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Oncology

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The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma
Zirong Chen, … , Frederic J. Kaye, Lizi Wu
Zirong Chen, … , Frederic J. Kaye, Lizi Wu
Published April 8, 2021
Citation Information: JCI Insight. 2021;6(7):e139497. https://doi.org/10.1172/jci.insight.139497.
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The CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma

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Abstract

No effective systemic treatment is available for patients with unresectable, recurrent, or metastatic mucoepidermoid carcinoma (MEC), the most common salivary gland malignancy. MEC is frequently associated with a t(11;19)(q14-21;p12-13) translocation that creates a CRTC1-MAML2 fusion gene. The CRTC1-MAML2 fusion exhibited transforming activity in vitro; however, whether it serves as an oncogenic driver for MEC establishment and maintenance in vivo remains unknown. Here, we show that doxycycline-induced CRTC1-MAML2 knockdown blocked the growth of established MEC xenografts, validating CRTC1-MAML2 as a therapeutic target. We further generated a conditional transgenic mouse model and observed that Cre-induced CRTC1-MAML2 expression caused 100% penetrant formation of salivary gland tumors resembling histological and molecular characteristics of human MEC. Molecular analysis of MEC tumors revealed altered p16-CDK4/6-RB pathway activity as a potential cooperating event in promoting CRTC1-MAML2–induced tumorigenesis. Cotargeting of aberrant p16-CDK4/6-RB signaling and CRTC1-MAML2 fusion–activated AREG/EGFR signaling with the respective CDK4/6 inhibitor Palbociclib and EGFR inhibitor Erlotinib produced enhanced antitumor responses in vitro and in vivo. Collectively, this study provides direct evidence for CRTC1-MAML2 as a key driver for MEC development and maintenance and identifies a potentially novel combination therapy with FDA-approved EGFR and CDK4/6 inhibitors as a potential viable strategy for patients with MEC.

Authors

Zirong Chen, Wei Ni, Jian-Liang Li, Shuibin Lin, Xin Zhou, Yuping Sun, Jennifer W. Li, Marino E. Leon, Maria D. Hurtado, Sergei Zolotukhin, Chen Liu, Jianrong Lu, James D. Griffin, Frederic J. Kaye, Lizi Wu

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Selective targeting of KRAS-driven lung tumorigenesis via unresolved ER stress
Iwao Shimomura, … , Takahiro Ochiya, Yusuke Yamamoto
Iwao Shimomura, … , Takahiro Ochiya, Yusuke Yamamoto
Published April 8, 2021
Citation Information: JCI Insight. 2021;6(7):e137876. https://doi.org/10.1172/jci.insight.137876.
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Selective targeting of KRAS-driven lung tumorigenesis via unresolved ER stress

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Abstract

Lung cancer with oncogenic KRAS makes up a significant proportion of lung cancers and is accompanied by a poor prognosis. Recent advances in understanding the molecular pathogenesis of lung cancer with oncogenic KRAS have enabled the development of drugs, yet mutated KRAS remains undruggable. We performed small-molecule library screening and identified verteporfin, a yes-associated protein 1 (YAP1) inhibitor; verteporfin treatment markedly reduced cell viability in KRAS-mutant lung cancer cells in vitro and suppressed KRAS-driven lung tumorigenesis in vivo. Comparative functional analysis of verteporfin treatment and YAP1 knockdown with siRNA revealed that the cytotoxic effect of verteporfin was at least partially independent of YAP1 inhibition. A whole-transcriptome approach revealed the distinct expression profiles in KRAS-mutant lung cancer cells between verteporfin treatment and YAP1 knockdown and identified the selective involvement of the ER stress pathway in the effects of verteporfin treatment in KRAS-mutant lung cancer, leading to apoptotic cell death. These data provide novel insight to uncover vulnerabilities in KRAS-driven lung tumorigenesis.

