Oncotarget

A new research perspective was published in Oncotarget's Volume 14 on May 4, 2023, entitled, “Using cancer proteomics data to identify gene candidates for therapeutic targeting.”

Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. In their new research perspective, researchers Diana Monsivais, Sydney E. Parks, Darshan S. Chandrashekar, Sooryanarayana Varambally, and Chad J. Creighton from Baylor College of Medicine and University of Alabama at Birmingham discuss their recent study where they surveyed proteomic correlates of tumor grade across multiple cancer types and identified specific protein kinases having a functional impact on uterine endometrial cancer cells.

“This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients.”

Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer cell lines, CRISPR loss of function and drug sensitivity scoring can be readily integrated with protein data to predict any gene’s functional impact before bench experiments are carried out. Public data portals make cancer proteomics data more accessible to the research community. Drug discovery platforms can screen hundreds of millions of small molecule inhibitors for those that target a gene or pathway of interest.

“Here, we discuss some of the available public genomic and proteomic resources while considering approaches to how these could be leveraged for molecular biology insights or drug discovery. We also demonstrate the inhibitory effect of BAY1217389, a TTK inhibitor recently tested in a Phase I clinical trial for the treatment of solid tumors, on uterine cancer cell line viability.”

DOI: https://doi.org/10.18632/oncotarget.28420

Correspondence to: Chad J. Creighton - [email protected]

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Keywords: proteomics, proteogenomics, multi-omics, cancer, TTK protein kinase

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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Dr. Georg F. Weber, from the University of Cincinnati Academic Health Center, describes a research perspective he authored that was published by Oncotarget in Volume 14, entitled, “Crossroads: the role of biomarkers in the management of lumps in the breast.”

DOI - https://doi.org/10.18632/oncotarget.28402

Correspondence to - Georg F. Weber - [email protected]

Abstract

Premalignant lesions in the breast pose a difficult decision-making problem, whether to treat proactively and accept the side effects or to engage in watchful waiting and possibly encounter a later diagnosis of invasive cancer. A biomarker or set of biomarkers to inform on the individual progression risk would be beneficial to the patient and cost-effective for the healthcare system. The gene products of tumor progression may be expressed in early non-cancerous (“premalignant”) lesions, where they are associated with a high probability for full transformation in breast cancers. One such molecule is the OPN splice variant-c. OPN-c is also present in a fraction of the premalignant lesions, where it reflects an elevated risk for progression to cancer within 5 years, regardless of the lesion’s subtype. This marker has the properties needed to facilitate decisions to treat at the premalignant stage.

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Keywords - breast cancer premalignant lesion, biomarker, biopsy, mammography

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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A new research paper was published in Oncotarget's Volume 14 on May 4, 2023, entitled, “Human LY6 gene family: potential tumor-associated antigens and biomarkers of prognosis in uterine corpus endometrial carcinoma.”

The human Lymphocyte antigen-6 (LY6) gene family has recently gained interest for its possible role in tumor progression. In this new study, researchers Luke A. Rathbun, Anthony M. Magliocco and Anil K. Bamezai from Villanova University carried out in silico analyses of all known LY6 gene expression and amplification in different cancers using TNMplot and cBioportal. In addition, the team analyzed patient survival by Kaplan-Meier plotter after mining the TCGA database.

“We report that upregulated expression of many LY6 genes is associated with poor survival in uterine corpus endometrial carcinoma (UCEC) cancer patients.”

Importantly, the expression of several LY6 genes is elevated in UCEC when compared to the expression in normal uterine tissue. For example, LY6K expression is 8.25× higher in UCEC compared to normal uterine tissue, and this high expression is associated with poor survival with a hazard ratio of 2.42 (p-value = 0.0032). Therefore, some LY6 gene products may serve as tumor-associated antigens in UCEC, biomarkers for UCEC detection, and possibly targets for directing UCEC patient therapy.

