RARE-21Sox2 plays an important role in choroid plexus tumor development

Neuro-Oncology

2022 Jun 03

Faltings, L;Sarowar, T;Virga, J;Singh, N;Kwa, B;Zhao, H;
| DOI: 10.1093/neuonc/noac079.046

Choroid plexus (CP) tumors are rare primary brain neoplasms found most commonly in children and are thought to arise from CP epithelial cells. Sox2 is a transcription factor that not only plays a role in development in the ventricular zone, CP, and roof plate, but also contributes to cancer stemness, tumorigenesis, and drug resistance. Gene expression studies demonstrate aberrant Sox2 expression in human CP tumors, suggesting a role in tumor development. A subset of CP tumors exhibit abnormal NOTCH pathway activity. Using animal models, we previously show that sustained NOTCH activity leads to CP tumors. Immunofluorescence, RT-qPCR, and RNA scope assays have revealed increased Sox2 levels in NOTCH-driven CP tumors compared to wild type CP in mice. To investigate the role of Sox2 in CP tumors, we eliminated Sox2 expression in NOTCH-driven CP tumors. Loss of Sox2 almost completely blocked NOTCH-driven CP tumor growth in these mice, supporting a role for Sox2 in these tumors. Ciliation regulation is one proposed functional pathway for tumorigenesis in CP tumors. Using immunofluorescence assays for cilia (ARL13b) and aquaporin transport protein 1 (AQP1) in combination with super resolution microscopy, we observe a stark contrast between wild type CP epithelial cells which are multiciliated and homogeneously express AQP1, indicative of normal epithelial differentiation, compared to NOTCH-driven CP tumors consisting of mono-ciliated cells with loss of AQP1 expression. In Sox2-deficient NOTCH-driven CP tumors, we observe tumor cells remain mono-ciliated and AQP1-negative, indicating that Sox2 loss does not affect the ciliation machinery. Together this warrants further study into the mechanisms of Sox2 functions in CP tumors. By unraveling the role of Sox2 in CP tumors, we may better understand their origin and biology to ultimately design improved treatment options.

Suppression of mutant Kirsten-RAS (KRASG12D)-driven pancreatic carcinogenesis by dual-specificity MAP kinase phosphatases 5 and 6

Oncogene

2022 Apr 13

Kidger, AM;Saville, MK;Rushworth, LK;Davidson, J;Stellzig, J;Ono, M;Kuebelsbeck, LA;Janssen, KP;Holzmann, B;Morton, JP;Sansom, OJ;Caunt, CJ;Keyse, SM;
PMID: 35418690 | DOI: 10.1038/s41388-022-02302-0

The cytoplasmic phosphatase DUSP6 and its nuclear counterpart DUSP5 are negative regulators of RAS/ERK signalling. Here we use deletion of either Dusp5 or Dusp6 to explore the roles of these phosphatases in a murine model of KRASG12D-driven pancreatic cancer. By 56-days, loss of either DUSP5 or DUSP6 causes a significant increase in KRASG12D-driven pancreatic hyperplasia. This is accompanied by increased pancreatic acinar to ductal metaplasia (ADM) and the development of pre-neoplastic pancreatic intraepithelial neoplasia (PanINs). In contrast, by 100-days, pancreatic hyperplasia is reversed with significant atrophy of pancreatic tissue and weight loss observed in animals lacking either DUSP5 or DUSP6. On further ageing, Dusp6-/- mice display accelerated development of metastatic pancreatic ductal adenocarcinoma (PDAC), while in Dusp5-/- animals, although PDAC development is increased this process is attenuated by atrophy of pancreatic acinar tissue and severe weight loss in some animals before cancer could progress. Our data suggest that despite a common target in the ERK MAP kinase, DUSP5 and DUSP6 play partially non-redundant roles in suppressing oncogenic KRASG12D signalling, thus retarding both tumour initiation and progression. Our data suggest that loss of either DUSP5 or DUSP6, as observed in certain human tumours, including the pancreas, could promote carcinogenesis.