Authors

Iwao Shimomura, Naoaki Watanabe, Tomofumi Yamamoto, Minami Kumazaki, Yuji Tada, Koichiro Tatsumi, Takahiro Ochiya, Yusuke Yamamoto

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PALLD mutation in a European family conveys a stromal predisposition for familial pancreatic cancer
Lucia Liotta, … , Maximilian Reichert, Michael Quante
Lucia Liotta, … , Maximilian Reichert, Michael Quante
Published March 25, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.141532.
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PALLD mutation in a European family conveys a stromal predisposition for familial pancreatic cancer

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Abstract

Background and aims: Pancreatic cancer is one of the deadliest cancers, still with low long term survival rates. Despite recent advances in treatment, it is extremely important to screen high-risk individuals in order to establish preventive and early detection measures and, in some cases, molecular driven therapeutic options. Familial pancreatic cancer (FPC) accounts for 4%-10% of pancreatic cancers. Several germline mutations are known to be related with an increased risk and might offer novel screening and therapy options. In this study, our goal was to discover the identity of a familial pancreatic cancer gene in two members of a family with FPC. Methods: Whole exome sequencing and PCR confirmation was performed on the surgical specimen and peripheral blood of an index patient and her sister in a family with high incidence of pancreatic cancer, to identify somatic and germline mutations associated with familial pancreatic cancer. Compartment-specific gene expression data and immunohistochemistry was used to characterize PALLD expression. Results: A germline mutation of the PALLD gene (NM_001166108.1:c.G154A:p.D52N) was detected in the index patient with pancreatic cancer. The identical PALLD mutation was identified in the tumor tissue of her sister. Whole genome sequencing showed similar somatic mutation patterns between the two sisters. Apart from the PALLD mutation, commonly mutated genes that characterize PDAC (KRAS and CDKN2A) were found in both tumor samples. However, the two patients harbored different somatic KRAS mutations (respectively G12D in the index patient and G12V in the index patient’s sister). Analysis for PALLD mutation in the healthy siblings of the two sisters was negative, indicating that the identified PALLD mutation might have a disease specific impact. Of note, compartment-specific gene expression data and IHC suggested a predominant role in cancer associated fibroblasts (CAFs). Conclusion: We identified a germline mutation of the palladin (PALLD) gene in two siblings in Europe, affected by familial pancreatic cancer, with a predominant function in the tumor stroma.

Authors

Lucia Liotta, Sebastian Lange, H. Carlo Maurer, Kenneth P. Olive, Rickmer Braren, Nicole Pfarr, Alexander Muckenhuber, Moritz Jesinghaus, Wilko Weichert, Katja Steiger, Sebastian Burger, Helmut Friess, Roland M. Schmid, Hana Alguel, Philipp Jost, Juliane Ramser, Christine Fischer, Anne S. Quante, Maximilian Reichert, Michael Quante

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Importance of lymph node immune responses in MSI-H/dMMR colorectal cancer
Koji Inamori, … , Masaaki Ito, Hiroyoshi Nishikawa
Koji Inamori, … , Masaaki Ito, Hiroyoshi Nishikawa
Published March 23, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.137365.
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Importance of lymph node immune responses in MSI-H/dMMR colorectal cancer

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Abstract

Patients with colorectal cancers (CRCs) generally exhibit improved survival through intensive lymph node (LN) dissection. However, recent progress in cancer immunotherapy revisits the potential importance of regional LNs, where T cells are primed to attack tumor cells. To elucidate the role of regional LN, we investigated the immunological status of non-metastatic regional LN lymphocytes (LNLs) in comparison with those in the tumor microenvironment (tumor-infiltrating lymphocytes; TILs) using flow cytometry and next-generation sequencing. LNLs comprised an intermediate level of the effector T cell population between peripheral blood lymphocytes (PBLs) and TILs. Significant overlap of the T-cell receptor (TCR) repertoire was observed in microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) CRCs with high tumor mutation burden (TMB), although limited TCRs were shared between non-metastatic LNs and primary tumors in microsatellite stable (MSS)/MMR proficient (pMMR) CRC patients with low TMB. In line with the overlap of the TCR repertoire, an excessive LN dissection did not provide a positive impact on long-term prognosis in our MSI-H/dMMR CRC cohort (n =130). We propose that regional LNs play an important role in antitumor immunity, particularly in MSI-H/dMMR CRCs with high TMB, requiring to be careful of excessive non-metastatic LN dissection in MSI-H/dMMR CRC patients.

