Oncotarget

Listen to summaries of the latest oncology-focused research published in this week’s issue of Oncotarget, Volume 12, Issue 20.

https://www.oncotarget.com/archive/v12/i20/

Priority Research Paper (Cover) - “Identification of Smurf2 as a HIF-1α degrading E3 ubiquitin ligase”

https://doi.org/10.18632/oncotarget.28081

Research Paper - “A high-throughput customized cytokinome screen of colon cancer cell responses to small-molecule oncology drugs”

https://doi.org/10.18632/oncotarget.28079

Research Paper - “Opposing effects of BRCA1 mRNA expression on patient survival in breast and colorectal cancer and variations among African American, Asian, and younger patients”

https://doi.org/10.18632/oncotarget.28082

Research Paper - “Pan-drug and drug-specific mechanisms of 5-FU, irinotecan (CPT-11), oxaliplatin, and cisplatin identified by comparison of transcriptomic and cytokine responses of colorectal cancer cells” https://doi.org/10.18632/oncotarget.28075

Research Paper - “Comparative microsomal proteomics of a model lung cancer cell line NCI-H23 reveals distinct differences between molecular profiles of 3D and 2D cultured cells” https://doi.org/10.18632/oncotarget.28072

Research Paper - “Tissue biodistribution and tumor targeting of near-infrared labelled anti-CD38 antibody-drug conjugate in preclinical multiple myeloma”

https://doi.org/10.18632/oncotarget.28074

Research Paper - “Multipeptide stimulated PBMCs generate TEM/TCM for adoptive cell therapy in multiple myeloma” https://doi.org/10.18632/oncotarget.28067

Research Paper - “NEDD8-activating enzyme inhibition induces cell cycle arrest and anaphase catastrophe in malignant T-cells” https://doi.org/10.18632/oncotarget.28063

Research Paper - “Safety and initial efficacy of ablative radioembolization for the treatment of unresectable intrahepatic cholangiocarcinoma” https://doi.org/10.18632/oncotarget.28060

Review - “Switching Hedgehog inhibitors and other strategies to address resistance when treating advanced basal cell carcinoma” https://doi.org/10.18632/oncotarget.28080

Editorial - “Fibrocytes in primary myelofibrosis”

https://doi.org/10.18632/oncotarget.27971 (PDF Download)

Research Perspective - “Ras-p53 genomic cooperativity as a model to investigate mechanisms of innate immune regulation in gastrointestinal cancers”

https://doi.org/10.18632/oncotarget.27983

Keywords - cytokine profiling, breast cancer, colorectal cancer, colon cancer, lung cancer, multiple myeloma (MM), cellular therapy, T-cell lymphoma, cholangiocarcinoma, basal cell carcinoma, myelofibrosis, gastrointestinal cancer, cancer, science, research, oncology

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Nutrigenomics is the scientific study of the relationship between nutrition, health and the human genome. Nutritional benefits from dark, leafy greens are not merely limited to eliminating free radicals and reducing inflammation—they may also protect our DNA and slow tumor growth. Research reveals that sulforaphane (SFN), a chemical compound found in cruciferous vegetables (such as broccoli, brussels sprouts and cabbage), is capable of activating the expression of several cellular protective genes.

“The phytochemical and bioactive agent sulforaphane (SFN) has nutrigenomic potential in activating the expression of several cellular protective genes via the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2).”

Researchers have previously evaluated the nutrigenomic potential of this compound in combination with a carbonic anhydrase inhibitor drug, acetazolamide (AZ), to treat cancers, including bladder cancer and lung bronchial carcinoids (BCs). BCs are rare, well-differentiated and malignant neuroendocrine tumors (NETs). When combined, these compounds were found to significantly inhibit the viability, clonogenicity and in vitro growth of two BC cell lines.