Discovery of potent and selective HER2 inhibitors with efficacy against HER2 exon 20 insertion-driven tumors, which preserve wild-type EGFR signaling

Nature cancer

2022 Jul 01

Wilding, B;Scharn, D;Böse, D;Baum, A;Santoro, V;Chetta, P;Schnitzer, R;Botesteanu, DA;Reiser, C;Kornigg, S;Knesl, P;Hörmann, A;Köferle, A;Corcokovic, M;Lieb, S;Scholz, G;Bruchhaus, J;Spina, M;Balla, J;Peric-Simov, B;Zimmer, J;Mitzner, S;Fett, TN;Beran, A;Lamarre, L;Gerstberger, T;Gerlach, D;Bauer, M;Bergner, A;Schlattl, A;Bader, G;Treu, M;Engelhardt, H;Zahn, S;Fuchs, JE;Zuber, J;Ettmayer, P;Pearson, M;Petronczki, M;Kraut, N;McConnell, DB;Solca, F;Neumüller, RA;
PMID: 35883003 | DOI: 10.1038/s43018-022-00412-y

Oncogenic alterations in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of patients with non-small cell lung cancer and predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinical-grade tyrosine kinase inhibitors are limited by either insufficient selectivity against wild-type (WT) epidermal growth factor receptor (EGFR), which is a major cause of dose-limiting toxicity or by potency against HER2 exon 20 mutant variants. Here we report the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing WT EGFR, which reduce tumor cell survival and proliferation in vitro and result in regressions in preclinical xenograft models of HER2 exon 20 mutant non-small cell lung cancer, concomitant with inhibition of downstream HER2 signaling. Our results suggest that HER2 exon 20 insertion-driven tumors can be effectively treated by a potent and highly selective HER2 inhibitor while sparing WT EGFR, paving the way for clinical translation.

Oncogenic Kras G12D specific non-covalent inhibitor reprograms tumor microenvironment to prevent and reverse early pre-neoplastic pancreatic lesions and in combination with immunotherapy regresses advanced PDAC in a CD8 + T cells dependent manner

bioRxiv : the preprint server for biology

2023 Feb 18

Mahadevan, KK;McAndrews, KM;LeBleu, VS;Yang, S;Lyu, H;Li, B;Sockwell, AM;Kirtley, ML;Morse, SJ;Moreno Diaz, BA;Kim, MP;Feng, N;Lopez, AM;Guerrero, PA;Sugimoto, H;Arian, KA;Ying, H;Barekatain, Y;Kelly, PJ;Maitra, A;Heffernan, TP;Kalluri, R;
PMID: 36824971 | DOI: 10.1101/2023.02.15.528757

Pancreatic ductal adenocarcinoma (PDAC) is associated with mutations in Kras, a known oncogenic driver of PDAC; and the KRAS G12D mutation is present in nearly half of PDAC patients. Recently, a non-covalent small molecule inhibitor (MRTX1133) was identified with specificity to the Kras G12D mutant protein. Here we explore the impact of Kras G12D inhibition by MRTX1133 on advanced PDAC and its influence on the tumor microenvironment. Employing different orthotopic xenograft and syngeneic tumor models, eight different PDXs, and two different autochthonous genetic models, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8 + effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. Autochthonous genetic mouse models treated with MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8 + T cells and immune checkpoint blockade therapy (iCBT) synergizes with MRTX1133 to eradicate PDAC and prolong overall survival. Mechanistically, inhibition of mutant Kras in advanced PDAC and human patient derived organoids (PDOs) induces Fas expression in cancer cells and facilitates CD8 + T cell mediated death. These results demonstrate the efficacy of MRTX1133 in different mouse models of PDAC associated with reprogramming of stromal fibroblasts and a dependency on CD8 + T cell mediated tumor clearance. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with iCBT in clinical trials.

A Phase I, Multicenter, Dose-Escalation Study of the Oral Selective FGFR inhibitor Debio 1347 in Patients with Advanced Solid Tumors Harboring FGFR Gene Alterations.

Clin Cancer Res.

2019 Feb 11

Voss MH, Hierro C, Heist RS, Cleary JM, Meric-Bernstam F, Tabernero J, Janku F, Gandhi L, Iafrate AJ, Borger DR, Ishii N, Hu Y, Kirpicheva Y, Nicolas-Metral V, Pokorska-Bocci A, Vaslin Chessex A, Zanna C, Flaherty KT, Baselga J.
PMID: 30745300 | DOI: 10.1158/1078-0432.CCR-18-1959

Abstract

PURPOSE:

To investigate tolerability, efficacy, and pharmacokinetics/-dynamics (PK/PD) of Debio 1347, a selective fibroblast growth factor receptor (FGFR) Inhibitor.