“Further analysis of tumor-specific expression of LY6 gene family members and LY6-triggered signaling pathways is needed to uncover the function of LY6 proteins and their ability to endow tumor survival and poor prognosis in UCEC patients.”

DOI - https://doi.org/10.18632/oncotarget.28409

Correspondence to - Anil K. Bamezai - [email protected]

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Keywords - LY6 gene family, uterine cancer, tumor-associated antigen, patient survival, biomarker

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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A new review paper was published in Oncotarget's Volume 14 on April 26, 2023, entitled, “Systemic AL amyloidosis: current approach and future direction.”

In this review, researchers Maroun Bou Zerdan, Lewis Nasr, Farhan Khalid, Sabine Allam, Youssef Bouferraa, Saba Batool, Muhammad Tayyeb, Shubham Adroja, Mahinbanu Mammadii, Faiz Anwer, Shahzad Raza, and Chakra P. Chaulagain from SUNY Upstate Medical University, University of Texas MD Anderson Cancer Center, Monmouth Medical Center, University of Balamand, Cleveland Clinic Ohio, UnityPoint Methodist, Houston Methodist Cancer Center, and Cleveland Clinic Florida report the literature on the latest treatment updates of Systemic Light chain (AL) amyloidosis and the ongoing clinical trials highlighting the future treatments.

“In this manuscript, we discuss the general approach towards treating patients with amyloidosis and dive into the future perspectives in this multi-systemic disease.”

Systemic AL amyloidosis is a monoclonal plasma cell proliferative disorder characterized by deposition of amyloidogenic monoclonal light chain fragments causing organ dysfunction. It is a fatal disease and if not diagnosed and treated early can lead to organ failure and potentially death. The renal system along with the cardiovascular system are the most common organs involved, but other organs such as the gut and liver can be involved as well.

The initial evaluation of patients requires confirming the diagnosis with tissue biopsy and staining with Congo red followed by confirmatory typing with mass spectrometry of the Congo red positive tissue. Then establishing the extent of the organs involvement by various staging and biomarkers testing. The treatment options and the tolerability of therapy depend on the disease staging, frailty and co-morbidities.

The autologous hematopoietic cell transplantation (HCT) after high dose melphalan therapy is an effective strategy which is usually done after initial bortezomib induction therapy. Unfortunately, most systemic AL amyloidosis patients are not candidates for HCT due to frailty, old age, multi-organ involvement, and renal or heart failure at the time of diagnosis. While it is widely accepted that the patients need to be treated until they achieve complete hematologic response, the maintenance therapy after HCT is not well established in AL amyloidosis.

“The relationship between AL amyloidosis and MGUS is less clear, but some studies suggest that the risk of developing AL amyloidosis may be increased in patients with MGUS. It is important for patients with these conditions to undergo regular monitoring and evaluation for signs of AL amyloidosis, as early diagnosis and treatment can improve outcomes.”

DOI - https://doi.org/10.18632/oncotarget.28415

Correspondence to - Chakra P. Chaulagain - [email protected]

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Keywords - amyloidosis, management

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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A new research perspective was published in Oncotarget's Volume 14 on April 26, 2023, entitled, “Disruption of retinol-mediated IL-6 expression in colon cancer-associated fibroblasts: new perspectives on the role of vitamin A metabolism.”

Colon cancer (CRC) is one of the most common malignancies and is a leading cause of cancer-related deaths worldwide. While the tumor microenvironment (TME) supports tumor growth and immune escape through tumor-promoting inflammation, the mechanisms by which the TME promotes CRC are far from being elucidated. Stromal myo-/fibroblasts (MFs) account for up to 30% of lamina propria cells in the normal human colon and their number is dramatically increased in CRC.