In a new study, researchers—from The Hospital for Sick Children, University of Massachusetts, Queen’s University, IRCCS Casa Sollievo della Sofferenza, University of Chicago, Q.P.S. Holdings LLC, University of Toronto, Indian Institute of Technology Guwahati, and the Forsyth Institute—investigated the mechanisms modulated by SFN, AZ and by SFN and AZ combined, using in vitro and in vivo models of BC cell lines. Their paper was published by Oncotarget in 2021 and entitled, “Next-generation multimodality of nutrigenomic cancer therapy: sulforaphane in combination with acetazolamide actively target bronchial carcinoid cancer in disabling the PI3K/Akt/mTOR survival pathway and inducing apoptosis.”

Full blog - https://www.oncotarget.org/2021/09/21/compound-in-cruciferous-vegetables-inhibits-cancer-cells/

Press release - https://www.oncotarget.com/news/pr/disabling-the-pi3k-akt-mtor-survival-pathway-and-inducing-apoptosis/

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DOI - https://doi.org/10.18632/oncotarget.28011

Full text - https://www.oncotarget.com/article/28011/text/

Correspondence to - Herman Yeger - [email protected], Reza Bayat Mokhtari - [email protected], and Myron R. Szewczuk - [email protected]

Keywords - sulforaphane, acetazolamide, bronchial carcinoid tumors, serotonin, carbonic anhydrase

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Oncotarget Volume 11, Issue 27 published "Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT" by Jia et al. which reported that Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition are central to metastatic aggressiveness and therapy resistance in solid tumors.

While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies.

Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals.

While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging.

Here, the authors' identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division.

Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, the authors' use mechanistic mathematical models to show how GRHL2 can be involved in both the above mentioned processes, thus driving an irreversible MET. This study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.

Dr. Herbert Levine from The Center for Theoretical Biological Physics at Rice University as well as The Department of Physics at Northeastern University and Dr. Mohit Kumar Jolly from The Centre for BioSystems Science and Engineering at The Indian Institute of Science said "Epithelial-Mesenchymal Transition (EMT) is a cell biological process involved in driving cancer metastasis and therapy resistance?the two grand clinically unsolved challenges."

These hybrid E/M phenotypes may drive collective cell migration as clusters of tumor cells and can be more aggressive than cells in pure epithelial or mesenchymal phenotypes.

Recent experiments decoding the dynamics of EMT/MET using live-cell imaging and/or induction and withdrawal of various EMT-inducing external signals such as TGF? or tuning the levels of EMT-specific transcription factors have provided important insights into the reversibility of EMT and MET. Cells induced to undergo EMT for shorter durations may revert to an epithelial state after withdrawal of the signal/stimulus.

However, similar investigations about the irreversibility of MET, or in other words, the resistance of epithelial cells to undergo EMT in response to EMT-inducing signals, remain to be done.

Here, the authors' propose two independent mechanism that may explain the resistance of epithelial tumor cells to undergo EMT:

1) epigenetic feedback mediated via GRHL2?an MET-inducing transcription factor ; and

2) stochastic partitioning of parent cell biomolecules among the daughter cells at the time of cell division.

Conversely, here, the authors' show that incorporating this epigenetic feedback loop acting on the inhibition of ZEB1 by GRHL2 can cause an irreversible MET. Cells undergoing irreversible MET may exhibit resistance in undergoing EMT when exposed to EMT-inducing signals.

The Levine/Jolly Research Team concluded in their Oncotarget Research Paper that their results offer mechanistic insights into two possible mechanisms that may drive varying degrees of susceptibility and resistance to undergoing EMT in response to an EMT-inducing signal in a given isogenic population.

DOI - https://doi.org/10.18632/oncotarget.27651

Picture the human body’s immune response as analogous to the action of an army of military soldiers. For the most part, a healthy immune system can “hold down the fort” and protect the body from many perils of the outside world. We often rely on our immune system’s discretion to determine when and which invaders our soldiers (T cells, for example) should attack. However, when it comes to fighting the most dangerous and formidable opponents, including cancer, researchers have invested in developing new immunotherapies to help boost the body’s own immune response.