Authors

Koji Inamori, Yosuke Togashi, Shota Fukuoka, Kiwamu Akagi, Kouetsu Ogasawara, Takuma Irie, Daisuke Motooka, Yoichi Kobayashi, Daisuke Sugiyama, Motohiro Kojima, Norihiko Shiiya, Shota Nakamura, Shoichi Maruyama, Yutaka Suzuki, Masaaki Ito, Hiroyoshi Nishikawa

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Resistance to androgen receptor signaling inhibition does not necessitate development of neuroendocrine prostate cancer
W. Nathaniel Brennen, … , William B. Isaacs, John T. Isaacs
W. Nathaniel Brennen, … , William B. Isaacs, John T. Isaacs
Published March 16, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.146827.
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Resistance to androgen receptor signaling inhibition does not necessitate development of neuroendocrine prostate cancer

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Abstract

Resistance to AR signaling inhibitors (ARSi) in a subset of metastatic castration-resistant prostate cancers (mCRPC) occurs with emergence of AR-negative Neuroendocrine Prostate Cancer (NEPC), coupled with mutations/deletions in PTEN, TP53, RB1, and overexpression of DNMTs, EZH2, and/or SOX2. To resolve whether lack of AR is the driving factor for the emergence of the NE phenotype, molecular, cell, and tumor biology analyses were performed on 23 prostate cancer patient-derived xenografts recapitulating the full spectrum of genetic alterations proposed to drive NE differentiation. Additionally, phenotypic response to CRISPR-Cas9-mediated AR knockout in AR-positive CRPC cells was evaluated. These analyses document that: 1) ARSi-resistant NEPC can develop without androgen deprivation treatment; 2) AR signaling in ARSi-resistant AR+/NE+ double positive “amphicrine” mCRPCs does not suppress NE differentiation; 3) lack of AR expression does not necessitate acquiring a NE phenotype despite concomitant mutations/deletions in PTEN and TP53, and loss of RB1, but can occur via emergence of an AR-/NE- double negative prostate cancer (DNPC); 4) despite DNPC cells having homogeneous genetic driver mutations, they are phenotypically heterogeneous, expressing basal lineage markers alone or in combination with luminal lineage markers; and 5) AR loss is associated with AR promoter hypermethylation in NEPCs but not in DNPCs.

Authors

W. Nathaniel Brennen, Yezi Zhu, Ilsa M. Coleman, Susan L. Dalrymple, Lizamma Antony, Radhika A. Patel, Brian Hanratty, Roshan Chikarmane, Alan K. Meeker, S. Lilly Zheng, Jody E. Hooper, Jun Luo, Angelo M. De Marzo, Eva Corey, Jianfeng Xu, Srinivasan Yegnasubramanian, Michael C. Haffner, Peter S. Nelson, William G. Nelson, William B. Isaacs, John T. Isaacs

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A global live cell barcoding approach for multiplexed mass cytometry profiling of mouse tumors
Soren Charmsaz, … , Elizabeth Jaffee, Won Jin Ho
Soren Charmsaz, … , Elizabeth Jaffee, Won Jin Ho
Published March 9, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.143283.
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A global live cell barcoding approach for multiplexed mass cytometry profiling of mouse tumors

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Abstract

With the advent of cancer immunology, mass cytometry has been increasingly employed to characterize the responses to cancer therapies and the tumor microenvironment (TME). One of its most notable applications is efficient multiplexing of samples into batches by dedicating a number of metal isotope channels to barcodes, enabling robust data acquisition and analysis. Barcoding is most effective when markers are present in all cells of interest. While CD45 has been shown to be a reliable marker for barcoding all immune cells in a given sample, a strategy to reliably barcode mouse cancer cells has not been demonstrated. To this end, we identified CD29 and CD98 as markers widely expressed by commonly used mouse cancer cell lines. We conjugated anti-CD29 and anti-CD98 antibodies to cadmium or indium metals and validated their utility in 10-plex barcoding of live cells. Finally, we established a novel barcoding system incorporating the combination of CD29, CD98, and CD45 to multiplex ten tumors from subcutaneous MC38 and KPC tumor models, while successfully recapitulating the known contrast in the PD1-PDL1 axis between the two models. The ability to barcode tumor cells along with immune cells empowers the interrogation of the tumor-immune interactions in mouse TME studies.