Fibroblasts from cancers, also known as cancer-associated fibroblasts (CAFs), differ from normal colonic MF (N-MFs) and support tumor-promoting inflammation, in part due to increased IL-6 secretion. CAFs are very abundant in the TME and are among the major cells involved in tumor inflammation and progression. In this research perspective, researchers Romain Villéger, Marina Chulkina, Randy C. Mifflin, Don W. Powell, and Irina V. Pinchuk from the Université de Poitiers, Penn State Health Milton S. Hershey Medical Center and The University of Texas Medical Branch highlight recent data obtained regarding IL-6 regulation in colorectal cancer CAFs through vitamin A (retinol) metabolism, discuss current limitations in our understanding of the mechanisms leading to the CAF pro-inflammatory phenotype, and discuss potential approaches to target CAF retinoid metabolism during CRC treatment.

"While the overall mechanisms responsible for the IL-6 increase within the CRC tumor stroma remain to be elucidated, our study highlights the crucial role of stromal vitamin A pathway in IL-6 regulation."

DOI: https://doi.org/10.18632/oncotarget.28399

Correspondence to - Iryna V. Pinchuk - [email protected]

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Keywords - tumor microenvironment, colon cancer, inflammation, fibroblasts, IL-6

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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A new research perspective was published in Oncotarget's Volume 14 on April 24, 2023, entitled, “Crossroads: the role of biomarkers in the management of lumps in the breast.”

Here, Dr. Georg F. Weber from the University of Cincinnati Academic Health Center discusses a long-standing issue in women’s health: lumps in the breast. Women over the age of 40 years often have lumps in their breasts that are not cancerous at the time of biopsy (comprising atypias, hyperplasias, papillomas, radial scars, lobular carcinoma in situ, ductal carcinoma in situ (DCIS)). These premalignant lesions in the breast pose a difficult decision-making problem, whether to treat proactively and accept the side effects or to engage in watchful waiting and possibly encounter a later diagnosis of invasive cancer.

These patients need to make the difficult decision whether to treat the lesions proactively and accept the substantial compromise in their quality of life (from surgery, radiation, or hormone therapy: Surgery often ensues for definitive diagnosis. Radiation may follow the surgical resection of DCIS by lumpectomy. Hormone therapy can come into play as a strategy for risk reduction if the estimated 5-year risk exceeds 1.6% in the Gail model [2]) or to engage in watchful waiting and risk a later diagnosis of invasive cancer (the proverbial sword of Damocles). Currently, two forms of assessment are available to facilitate making that choice.

Decades of cancer diagnosis and treatment have achieved substantial improvements. Yet, with every milestone of progress, new needs have surfaced. Breast care is privileged to have the availability of mammography and biopsy to assess the propensities of lumps.

“A meaningful next step needs to entail biomarker development, pointing the way toward either preemptive treatment or watchful waiting at the crossroad.”

DOI: https://doi.org/10.18632/oncotarget.28402

Correspondence to - Georg F. Weber - [email protected]

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Keywords - breast cancer premalignant lesion, biomarker, biopsy, mammography

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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Listen to a blog summary of an editorial perspective that was published in Oncotarget’s Volume 14, entitled, “EGFR endocytosis: more than meets the eye.”

_________________________________

EGFR (epidermal growth factor receptor) is a crucial protein that plays a significant role in various biological processes such as cell growth, proliferation, differentiation, and survival. Dysregulation of EGFR signaling has been implicated in the development and progression of numerous human cancers, including lung, breast and colon cancer. Therefore, EGFR has emerged as an attractive target for cancer therapy, and several drugs that target EGFR are in clinical use or under investigation.

In recent years, endocytosis, the process by which cells internalize molecules and transport them into intracellular compartments, has emerged as a critical modulator of EGFR signaling. Endocytosis of EGFR not only regulates the duration and intensity of EGFR signaling but also modulates the signaling output. Dysregulation of EGFR endocytosis has been implicated in the development of drug resistance to EGFR-targeted therapies, highlighting the importance of understanding the mechanisms that regulate EGFR endocytosis.