One method of immunotherapy drug delivery is liposomal nanoparticles. Natural liposomes are spherical sacs that contain phospholipids; liposomes can also be formed artificially to carry drugs and other substances into tissues. A new immunotherapy technology using liposomal nanoparticles was recently developed, called a nanoparticle-based T cell engager (nanoTCE).

“We have previously developed a nanoparticle-based T cell engagers (nanoTCEs) technology that is based on conjugation of two monoclonal antibodies (mAbs) to the surface of a liposomal nanoparticle; one antibody is against a cancer antigen and the other is against the CD3 receptor on T cells.”

The nanoTCE is a highly customizable technology that combines T cell activation with targeted cancer therapy. Researchers, from Washington University School of Medicine and Washington University McKelvey School of Engineering, claim that this highly specific technology can be engineered to engage with any immune cell to target and treat any cancer of interest. The team conducted a study using the nanoTCE technology in the treatment of acute myeloid leukemia (AML). Their paper was published on the cover of Oncotarget’s Volume 12, Issue 19, and entitled, “Nanoparticle T cell engagers for the treatment of acute myeloid leukemia.”

Full blog - https://www.oncotarget.org/2021/09/15/new-study-nanoparticles-target-acute-myeloid-leukemia/

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DOI - https://doi.org/10.18632/oncotarget.28054

Full text - https://www.oncotarget.com/article/28054/text/

Correspondence to - Abdel Kareem Azab - [email protected]

Keywords - acute myeloid leukemia, T cell engagers, nanoparticles, 3D tissue culture model

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Listen to summaries of the latest oncology-focused research published in this week’s issue of Oncotarget, Volume 12, Issue 19.

https://www.oncotarget.com/archive/v12/i19/

Cover Paper - “Nanoparticle T cell engagers for the treatment of acute myeloid leukemia”

https://doi.org/10.18632/oncotarget.28054

News - “Old drug, new trick: proton pump inhibitors find new purpose in cancer care”

https://doi.org/10.18632/oncotarget.28053 (PDF Download)

Research Paper - “Novel insights into the molecular mechanisms underlying risk of colorectal cancer from smoking and red/processed meat carcinogens by modeling exposure in normal colon organoids”

https://doi.org/10.18632/oncotarget.28058

Research Paper - “Altered glucuronidation deregulates androgen dependent response profiles and signifies castration resistance in prostate cancer” https://doi.org/10.18632/oncotarget.28059

Research Paper - “The antitumoral effects of chemerin are independent from leukocyte recruitment and mediated by inhibition of neoangiogenesis” https://doi.org/10.18632/oncotarget.28056

Research Paper - “Exploratory comparisons between different anti-mitotics in clinically-used drug combination in triple negative breast cancer”

https://doi.org/10.18632/oncotarget.28068

Research Paper - “High expression of Myosin 1g in pediatric acute lymphoblastic leukemia” https://doi.org/10.18632/oncotarget.28055

Case Report - “Polyclonal on- and off-target resistance mutations in an EML4-ALK positive non-small cell lung cancer patient under ALK inhibition” https://doi.org/10.18632/oncotarget.28062

Research Perspective - “Towards precision oncology in angiosarcomas using next generation “omic” technologies” https://doi.org/10.18632/oncotarget.27996

Research Perspective - “Targeting AP-1 transcription factors by CRISPR in the prostate” https://doi.org/10.18632/oncotarget.27997

Research Perspective - “The role of dynamic phenotypes in cancer”

https://doi.org/10.18632/oncotarget.28006

Keywords - colon organoids, acute myeloid leukemia, prostate cancer, chemerin, KIF11 inhibition, breast cancer, acute lymphoblastic leukemia, ALK inhibitors, rare cancer, dynamic phenotype, Lung cancer, cancer, science, research, oncology

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Oncotarget recently published "Evaluations of CRC2631 toxicity, tumor colonization, and genetic stability in the TRAMP prostate cancer model" which reported that the toxicological, tumor-targeting, and efficacy profiles of Salmonella enterica serovar Typhimurium CRC2631 in a syngeneic and autochthonous TRAMP model of aggressive prostate cancer.