EXPERIMENTAL DESIGN:

This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1-3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose limiting toxicities (DLTs) were evaluated during the first 4 weeks on treatment, PK/PD post-first dose and after 4 weeks.

RESULTS:

Seventy-one patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had 6 DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, stomatitis). The maximum tolerated dose was not reached, but dermatological toxicity became sometimes dose-limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, three with FGFR fusions, demonstrated partial responses, 10 additional patients tumor size regressions of ≤30%. Plasma half-life was 11.5 h. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.

CONCLUSIONS:

Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.

Neural network learning defines glioblastoma features to be of neural crest perivascular or radial glia lineages

Science advances

2022 Jun 10

Hu, Y;Jiang, Y;Behnan, J;Ribeiro, MM;Kalantzi, C;Zhang, MD;Lou, D;Häring, M;Sharma, N;Okawa, S;Del Sol, A;Adameyko, I;Svensson, M;Persson, O;Ernfors, P;
PMID: 35675414 | DOI: 10.1126/sciadv.abm6340

Glioblastoma is believed to originate from nervous system cells; however, a putative origin from vessel-associated progenitor cells has not been considered. We deeply single-cell RNA-sequenced glioblastoma progenitor cells of 18 patients and integrated 710 bulk tumors and 73,495 glioma single cells of 100 patients to determine the relation of glioblastoma cells to normal brain cell types. A novel neural network-based projection of the developmental trajectory of normal brain cells uncovered two principal cell-lineage features of glioblastoma, neural crest perivascular and radial glia, carrying defining methylation patterns and survival differences. Consistently, introducing tumorigenic alterations in naïve human brain perivascular cells resulted in brain tumors. Thus, our results suggest that glioblastoma can arise from the brains' vasculature, and patients with such glioblastoma have a significantly poorer outcome.

Combined KRAS G12C and SOS1 inhibition enhances and extends the anti-tumor response in KRAS G12C-driven cancers by addressing intrinsic and acquired resistance

bioRxiv : the preprint server for biology

2023 Jan 23

Thatikonda, V;Lu, H;Jurado, S;Kostyrko, K;Bristow, CA;Bosch, K;Feng, N;Gao, S;Gerlach, D;Gmachl, M;Lieb, S;Jeschko, A;Machado, AA;Marszalek, ED;Mahendra, M;Jaeger, PA;Sorokin, A;Strauss, S;Trapani, F;Kopetz, S;Vellano, CP;Petronczki, M;Kraut, N;Heffernan, TP;Marszalek, JR;Pearson, M;Waizenegger, I;Hofmann, MH;
PMID: 36747713 | DOI: 10.1101/2023.01.23.525210

Efforts to improve the anti-tumor response to KRAS G12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRAS G12C inhibitor (KRAS G12C i) to those induced by KRAS G12C i alone or combined with SHP2 or EGFR inhibitors. In lung cancer and colorectal cancer (CRC) models, BI-3406 plus KRAS G12C i induces an anti-tumor response stronger than that observed with KRAS G12C i alone and comparable to those by the other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRAS G12C i treatment delays the emergence of acquired adagrasib resistance in both CRC and lung cancer models and is associated with re-establishment of anti-proliferative activity in KRAS G12C i-resistant CRC models. Our findings position KRAS G12C plus SOS1 inhibition therapy as a promising strategy for treating both KRAS G12C -mutated tumors as well as for addressing acquired resistance to KRAS G12C i.

Myeloid cell interferon secretion restricts Zika flavivirus infection of developing and malignant human neural progenitor cells

Neuron

2022 Sep 26

Bulstrode, H;Girdler, GC;Gracia, T;Aivazidis, A;Moutsopoulos, I;Young, AMH;Hancock, J;He, X;Ridley, K;Xu, Z;Stockley, JH;Finlay, J;Hallou, C;Fajardo, T;Fountain, DM;van Dongen, S;Joannides, A;Morris, R;Mair, R;Watts, C;Santarius, T;Price, SJ;Hutchinson, PJA;Hodson, EJ;Pollard, SM;Mohorianu, I;Barker, RA;Sweeney, TR;Bayraktar, O;Gergely, F;Rowitch, DH;
PMID: 36174572 | DOI: 10.1016/j.neuron.2022.09.002