In a new editorial perspective, researchers Aysegul Sapmaz and Ayse Elif Erson-Bensan from Middle East Technical University provide an overview of the recent advances in our understanding of EGFR endocytosis and its role in EGFR signaling and cancer. The authors highlight the importance of the dynamic interplay between EGFR endocytosis and downstream signaling pathways and discuss how aberrant EGFR endocytosis contributes to drug resistance to EGFR-targeted therapies. On April 10, 2023, their editorial perspective was published in Oncotarget’s Volume 14, entitled, “EGFR endocytosis: more than meets the eye.”

“Here we review the role of the EGF-SNX3-EGFR axis in breast cancers with an extended discussion on deregulated EGFR endocytosis in cancer.”

Full blog - https://www.oncotarget.org/2023/04/27/defining-the-complexity-of-egfr-endocytosis-in-cancer/

Paper DOI - https://doi.org/10.18632/oncotarget.28400

Correspondence to - Ayse Elif Erson-Bensan - [email protected]

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Keywords - EGFR, SNX3, USP32, endocytosis, cancer, breast cancer

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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A new research paper was published in Oncotarget's Volume 14 on April 24, 2023, entitled, “Differential silencing of STAT3 isoforms leads to changes in STAT3 activation.”

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor involved in multiple fundamental biological processes and a key player in cancer development and progression. STAT3 is activated upon tyrosine phosphorylation and is constitutively active in various malignancies; therefore, the expression of phospho-STAT3 (pSTAT3) has been recognized as a predictor of poor survival. STAT3 encodes two alternatively-spliced STAT3 isoforms: the full-length STAT3α isoform and the truncated STAT3β isoform.

These isoforms have been suggested as the reason for the occasionally observed opposing roles of STAT3 in cancer: an oncogene, on one hand, and a tumor suppressor on the other. In this new study, researchers Inbal Shamir, Ilan Tsarfaty, Gidi Paret, and Yael Nevo-Caspi from Sheba Medical Center and Tel Aviv University investigated the roles of STAT3α and STAT3β in aggressive breast cancer. They manipulated endogenous STAT3 isoform expression and measured outcomes to mimic physiological changes more accurately.

“In this study we examined the roles of STAT3 isoforms using specific siRNAs that target either STAT3α or STAT3β. We used the MDA-MB-231 cell line which represents an aggressive and mortal subtype of breast cancer, in which STAT3 is overexpressed and constitutively activated [14].”

The team separately silenced each isoform in the MDA-MB-231 cell line and found that they affect each other’s activation, impacting cell viability, cytokine expression, and migration. Their results show that each of the isoforms affects the activation (i.e., phosphorylation) of the other isoform and leads to changes in the outcome of the cells. They conclude that both STAT3α and STAT3β play a crucial role in the function of STAT3. Distinguishing between the two isoforms and their active forms is crucial for STAT3-related cancer diagnosis and therapy.

“Referring to STAT3 as a single protein can lead to wrong conclusions, as they have different functions. Current STAT3 inhibitors target both isoforms, but this approach should be revised for better patient care. We present an endogenous mechanism that can shift the balance in a favorable direction, and we suggest developing treatments that mimic this mechanism could lead to new avenues for cancer therapy.”

DOI: https://doi.org/10.18632/oncotarget.28412

Correspondence to - Yael Nevo-Caspi - [email protected]

Keywords - STAT3: Signal transducer and activator of transcription 3, ER: endoplasmic reticulum, TAD: transactivation domain, SH2: Src homology 2, RQ: Relative quantitative

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Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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A new editorial paper was published in Oncotarget's Volume 14 on April 10, 2023, entitled, “Tumor necroptosis promotes metastasis through modulating the interplay between tumor and host immunity.”

In this new editorial, researchers Zhaoshan Liu, Swati Choksi and Zheng-Gang Liu from the National Institutes of Health’s National Cancer Institute discuss cell death—which can happen as finely regulated programmed cell death (PCD) or non-regulated accidental cell death (necrosis). In addition to apoptosis, which is the first known PCD, several other forms of PCD such as necroptosis and ferroptosis have been identified and the underlying mechanisms of these forms of cell death have been well studied.

