Topographic mapping of the glioblastoma proteome reveals a triple-axis model of intra-tumoral heterogeneity

Glioblastoma is an aggressive form of brain cancer with well-established patterns of intra-tumoral heterogeneity implicated in treatment resistance and progression. While regional and single cell transcriptomic variations of glioblastoma have been recently resolved, downstream phenotype-level proteomic programs have yet to be assigned across glioblastoma’s hallmark histomorphologic niches. Here, we leverage mass spectrometry to spatially align abundance levels of 4,794 proteins to distinct histologic patterns across 20 patients and propose diverse molecular programs operational within these regional tumor compartments. Using machine learning, we overlay concordant transcriptional information, and define two distinct proteogenomic programs, MYC- and KRAS-axis hereon, that cooperate with hypoxia to produce a tri-dimensional model of intra-tumoral heterogeneity. Moreover, we highlight differential drug sensitivities and relative chemoresistance in glioblastoma cell lines with enhanced KRAS programs. Importantly, these pharmacological differences are less pronounced in transcriptional glioblastoma subgroups suggesting that this model may provide insights for targeting heterogeneity and overcoming therapy resistance.

TGFβ2 Induces the Soluble Isoform of CTLA-4 – Implications for CTLA-4 Based Checkpoint Inhibitor Antibodies in Malignant Melanoma

Malignant melanoma is an aggressive form of cancer, which can be treated with anti-CTLA-4 and anti-PD-1 checkpoint inhibitor antibodies but while anti-CTLA-4 antibodies have clear benefits for some patients with melanoma, productive responses are difficult to predict and often associated with serious immune related adverse events. Antibodies specific to CTLA-4 bind two major isoforms of CTLA-4 in humans, the receptor isoform and a second naturally secretable, soluble isoform - sCTLA-4. The primary aim here was to examine the effect of selectively blocking the function of sCTLA-4 on in vitro immune responses from volunteer healthy or melanoma patient PBMC samples. Addition of recombinant sCTLA-4 to healthy PBMC samples demonstrated sCTLA-4 to have immunosuppressive capacity comparable to recombinant CTLA4-Ig, partially reversible upon antibody blockade. Further, we identified a mechanistic relationship where melanoma patient TGFβ2 serum levels correlated with sCTLA-4 levels and provided the basis for a novel protocol to enhance sCTLA-4 production and secretion by T cells with TGFβ2. Finally, a comparison of selective antibody blockade of sCTLA-4 demonstrated that both healthy and melanoma patient effector cytokine responses can be significantly increased. Overall, the data support the notion that sCTLA-4 is a contributory factor in cancer immune evasion.

Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies to Target Breast Cancer-Associated Fibroblasts

Breast cancer is the most diagnosed cancer and is the leading cause of cancer mortality in women. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Often, TNBC is not effectively treated due to the lack of specificity of conventional therapies and results in relapse and metastasis. Breast cancer-associated fibroblasts (BCAFs) are the predominant cells that reside in the tumor microenvironment (TME) and regulate tumorigenesis, progression and metastasis, and therapy resistance. BCAFs secrete a wide range of factors, including growth factors, chemokines, and cytokines, some of which have been proved to lead to a poor prognosis and clinical outcomes. This TME component has been emerging as a promising target due to its crucial role in cancer progression and chemotherapy resistance. A number of therapeutic candidates are designed to effectively target BCAFs with a focus on their tumor-promoting properties and tumor immune response. This review explores various agents targeting BCAFs in TNBC, including small molecules, nucleic acid-based agents, antibodies, proteins, and finally, nanoparticles.