CRC2631 preferentially colonize primary and metastatic tumors in the TRAMP animals.

In addition, longitudinal whole genome sequencing studies of CRC2631 recovered from prostate tumor tissues demonstrate that CRC2631 is genetically stable.

Combination of CRC2631 with checkpoint blockade reduces metastasis burden.

Collectively, these Oncotarget findings demonstrate a potential for CRC2631 in cancer immunotherapy strategies.

Dr. Yves C. Chabu from The University of Missouri said, "Conventional cancer chemotherapies are not specific and, as such, generate significant morbidities."

Several bacterial strains have been developed, including the Salmonella enterica serovar Typhimurium strain VNP20009, one of the most studied tumor-targeting strains.

VNP20009 was first isolated in a genetic screen for hyper invasion mutants using a library of mutant strains derived from ultraviolet and chemical mutagenesis of strain 14028.

CRC2631 was derived from a parent strain that was derived from the prototrophic wild-type Salmonella typhimurium LT2 strain.

This collection consists of mutant strains that arose naturally under nutrient-limiting conditions for over four decades, generating a wealth of genetically diverse and potentially attenuated strains.

Similar to prostate cancers in men, these murine carcinomas disseminate throughout visceral organs, differentiate into neuroendocrine prostate cancer, and ultimately kill the host.

The Chabu Research Team concluded in their Oncotarget Research Paper, "Importantly, CRC2631 reduced metastasis incidence in the setting of checkpoint blockade. This is significant because metastasis is the main cause of cancer-associated deaths and no effective immunotherapy against prostate cancer currently exist."

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DOI - https://doi.org/10.18632/oncotarget.27769

Full text - https://www.oncotarget.com/article/27769/text/

Correspondence to - Yves C. Chabu - [email protected]

Keywords - salmonella, cancer targeting, prostate cancer, immunotherapy, TRAMP

About Oncotarget

Oncotarget is a biweekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Oncotarget recently published "Evaluations of CRC2631 toxicity, tumor colonization, and genetic stability in the TRAMP prostate cancer model" which reported that the toxicological, tumor-targeting, and efficacy profiles of Salmonella enterica serovar Typhimurium CRC2631 in a syngeneic and autochthonous TRAMP model of aggressive prostate cancer.

CRC2631 preferentially colonize primary and metastatic tumors in the TRAMP animals.

In addition, longitudinal whole genome sequencing studies of CRC2631 recovered from prostate tumor tissues demonstrate that CRC2631 is genetically stable.

Combination of CRC2631 with checkpoint blockade reduces metastasis burden.

Collectively, these Oncotarget findings demonstrate a potential for CRC2631 in cancer immunotherapy strategies.

Dr. Yves C. Chabu from The University of Missouri said, "Conventional cancer chemotherapies are not specific and, as such, generate significant morbidities."

Several bacterial strains have been developed, including the Salmonella enterica serovar Typhimurium strain VNP20009, one of the most studied tumor-targeting strains.

VNP20009 was first isolated in a genetic screen for hyper invasion mutants using a library of mutant strains derived from ultraviolet and chemical mutagenesis of strain 14028.

CRC2631 was derived from a parent strain that was derived from the prototrophic wild-type Salmonella typhimurium LT2 strain.

This collection consists of mutant strains that arose naturally under nutrient-limiting conditions for over four decades, generating a wealth of genetically diverse and potentially attenuated strains.

Similar to prostate cancers in men, these murine carcinomas disseminate throughout visceral organs, differentiate into neuroendocrine prostate cancer, and ultimately kill the host.