Authors

Soren Charmsaz, Nicole Gross, Elizabeth Jaffee, Won Jin Ho

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Characterization of a recombinant gorilla-adenovirus HPV therapeutic vaccine (PRGN-2009)
Samuel T. Pellom, … , Jeffrey Schlom, Caroline Jochems
Samuel T. Pellom, … , Jeffrey Schlom, Caroline Jochems
Published March 2, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.141912.
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Characterization of a recombinant gorilla-adenovirus HPV therapeutic vaccine (PRGN-2009)

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Abstract

There are approximately 44,000 cases of human papilloma virus (HPV)‒associated cancer each year in the United States, most commonly caused by HPV16/18. Prophylactic vaccines successfully prevent healthy people from acquiring HPV infections via HPV-specific antibodies. To treat established HPV-associated malignancies, however, new therapies are necessary. Multiple recombinant gorilla adenovirus HPV vaccine constructs were evaluated in NSG β2m-/- peripheral blood mononuclear cell–humanized mice bearing SiHa, a human HPV16+ cervical tumor, and/or in the syngeneic HPV16+ TC-1 model. PRGN-2009 is a new therapeutic gorilla adenovirus HPV vaccine containing multiple cytotoxic T-cell epitopes of the viral oncoproteins HPV 16/18 E6 and E7, including T-cell enhancer agonist epitopes. PRGN-2009 treatment reduced tumor volume and increased CD8 and CD4 T cells in the tumor microenvironment of humanized mice bearing the human cervical tumor SiHa. PRGN-2009 monotherapy in the syngeneic TC-1 model also reduced tumor volumes and weights, generated high levels of HPV16 E6-specific T cells, and increased multifunctional CD8 and CD4 T cells in the tumor microenvironment. These studies provide the first evaluation of a therapeutic gorilla adenovirus HPV vaccine, PRGN-2009, showing promising preclinical anti-tumor efficacy and induction of HPV-specific T cells, and the rationale for its evaluation in clinical trials.

Authors

Samuel T. Pellom, Claire Smalley Rumfield, Y. Maurice Morillon II, Nicholas Roller, Lisa K. Poppe, Douglas E. Brough, Helen Sabzevari, Jeffrey Schlom, Caroline Jochems

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FcγRIIB is a T cell checkpoint in antitumor immunity
Clara R. Farley, … , Michael C. Lowe, Mandy L. Ford
Clara R. Farley, … , Michael C. Lowe, Mandy L. Ford
Published February 22, 2021
Citation Information: JCI Insight. 2021;6(4):e135623. https://doi.org/10.1172/jci.insight.135623.
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FcγRIIB is a T cell checkpoint in antitumor immunity

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Abstract

In the setting of cancer, T cells upregulate coinhibitory molecules that attenuate TCR signaling and lead to the loss of proliferative capacity and effector function. Checkpoint inhibitors currently in clinical use have dramatically improved mortality from melanoma yet are not effective in all patients, suggesting that additional pathways may contribute to suppression of tumor-specific CD8+ T cell responses in melanoma. Here, we show that FcγRIIB, an inhibitory Fc receptor previously thought to be exclusively expressed on B cells and innate immune cells, is upregulated on tumor-infiltrating effector CD8+ T cells in an experimental melanoma model and expressed on CD8+ T cells in patients with melanoma. Genetic deficiency of Fcgr2b resulted in enhanced tumor-infiltrating CD8+ T cell responses and significantly reduced tumor burden. Adoptive transfer experiments of Fcgr2b–/– tumor antigen-specific T cells into FcγRIIB-sufficient hosts resulted in an increased frequency of tumor-infiltrating CD8+ T cells with greater effector function. Finally, FcγRIIB was expressed on CD8+ memory T cells isolated from patients with melanoma. These data illuminate a cell-intrinsic role for the FcγRIIB checkpoint in suppressing tumor-infiltrating CD8+ T cells.