Mechanisms underlying melanoma invasion as a consequence of MLK3 loss

Invasive melanoma is an aggressive form of skin cancer with high incidence of mortality. The process of invasion is a crucial primary step in the metastatic cascade, yet the mechanisms involved are still under investigation. Here we document a critical role for MLK3 (MAP3K11) in the regulation of melanoma cell invasion. We report that cellular loss of MLK3 in melanoma cells promotes cell invasion. Knock down of MLK3 expression results in the hyperactivation of ERK, which is linked to the formation of a BRAF/Hsp90/Cdc37 protein complex. ERK hyperactivation leads to enhanced phosphorylation and inactivation of GSK3β and the stabilization of c-Jun and JNK activity. Blocking of ERK and JNK signaling as well as Hsp90 activity downstream of MLK3-silencing significantly reduces melanoma invasion. Furthermore, our studies show that ERK activation in the aforementioned context is coupled to MT1-MMP transcription as well as the TOM1L1-dependent localization of the membrane protease to invadopodia at the invasive front. These studies provide critical insight into the mechanisms that couple MLK3 loss with BRAF hyperactivation and its consequence on melanoma invasion.

Hypoxia: The Cornerstone of Glioblastoma

Glioblastoma is the most aggressive form of brain tumor in adults and is characterized by the presence of hypervascularization and necrosis, both caused by a hypoxic microenvironment. In this review, we highlight that hypoxia-induced factor 1 (HIF-1), the main factor activated by hypoxia, is an important driver of tumor progression in GB patients. HIF-1α is a transcription factor regulated by the presence or absence of O2. The expression of HIF-1 has been related to high-grade gliomas and aggressive tumor behavior. HIF-1 promotes tumor progression via the activation of angiogenesis, immunosuppression, and metabolic reprogramming, promoting cell invasion and survival. Moreover, in GB, HIF-1 is not solely modulated by oxygen but also by oncogenic signaling pathways, such as MAPK/ERK, p53, and PI3K/PTEN. Therefore, the inhibition of the hypoxia pathway could represent an important treatment alternative in a disease with very few therapy options. Here, we review the roles of HIF-1 in GB progression and the inhibitors that have been studied thus far, with the aim of shedding light on this devastating disease.

Fallbericht: Analyse der zirkulierenden Tumor-DNA-Fraktion mittels Ultra-Low-Pass Whole-Genome Sequencing korreliert bei kleinzelligem Stage-IV-Zervixkarzinom mit Ansprechen auf Radiochemotherapie und Rezidivierung – Eine Längsschnittstudie

Das neuroendokrine Karzinom der Cervix uteri ist eine seltene und aggressive Form von Gebärmutterhalskrebs, die durch häufige Metastasierung schon bei Diagnosestellung und durch hohe Rezidivraten gekennzeichnet ist. Die Primärtherapie ist multimodal und beinhaltet oft eine Chemotherapie, zum Teil in Verbindung mit einer Strahlentherapie. Es liegen keine Daten vor, die Orientierung für das Vorgehen bei Rezidiven geben; Zweitlinientherapien werden aus Daten zum kleinzelligen Bronchialkarzinom abgeleitet. Die engmaschige Überwachung dieser Patientinnen im Hinblick auf Rezidive ist von größter Bedeutung. Dafür stellt die Bestimmung der zirkulierenden Tumor-DNA (ctDNA) im peripheren Blut eine attraktive, weil nicht-invasive Option dar. Mit dem ULP-WGS-Verfahren (<i>ultra-low-pass whole-genome sequencing</i>) lassen sich die Tumorlast und das Tumoransprechen beurteilen und Prognosen zur Rezidivierung abgeben; allerdings mangelt es bisher noch an Daten zur Rolle der ULP-WGS beim kleinzelligen Zervixkarzinom. Die vorliegende Arbeit stellt eine Patientin vor, deren Chemotherapie-Ansprechen und Tumor-Rezidivierung durch die ctDNA-Analyse korrekt überwacht wurden, wie radiologische Befunde bestätigten.

Metabolic risk factors in NZ Glioblastoma cohort 2005-2020: A retrospective analysis