Zika virus (ZIKV) can infect human developing brain (HDB) progenitors resulting in epidemic microcephaly, whereas analogous cellular tropism offers treatment potential for the adult brain cancer, glioblastoma (GBM). We compared productive ZIKV infection in HDB and GBM primary tissue explants that both contain SOX2+ neural progenitors. Strikingly, although the HDB proved uniformly vulnerable to ZIKV infection, GBM was more refractory, and this correlated with an innate immune expression signature. Indeed, GBM-derived CD11b+ microglia/macrophages were necessary and sufficient to protect progenitors against ZIKV infection in a non-cell autonomous manner. Using SOX2+ GBM cell lines, we found that CD11b+-conditioned medium containing type 1 interferon beta (IFNβ) promoted progenitor resistance to ZIKV, whereas inhibition of JAK1/2 signaling restored productive infection. Additionally, CD11b+ conditioned medium, and IFNβ treatment rendered HDB progenitor lines and explants refractory to ZIKV. These findings provide insight into neuroprotection for HDB progenitors as well as enhanced GBM oncolytic therapies.

Cell Populations Expressing Stemness-Associated Markers in Lung Adenocarcinoma

Life (Basel, Switzerland)

2021 Oct 18

Paterson, C;Kilmister, EJ;Brasch, HD;Bockett, N;Patel, J;Paterson, E;Purdie, G;Galvin, S;Davis, PF;Itinteang, T;Tan, ST;
PMID: 34685477 | DOI: 10.3390/life11101106

The stemness-associated markers OCT4, NANOG, SOX2, KLF4 and c-MYC are expressed in numerous cancer types suggesting the presence of cancer stem cells (CSCs). Immunohistochemical (IHC) staining performed on 12 lung adenocarcinoma (LA) tissue samples showed protein expression of OCT4, NANOG, SOX2, KLF4 and c-MYC, and the CSC marker CD44. In situ hybridization (ISH) performed on six of the LA tissue samples showed mRNA expression of OCT4, NANOG, SOX2, KLF4 and c-MYC. Immunofluorescence staining performed on three of the tissue samples showed co-expression of OCT4 and c-MYC with NANOG, SOX2 and KLF4 by tumor gland cells, and expression of OCT4 and c-MYC exclusively by cells within the stroma. RT-qPCR performed on five LA-derived primary cell lines showed mRNA expression of all the markers except SOX2. Western blotting performed on four LA-derived primary cell lines demonstrated protein expression of all the markers except SOX2 and NANOG. Initial tumorsphere assays performed on four LA-derived primary cell lines demonstrated 0-80% of tumorspheres surpassing the 50 µm threshold. The expression of the stemness-associated markers OCT4, SOX2, NANOG, KFL4 and c-MYC by LA at the mRNA and protein level, and the unique expression patterns suggest a putative presence of CSC subpopulations within LA, which may be a novel therapeutic target for this cancer. Further functional studies are required to investigate the possession of stemness traits.

Expression of Embryonic Stem Cell Markers on the Microvessels of WHO Grade I Meningioma

Front. Surg.

2018 Oct 26

Shivapathasundram G, Wickremesekera AC, Brasch HD, Marsh R, Tan ST, Itinteang T.
PMID: - | DOI: 10.3389/fsurg.2018.00065

Aim: The presence of cells within meningioma (MG) that express embryonic stem cell (ESC) markers has been previously reported. However, the precise location of these cells has yet to be determined.

Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining was performed on 11 WHO grade I MG tissue samples for the expression of the ESC markers OCT4, NANOG, SOX2, KLF4 and c-MYC. Immunofluorescence (IF) IHC staining was performed to investigate the localization of each of these ESC markers. NanoString and colorimetric in situ hybridization (CISH) mRNA expression analyses were performed on six snap-frozen MG tissue samples to confirm transcriptional activation of these proteins, respectively.

Results: DAB IHC staining demonstrated expression of OCT4, NANOG, SOX2, KLF4, and c-MYC within all 11 MG tissue samples. IF IHC staining demonstrated the expression of the ESC markers OCT4, NANOG, SOX2, KLF4, and c-MYC on both the endothelial and pericyte layers of the microvessels. NanoString and CISH mRNA analyses confirmed transcription activation of these ESC markers.

Conclusion: This novel finding of the expression of all aforementioned ESC markers in WHO grade I MG infers the presence of a putative stem cells population which may give rise to MG.

	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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