For necroptosis, a regulated necrotic cell death, Mixed lineage kinase domain-like protein (MLKL) was found to be the key executor of the death process and its oligomerization and translocation to the plasma membrane results in the shedding of cell surface proteins and the rupture of the cell plasma membrane of necroptotic cells. The role of the different forms of PCD in tumorigenesis has been extensively investigated.

While apoptosis and ferroptosis inhibit tumor progression, necroptosis seems to have a promoting role in tumor progression. The researchers here recently found that necroptosis is the main form of cell death observed in tumor necrosis, the foci of cell death in core regions of solid tumors under hypoxia and nutrient deprivation. More importantly, they found that blocking necroptosis leads to the inhibition of metastasis in mouse breast cancer models.

“Developing novel necroptosis inhibitor[s] by targeting other proteins such as MLKL may be critical for successfully blocking necroptosis in cancer and mitigating metastasis.”

Full editorial: DOI: https://doi.org/10.18632/oncotarget.28404

Correspondence to - Zheng-Gang Liu - [email protected]

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Keywords - necroptosis, breast cancer, metastasis, E-cadherin, immunity

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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A new research paper was published in Oncotarget's Volume 14 on April 15, 2023, entitled, “Importance of carbohydrate antigen (CA 19-9) and carcinoembrionic antigen (CEA) in the prognosis of patients with duodenal adenocarcinoma: a retrospective single-institution cohort study.”

Duodenal adenocarcinoma (DA) is a rare malignancy without validated tumor markers. In practice, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) are often used in the management of DA, though their prognostic value is unknown.

In this new study, researchers Ellery Altshuler, Raymond Richhart, William King, Mahmoud Aryan, Akash Mathavan, Akshay Mathavan, Keegan Hones, Daniel Leech, Logan Pucci, Joshua Riklan, Pat Haley, Ilyas Sahin, Brian Ramnaraign, Sherise Rogers, Ibrahim Nassour, Steven Hughes, Thomas J. George, and Jesus Fabregas from the University of Florida, University of Florida Health Cancer Center and University of Alabama at Birmingham conducted a single-institution retrospective review including patients diagnosed with biopsy-confirmed adenocarcinoma of the duodenum between 2006 and 2021.

“To our knowledge, this is the first study to evaluate the role of tumor markers in patients with DA. In fact, this is the largest single institution study in the US evaluating this disease.”

Peri-ampullary tumors were excluded. Levels of CA 19-9 and CEA were collected as continuous variables and were analyzed as binary variables: normal vs. high, using the maximum normal value as a cut-off (normal Ca 19-9 <35 U/ml; CEA <3 ng/ml). Survival analysis was conducted using Kaplan Meier curves, log-rank test and Cox proportional hazards model.

There were 68 patients included in the final analysis. Median age was 67 years old and median follow-up time was 22.2 months. CA 19-9 and CEA were elevated in 36.8% and 48.5% of patients, respectively. A concomitant elevation of both tumor markers was associated with worsened OS (HR 2.140, 95% CI: 1.114–4.112; p = 0.019). After controlling for age and sex on multivariate analysis, elevation in both CA 19-9 ≥35 and CEA ≥3.0 remained significantly associated with increased mortality (HR 2.278, 95% CI: 1.162–4.466; p = 0.016).

“In summary, CA 19-9 and, to a lesser extent, CEA, show promise as prognostic markers in DA. Larger studies are needed to validate their use and to evaluate their performance as markers of recurrence.”

DOI: https://doi.org/10.18632/oncotarget.28406

Correspondence to: Ellery Altshuler - [email protected]

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Keywords - DA: duodenal adenocarcinoma, CEA: carcinoembryonic antigen, CA, carbohydrate antigen

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Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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