Background Glioblastoma multiforme (GBM) is the most aggressive form of glioma. There is growing recognition that mitochondrial metabolism plays a role in cancer development. Metabolic syndrome is a risk factor for several cancers; however, the prevalence in GBM patients in New Zealand (NZ) is unknown. We hypothesised that patients with GBM would show a higher prevalence of metabolic syndrome compared to the general NZ population and that metabolic syndrome may be associated with worsened overall survival (OS) in GBM. Methods We performed a retrospective analysis in 170 patients diagnosed and treated for GBM between 2005-2020. Clinical and biochemical data were collected with regards to five metabolic criteria. OS was determined from the date of initial surgical diagnosis to the date of death or date of data acquisition. Results 31 (18.2%) of GBM patients met the diagnostic criteria for metabolic syndrome. The prevalence of metabolic syndrome in our cohort did not significantly differ from that of the general NZ population. However, OS in patients with metabolic syndrome was significantly worse compared to patients without metabolic syndrome [8.0 vs 13.0 months, P = 0.016]. Patients who received a lower dexamethasone dose had significantly better survival outcomes (15.0 vs 5.0 months, P &lt; 0.01). Differences in OS did not differ by gender or ethnicity. Conclusions We have shown that metabolic syndrome is associated with reduced OS in a New Zealand cohort of GBM patients. This finding further strengthens the possibility that a metabolic pathogenesis may underpin GBM. However, prospective clinical trials are needed.

BURKITT’S LYMPHOMA IN KIDNEY: A RARE ENTITY.

Burkitt’s Lymphoma is an aggressive form of Non-Hodgkin’s Lymphoma, with higher incidence in children comprising 30% of pediatric lymphoma. The hallmark of which is a translocation involving c-MYC gene on chromosome 8. Burkitt’s Lymphoma comprises of 6.35% of all lymphoma cases in Pakistan, with male predominance. Lymphoma rarely presents as a primary pathology of acute kidney injury. Burkitt’s lymphoma in adult population is uncommon and few cases have been reported where Burkitt’s lymphoma presents as a cause of acute kidney injury. There are three epidemiological subtypes Endemic (African), sporadic (non-endemic) and immunodeficiency related. Sporadic cases dominate amongst others in Pakistan.

Pure Erythroid Leukaemia- Report of An Extremely Rare Case with Dismal Prognosis

Pure erythroid leukaemia (PEL) is a rare and aggressive form of acute leukaemia whose biology remains poorly characterized. The category of acute erythroid leukaemia was signiûcantly revised in the 2016 revision to the World Health Organization (WHO) classiûcation of myeloid neoplasms. In the previous 2008 WHO classiûcation, acute erythroid leukaemia was categorized into two subtypes: erythroleukaemia and pure erythroid leukaemia (PEL), whereas in the 2016 WHO update, erythroleukaemia was merged into myelodysplastic syndrome and PEL becomes the only type of acute erythroid leukaemia. De novo pure erythroid leukaemia is a disease of adults (median age 68 years), exhibits a striking male predominance, is universally associated with an abnormal karyotype and has an exceedingly poor overall median survival of 1.4 months. Given the limited number of reports of this rare and diagnostically challenging entity, we report clinicopathologic characteristics of a case of PEL, diagnosis was made by the bone marrow morphology and immunophenotyping. J Bangladesh Coll Phys Surg 2021; 39: 266-268

Road to Metastasis: The TWEAK Pathway as a Discriminant between Metastasizing and Non-Metastasizing Thick Melanomas

Cutaneous melanoma (CM) is the most aggressive form of skin cancer, and its worldwide incidence is rapidly increasing. Early stages can be successfully treated by surgery, but once metastasis has occurred, the prognosis is poor. However, some 5–10% of thick (≥2 mm) melanomas do not follow this scenario and run an unpredictable course. Little is known about the factors that contribute to metastasis in some patient with thick melanomas and the lack thereof in thick melanoma patients who never develop metastatic disease. We were therefore interested to study differential gene expression and pathway analysis and compare non-metastatic and metastatic thick melanomas. We found that the TNF-like weak inducer of apoptosis (TWEAK) pathway was upregulated in thick non-metastasizing melanomas. MAP3K14 (NIK1), BIRC2 (cIAP1), RIPK1, CASP7, CASP8, and TNF play an important role in inhibiting proliferation and invasion of tumor cells via the activation of the non-canonical NF-κB signaling pathway. In particular, this pathway sensitizes melanoma cells to TNF-alpha and activates the apoptosis module of the TWEAK pathway in thick non-metastasizing melanomas. Hence, our study suggests a potential role of the TWEAK pathway in inhibiting thick melanoma from metastasis. Exploitation of these genes and the pathway they control may open future therapeutic avenues.