The Chabu Research Team concluded in their Oncotarget Research Paper, "Importantly, CRC2631 reduced metastasis incidence in the setting of checkpoint blockade. This is significant because metastasis is the main cause of cancer-associated deaths and no effective immunotherapy against prostate cancer currently exist."

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DOI - https://doi.org/10.18632/oncotarget.27769

Full text - https://www.oncotarget.com/article/27769/text/

Correspondence to - Yves C. Chabu - [email protected]

Keywords - salmonella, cancer targeting, prostate cancer, immunotherapy, TRAMP

About Oncotarget

Oncotarget is a biweekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Impact Journals is a registered trademark of Impact Journals, LLC

When it comes to the mechanisms of tumor growth, the differences between epithelial and mesenchymal cell types are important to note. Normal epithelial cells are uniform, stationary and structured to bind together—forming a type of lining on/in organs (such as the outer layer of the skin), some cavities and blood vessels throughout the body. Normal mesenchymal cells are differentiated into a variety of mature cell types, including connective tissue, cartilage, lymphatic tissue, bone tissues, and etc.

Remarkably, these cells are capable of swapping phenotypes (given proper stimulation) and making epithelial-to-mesenchymal (and mesenchymal-to-epithelial) transitions (EMT). After the process of EMT, the former epithelial cells lose their cell-to-cell capacity and are endowed with migratory and invasive mesenchymal traits—with the potential to differentiate into a variety of cell lines. This process not only occurs in normal cells, but also in cancer cells. EMT enables cancer cells to transition into fluid mesenchymal traits and out of ridged and vulnerable epithelial phenotypes. Researchers believe that oxygen deprivation (hypoxia) at the core of solid tumors contributes to stimulating the formation of new vascular networks (neoangiogenesis), which induces the process of EMT to turn cancer cells stem-like.

“Hypoxia stimulates neoangiogenesis, promoting tumor outgrowth, and triggers the epithelial-mesenchymal transition (EMT), which bestows cells with mesenchymal traits and multi-lineage differentiation potential.”

However, researchers have not yet established a direct connection between the induction of EMT and the onset of neoangiogenesis in vivo. From The University of Texas MD Anderson Cancer Center, Texas A&M University, and Hamamatsu University School of Medicine, researchers conducted a study to determine whether cells undergoing EMT in a hypoxic environment “can acquire endothelial cell attributes and augment tumor growth by directly contributing to the tumor vasculature.” The proliferation of endothelial cells forms new blood vessels. Signals from endothelial cells can organize the growth and development of new endothelial cells. In April of 2021, the team published a research paper with Oncotarget on the significance of their study results, entitled, “Carcinoma cells that have undergone an epithelial-mesenchymal transition differentiate into endothelial cells and contribute to tumor growth.”

Full blog - https://www.impactjournals.com/journals/blog/oncotarget/trending-with-impact-mesenchymal-stem-cells-promote-neoangiogenesis/

Press release - https://www.oncotarget.com/news/pr/epithelial-mesenchymal-transitions-create-endothelial-cells-tumor-growth/

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DOI - https://doi.org/10.18632/oncotarget.27940

Full text - https://www.oncotarget.com/article/27940/text/

Correspondence to - Tapasree Roy Sarkar - [email protected]

Keywords - angiogenesis, endothelial transdifferentiation, epithelial-mesenchymal transition, vasculogenic mimicry, FOXC2

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Most people are aware by now that exercise has positive effects in “healthy” individuals and in patients with cancer. In cancer patients, exercise has been shown to reduce adverse events, improve quality-of-life and respiratory fitness, and even decrease the risk of breast cancer recurrence. These results, and many others, have prompted major national and international cancer organizations to make exercise recommendations.

“There also is a growing body of evidence that exercise may directly alter the tumor microenvironment to influence tumor growth, metastasis, and response to anticancer therapies.”