Authors

Clara R. Farley, Anna B. Morris, Marvi Tariq, Kelsey B. Bennion, Sayalee Potdar, Ragini Kudchadkar, Michael C. Lowe, Mandy L. Ford

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Chromosome 8 gain is associated with high-grade transformation in MPNST
Carina A. Dehner, … , Jack F. Shern, Angela C. Hirbe
Carina A. Dehner, … , Jack F. Shern, Angela C. Hirbe
Published February 16, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.146351.
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Chromosome 8 gain is associated with high-grade transformation in MPNST

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Abstract

One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma which commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven success in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared to the primary tumors from which they were derived using copy number analysis, whole-exome and RNA sequencing. We identified chromosome 8 gain as a recurrent genomic event in MPNST and validated its occurrence by FISH in the PDX and parental tumors, in a validation cohort, and by single cell sequencing in the PDX. Finally, we show that chromosome 8 gain is associated with inferior overall survival in soft tissue sarcomas. Taken together, these data suggest that chromosome 8 gain is a critical event in MPNST pathogenesis, and may account for the aggressive nature and poor outcomes in this sarcoma subtype.

Authors

Carina A. Dehner, Chang In Moon, Xiyuan Zhang, Zhaohe Zhou, Christopher A. Miller, Hua Xu, Xiaodan Wan, Kuangying Yang, R. Jay Mashl, Sara J.C. Gosline, Yuxi Wang, Xiaochun Zhang, Abigail Godec, Paul A. Jones, Sonika Dahiya, Himanshi Bhatia, Tina Primeau, Shunqiang Li, Kai Pollard, Fausto J. Rodriguez, Li Ding, Christine A. Pratilas, Jack F. Shern, Angela C. Hirbe

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Circulating nuclear DNA structural features, origins, and complete size profile revealed by fragmentomics
Cynthia Sanchez, … , Rita Tanos, Alain R. Thierry
Cynthia Sanchez, … , Rita Tanos, Alain R. Thierry
Published February 11, 2021
Citation Information: JCI Insight. 2021. https://doi.org/10.1172/jci.insight.144561.
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Circulating nuclear DNA structural features, origins, and complete size profile revealed by fragmentomics

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Abstract

To unequivocally address their unresolved intimate structures in blood, we scrutinized the size distribution of circulating cell-free DNA (cfDNA) using whole genome sequencing (WGS) from both double- and single-strand DNA library preparations (DSP and SSP), as well as using Q-PCR. The size profile in healthy individuals was remarkably homogenous when using either DSP sequencing (DSP-S) or SSP sequencing (SSP-S). Our findings also confirmed that cfDNA size profile shows a characteristic nucleosome fragmentation pattern. Overall, our data indicate that the proportion of cfDNA inserted in mono-nucleosomes, di-nucleosomes and chromatin of higher molecular size (>1,000bp) can be estimated as 67.5-80%, 9.4-11.5% and 8.5-21.0%, respectively. Thus, our data on WGS (N=7) and Q-PCR (N=116 taken together suggests that only a minor proportion of cfDNA is bigger than that existing in mono-nucleosome or transcription factor complexes circulating in blood. Although DNA on single chromatosomes or mono-nucleosomes is detectable, our data revealed that cfDNA is highly nicked (97-98%) on those structures, which appear to be subjected to continuous nuclease activity in the bloodstream. Fragments analysis allows the distinction of cfDNA of different origins: first, cfDNA size profile analysis may be useful in cfDNA extract quality control; second, subtle but reliable differences between healthy metastatic colorectal cancer (mCRC) patients and healthy individuals vary with the proportion of malignant cell-derived cfDNA in plasma extracts, pointing to a higher degree of cfDNA fragmentation and nuclease activity in samples with high malignant cell cfDNA content. Size profile analysis, or ‘fragmentomics’, has shown significant potential to improve diagnostics and cancer screening.

Authors

Cynthia Sanchez, Benoit Roch, Thilbault Mazard, Philippe Blache, Zahra Al Amir Dache, Brice Pastor, Ekaterina Pisareva, Rita Tanos, Alain R. Thierry

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