/drug therapy ; Diffuse Intrinsic Pontine Glioma/genetics ; Diffuse Intrinsic Pontine Glioma/metabolism ; Neoplasm Recurrence, Local ; DNA Repair ; Signal Transduction ; DNA/therapeutic use ; Brain Stem Neoplasms/drug therapy ; Brain Stem Neoplasms/genetics ; Brain Stem Neoplasms/pathology
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2023-08-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-23-0026
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Zs.A 5750: Show issues

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Article ; Online: Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions.

Carpenter, Eileen S / Elhossiny, Ahmed M / Kadiyala, Padma / Li, Jay / McGue, Jake / Griffith, Brian D / Zhang, Yaqing / Edwards, Jacob / Nelson, Sarah / Lima, Fatima / Donahue, Katelyn L / Du, Wenting / Bischoff, Allison C / Alomari, Danyah / Watkoske, Hannah R / Mattea, Michael / The, Stephanie / Espinoza, Carlos E / Barrett, Meredith /

Sonnenday, Christopher J / Olden, Nicholas / Chen, Chin-Tung / Peterson, Nicole / Gunchick, Valerie / Sahai, Vaibhav / Rao, Arvind / Bednar, Filip / Shi, Jiaqi / Frankel, Timothy L / Pasca di Magliano, Marina

Cancer discovery

2023 Volume 13, Issue 6, Page(s) 1324–1345

Abstract: The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors, thus avoiding any warm ... ...

Abstract	The adult healthy human pancreas has been poorly studied given the lack of indication to obtain tissue from the pancreas in the absence of disease and rapid postmortem degradation. We obtained pancreata from brain dead donors, thus avoiding any warm ischemia time. The 30 donors were diverse in age and race and had no known pancreas disease. Histopathologic analysis of the samples revealed pancreatic intraepithelial neoplasia (PanIN) lesions in most individuals irrespective of age. Using a combination of multiplex IHC, single-cell RNA sequencing, and spatial transcriptomics, we provide the first-ever characterization of the unique microenvironment of the adult human pancreas and of sporadic PanIN lesions. We compared healthy pancreata to pancreatic cancer and peritumoral tissue and observed distinct transcriptomic signatures in fibroblasts and, to a lesser extent, macrophages. PanIN epithelial cells from healthy pancreata were remarkably transcriptionally similar to cancer cells, suggesting that neoplastic pathways are initiated early in tumorigenesis. Significance: Precursor lesions to pancreatic cancer are poorly characterized. We analyzed donor pancreata and discovered that precursor lesions are detected at a much higher rate than the incidence of pancreatic cancer, setting the stage for efforts to elucidate the microenvironmental and cell-intrinsic factors that restrain or, conversely, promote malignant progression. See related commentary by Hoffman and Dougan, p. 1288. This article is highlighted in the In This Issue feature, p. 1275.
MeSH term(s)	Adult ; Humans ; Transcriptome ; Pancreas/pathology ; Pancreatic Neoplasms/pathology ; Carcinoma in Situ/genetics ; Carcinoma in Situ/metabolism ; Carcinoma in Situ/pathology ; Carcinoma, Pancreatic Ductal/pathology ; Tumor Microenvironment/genetics
Language	English
Publishing date	2023-03-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2159-8290.CD-23-0013
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 6916: Show issues

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Article ; Online: Apolipoprotein E Promotes Immune Suppression in Pancreatic Cancer through NF-κB-Mediated Production of CXCL1.

Kemp, Samantha B / Carpenter, Eileen S / Steele, Nina G / Donahue, Katelyn L / Nwosu, Zeribe C / Pacheco, Amanda / Velez-Delgado, Ashley / Menjivar, Rosa E / Lima, Fatima / The, Stephanie / Espinoza, Carlos E / Brown, Kristee / Long, Daniel / Lyssiotis, Costas A / Rao, Arvind / Zhang, Yaqing / Pasca di Magliano, Marina / Crawford, Howard C

Cancer research

2021 Volume 81, Issue 16, Page(s) 4305–4318

Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few effective therapeutic options. PDAC is characterized by an extensive fibroinflammatory stroma that includes abundant infiltrating immune cells. Tumor-associated macrophages (TAM) are ...