However, scientists and researchers have only scratched the surface of understanding the extent of the benefits that are capable of being harnessed by exercise. While research shows that exercise may impact tumors, the exercise prescription needed to induce these beneficial tumor-related outcomes is still unclear. In an effort to better harness the benefits of exercise, researchers from the University of Florida conducted a study on the effects of wheel running in breast cancer mouse models and chemotherapy. Their paper was published as the cover of Oncotarget’s Volume 12, Issue 18, and entitled, “Normal tissue and tumor microenvironment adaptations to aerobic exercise enhance doxorubicin anti-tumor efficacy and ameliorate its cardiotoxicity in retired breeder mice.”

“The goal of this study was to characterize the exercise prescription by evaluating the aerobic adaptations in both the normal tissue and the tumor microenvironment. Moreover, doxorubicin was used to assess the adjuvant effects of aerobic exercise on chemotherapy efficacy and toxicity.”

Full blog - https://www.impactjournals.com/journals/blog/oncotarget/new-study-how-exercise-boosted-chemotherapy-in-mice/

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DOI - https://doi.org/10.18632/oncotarget.28057

Full text - https://www.oncotarget.com/article/28057/text/

Correspondence to - Zachary R. Wakefield - [email protected]

Keywords - aerobic exercise, breast cancer, hypoxia, doxorubicin, cardiotoxicity

About Oncotarget

Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Listen to the latest oncology-focused research published in this week’s issue of Oncotarget, Volume 12, Issue 18.

https://www.oncotarget.com/archive/v12/i18/

Priority Research Paper (Cover) - “Normal tissue and tumor microenvironment adaptations to aerobic exercise enhance doxorubicin anti-tumor efficacy and ameliorate its cardiotoxicity in retired breeder mice”

https://doi.org/10.18632/oncotarget.28057

Research Paper - “Selinexor, a selective inhibitor of nuclear export, enhances the anti-tumor activity of olaparib in triple negative breast cancer regardless of BRCA1 mutation status”

https://doi.org/10.18632/oncotarget.28047

Research Paper - “Pim kinase inhibitor co-treatment decreases alternative non-homologous end-joining DNA repair and genomic instability induced by topoisomerase 2 inhibitors in cells with FLT3 internal tandem duplication”

https://doi.org/10.18632/oncotarget.28042

Research Paper - “Impact factor and citation metrics in phase III cancer trials” https://doi.org/10.18632/oncotarget.28044

Research Paper - “Inhibition of the MAP2K7-JNK pathway with 5Z-7-oxozeaenol induces apoptosis in T-cell acute lymphoblastic leukemia” https://doi.org/10.18632/oncotarget.28040

Research Paper - “Correlation between PD-L1 expression and MET gene amplification in patients with advanced non–small-cell lung cancer and no other actionable oncogenic driver”

https://doi.org/10.18632/oncotarget.28045

Research Paper - “Effect of hypertension and medication use regularity on postoperative delirium after maxillofacial tumors radical surgery” https://doi.org/10.18632/oncotarget.28048

Review - “Anti-aging: senolytics or gerostatics (unconventional view)” https://doi.org/10.18632/oncotarget.28049

Case Report - “The value of comprehensive genomic sequencing to maximize the identification of clinically actionable alterations in advanced cancer patients: a case series” https://doi.org/10.18632/oncotarget.28046

Editorial - “Juvenile polyposis without a germline variant in SMAD4/BMPR1A: defining a clinically distinct polyposis syndrome” https://doi.org/10.18632/oncotarget.28023 (PDF Download)

Research Perspective - “Targeting cancer stem cells via integrin β4”

https://doi.org/10.18632/oncotarget.27977

Keywords - aerobic exercise, breast cancer, selinexor, Pim kinase, journal impact factor, T-ALL, non–small-cell lung cancer, oral tumor surgery, geroscience, senolytics, RNA sequencing, cancer stem cells, cancer, science, research, oncology

About Oncotarget

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