Abstract	Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few effective therapeutic options. PDAC is characterized by an extensive fibroinflammatory stroma that includes abundant infiltrating immune cells. Tumor-associated macrophages (TAM) are prevalent within the stroma and are key drivers of immunosuppression. TAMs in human and murine PDAC are characterized by elevated expression of apolipoprotein E (ApoE), an apolipoprotein that mediates cholesterol metabolism and has known roles in cardiovascular and Alzheimer's disease but no known role in PDAC. We report here that ApoE is also elevated in peripheral blood monocytes in PDAC patients, and plasma ApoE protein levels stratify patient survival. Orthotopic implantation of mouse PDAC cells into syngeneic wild-type or in
MeSH term(s)	Animals ; Apolipoproteins E/metabolism ; Cell Line, Tumor ; Chemokine CXCL1/biosynthesis ; Fibroblasts/metabolism ; Humans ; Immune System ; Immunosuppression Therapy ; Inflammation ; Macrophages/metabolism ; Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Mice, Knockout, ApoE ; NF-kappa B/metabolism ; Pancreatic Neoplasms/immunology ; Pancreatic Neoplasms/metabolism ; RNA-Seq ; Receptors, LDL/metabolism ; Signal Transduction ; Single-Cell Analysis ; Treatment Outcome
Chemical Substances	ApoE protein, human ; Apoe protein, mouse ; Apolipoproteins E ; CXCL1 protein, human ; Chemokine CXCL1 ; Cxcl1 protein, mouse ; NF-kappa B ; Receptors, LDL
Language	English
Publishing date	2021-05-28
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-20-3929
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Article ; Online: KRT17High/CXCL8+ tumor cells display both classical and basal features and regulate myeloid infiltration in the pancreatic cancer microenvironment.

Carpenter, Eileen S / Kadiyala, Padma / Elhossiny, Ahmed M / Kemp, Samantha B / Li, Jay / Steele, Nina G / Nicolle, Rémy / Nwosu, Zeribe C / Freeman, Julia / Dai, Henry / Paglia, Daniel / Du, Wenting / Donahue, Katelyn / Morales, Jacqueline / Medina-Cabrera, Paola I / Bonilla, Monica E / Harris, Lindsey / The, Stephanie / Gunchick, Valerie /

Peterson, Nicole / Brown, Kristee / Mattea, Michael / Espinoza, Carlos E / McGue, Jake / Kabala, Sarah M / Baliira, Rachel K / Renollet, Nur M / Mooney, Ayden G / Liu, Jianhua / Bhalla, Sean / Farida, Jeremy P / Ko, Christopher / Machicado, Jorge D / Kwon, Richard S / Wamsteker, Erik-Jan / Schulman, Allison / Anderson, Michelle A / Law, Ryan / Prabhu, Anoop / Coulombe, Pierre A / Rao, Arvind / Frankel, Timothy L / Bednar, Filip / Shi, Jiaqi / Sahai, Vaibhav / Pasca di Magliano, Marina

Clinical cancer research : an official journal of the American Association for Cancer Research

2023

Abstract: Purpose: Pancreatic ductal adenocarcinoma (PDAC) is generally divided in two subtypes, classical and basal. Recently, single cell RNA sequencing has uncovered the co-existence of basal and classical cancer cells, as well as intermediary cancer cells, in ...

Abstract	Purpose: Pancreatic ductal adenocarcinoma (PDAC) is generally divided in two subtypes, classical and basal. Recently, single cell RNA sequencing has uncovered the co-existence of basal and classical cancer cells, as well as intermediary cancer cells, in individual tumors. The latter remains poorly understood; here, we sought to characterize them using a multimodal approach. Experimental design: We performed subtyping on a single cell RNA sequencing dataset containing 18 human PDAC samples to identify multiple intermediary subtypes. We generated patient-derived PDAC organoids for functional studies. We compared single cell profiling of matched blood and tumor samples to measure changes in the local and systemic immune microenvironment. We then leveraged longitudinally patient-matched blood to follow individual patients over the course of chemotherapy. Results: We identified a cluster of KRT17-high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines. The proportion of KRT17High/CXCL8+ cells in patient tumors correlated with intra-tumoral myeloid abundance, and, interestingly, high pro-tumor peripheral blood granulocytes, implicating local and systemic roles. Patient-derived organoids maintained KRT17High/CXCL8+cells and induced myeloid cell migration in an CXCL8-dependent manner. In our longitudinal studies, plasma CXCL8 decreased following chemotherapy in responsive patients, while CXCL8 persistence portended worse prognosis. Conclusions: Through single cell analysis of PDAC samples we identified KRT17High/CXCL8+ cancer cells as an intermediary subtype, marked by a unique cytokine profile and capable of influencing myeloid cells in the tumor microenvironment and systemically. The abundance of this cell population should be considered for patient stratification in precision immunotherapy.
Language	English
Publishing date	2023-10-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-1421
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Zs.A 4223: Show issues

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Article ; Online: A Knowledge, Attitudes and Practices Survey Conducted Three Years after Halting Ivermectin Mass Treatment for Onchocerciasis in Guatemala.

Richards, Frank O / Klein, Robert E / de León, Oscar / Mendizábal-Cabrera, Renata / Morales, Alba Lucía / Cama, Vitaliano / Crovella, Carol G / Díaz Espinoza, Carlos E / Morales, Zoraida / Sauerbrey, Mauricio / Rizzo, Nidia

PLoS neglected tropical diseases

2016 Volume 10, Issue 6, Page(s) e0004777

Abstract: Background: Mass drug administration (MDA) with ivermectin for onchocerciasis was provided in Guatemala's Central Endemic Zone (CEZ) over a 24 year period (1988-2011). Elimination of Onchocerca volvulus transmission was declared in 2015 after a three ... ...

Abstract	Background: Mass drug administration (MDA) with ivermectin for onchocerciasis was provided in Guatemala's Central Endemic Zone (CEZ) over a 24 year period (1988-2011). Elimination of Onchocerca volvulus transmission was declared in 2015 after a three year post MDA surveillance period (2012-2014) showed no evidence of recrudescence. The purpose of the present study was to evaluate the knowledge, attitudes and practices (KAP) towards onchocerciasis and ivermectin among residents in the post endemic CEZ. A major interest in this study was to determine what community residents thought about the end of the ivermectin MDA program. Methodology/principal findings: A total of 148 interviews were conducted in November 2014 in four formerly hyperendemic communities using a standard questionnaire on smart phones. The majority (69%) of respondents knew that the MDA program had ended because the disease was no longer present in their communities, but a slight majority (53%) was personally unsure that onchocerciasis had really been eliminated. Sixty-three percent wanted to continue to receive ivermectin because of this uncertainty, or because ivermectin is effective against intestinal worms. Eighty-nine percent of respondents said that they would seek medical attention immediately if a family member had symptoms of onchocerciasis (especially the presence of a nodule), which is a finding very important for ongoing surveillance. Conclusions/significance: Many respondents wanted to continue receive ivermectin and more than half did not believe onchocerciasis had been eliminated. The ministry of health outreach services should be prepared to address ongoing concerns about onchocerciasis in the post endemic CEZ.
MeSH term(s)	Adult ; Antiparasitic Agents/administration & dosage ; Female ; Guatemala/epidemiology ; Health Education ; Health Knowledge, Attitudes, Practice ; Health Surveys ; Humans ; Ivermectin/administration & dosage ; Male ; Onchocerciasis/epidemiology ; Onchocerciasis/prevention & control ; Surveys and Questionnaires
Chemical Substances	Antiparasitic Agents ; Ivermectin (70288-86-7)
Language	English
Publishing date	2016-06-24
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2735
ISSN (online)	1935-2735
ISSN	1935-2735
DOI	10.1371/journal.pntd.0004777
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Modeling Molecular Pathogenesis of Idiopathic Pulmonary Fibrosis-Associated Lung Cancer in Mice.

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Article: WITHDRAWN: Oncogenic KRAS

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Article ; Online: Targeting DNA Repair and Survival Signaling in Diffuse Intrinsic Pontine Gliomas to Prevent Tumor Recurrence.

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Article ; Online: Analysis of Donor Pancreata Defines the Transcriptomic Signature and Microenvironment of Early Neoplastic Lesions.

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Article ; Online: Apolipoprotein E Promotes Immune Suppression in Pancreatic Cancer through NF-κB-Mediated Production of CXCL1.

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Article ; Online: KRT17High/CXCL8+ tumor cells display both classical and basal features and regulate myeloid infiltration in the pancreatic cancer microenvironment.

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Article ; Online: A Knowledge, Attitudes and Practices Survey Conducted Three Years after Halting Ivermectin Mass Treatment for Onchocerciasis in Guatemala.

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