
SOWAHA, a cancer suppressor gene, plays a crucial role in the progression of various carcinomas, particularly through mechanisms involving metabolic reprogramming.


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sowaha-a-potential-cancer-suppressor-gene-influences-metabolic-reprogramming-in-multiple-cancer-types


SOWAHA, a Potential Cancer Suppressor Gene, Influences Metabolic Reprogramming in Multiple Cancer Types


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癌細胞は急速な増殖のために高レベルの鉄を必要とし、細胞表面の転移受容体1(TfR1)を大幅に上方制御する。この現象と TfR1 の高速エンドサイトーシス速度を利用して、TransTACs と呼ばれる膜タンパク質分解のためのヘテロ二重特異性抗体モダリティを開発した。


Transferrin receptor targeting chimeras have been developed that enable targeting of drug resistance in epidermal growth factor receptor-driven lung cancer and reversible control of human primary chimeric antigen receptor T cells, representing a promising new family of bifunctional antibodies for targeted cancer therapy.

Transferrin receptor targeting chimeras for membrane protein degradation - Nature

高鉄転移受容体標的キメラによるメンブレンタンパク質の分解


KRAS駆動がんにおいて、グリコスフィンゴ脂質合成は癌細胞の増殖には不可欠ではないが、免疫回避に必要不可欠である。


Functional genomics and lipidomic analyses reveal that sphingolipid synthesis is required for tumour immune evasion and tumour growth in vivo, mediated in part by the impact of glycosphingolipid synthesis on cell surface expression of IFNγ receptors.

Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer - Nature

kras駆動がんにおける免疫回避のメカニズム-グリコスフィンゴ脂質合成の役割


KRAS駆動がんにおける免疫回避のメカニズム:グリコスフィンゴ脂質合成の役割



Glycosphingolipid synthesis is an essential pathway for cancer cells to evade the immune system, despite being dispensable for cancer cell proliferation.


glycosphingolipid-synthesis-a-critical-pathway-for-cancer-immune-evasion


Glycosphingolipid Synthesis: A Critical Pathway for Cancer Immune Evasion



Androgen deprivation therapy induces a switch in tumor necrosis factor (TNF) signaling, leading to increased expression of the chemokine CCL2 that recruits immunosuppressive tumor-associated macrophages and promotes castration-resistant prostate cancer recurrence.


Androgen deprivation therapy (ADT) is an effective but not curative treatment for advanced and recurrent prostate cancer (PC). We investigated the mechanisms controlling the response to androgen-deprivation by surgical castration in genetically-engineered mouse models (GEMM) of PC, using high frequency ultrasound imaging to rigorously measure tumor volume. Castration initially causes almost all tumors to shrink in volume, but many tumors subsequently recur within 5-10 weeks. Blockade of tumor necrosis factor (TNF) signaling a few days in advance of castration surgery, using a TNFR2 ligand trap, prevents regression in a PTEN-deficient GEMM. Following tumor regression, a basal stem cell-like population within the tumor increases along with TNF protein levels. Tumor cell lines in culture recapitulate these in vivo observations, suggesting that basal stem cells are the source of TNF. When TNF signaling blockade is administered immediately prior to castration, tumors regress but recurrence is prevented. This implies that a late wave of TNF secretion within the tumor – which coincides with the expression of NFκB regulated genes – drives recurrence. The inhibition of signaling downstream of an NFκB-regulated protein – chemokine C-C motif ligand 2 (CCL2) – prevents post-castration tumor recurrence, phenocopying post-castration (late) TNF signaling blockade. CCL2 was originally identified as a macrophage chemoattractant and indeed at late times after castration gene sets related to chemotaxis and migration are up-regulated. Importantly, enhanced CCL2 signaling during the tumor recurrence phase coincides with an increase in pro-tumorigenic macrophages and a decrease in CD8 T cells, suggesting that recurrence is driven at least in part by tumor immunosuppression. In summary, we demonstrate that a therapy-induced switch in TNF signaling – a consequence of the increased stem cell-like character of the residual tumor cells surviving ADT – induces an immunosuppressive tumor microenvironment and concomitant tumor recurrence.

### Competing Interest Statement

The authors have declared no competing interest.

Androgen deprivation triggers a cytokine signaling switch to induce immune suppression and prostate cancer recurrence

androgen-deprivation-triggers-a-cytokine-signaling-switch-that-induces-immune-suppression-and-prostate-cancer-recurrence


Androgen Deprivation Triggers a Cytokine Signaling Switch that Induces Immune Suppression and Prostate Cancer Recurrence



PITAR, a long noncoding RNA, inhibits p53 by binding and stabilizing TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, thereby promoting p53 ubiquitination and degradation.


In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, PITAR ( p 53 I nactivating T RIM28 a ssociated R NA), as an inhibitor of p53. PITAR is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated PITAR, in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a TRIM28-dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by PITAR, which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose PITAR as a potential GBM therapeutic target.

### Competing Interest Statement

The authors have declared no competing interest.

PITAR, a DNA damage-inducible Cancer/Testis long noncoding RNA, inactivates p53 by binding and stabilizing TRIM28 mRNA

identification-and-characterization-of-pitar-a-dna-damage-inducible-long-noncoding-rna-that-inhibits-p53-by-stabilizing-trim28-mrna-in-glioblastoma


Identification and Characterization of PITAR, a DNA Damage-Inducible Long Noncoding RNA that Inhibits p53 by Stabilizing TRIM28 mRNA in Glioblastoma



がん細胞の好気的解糖代謝から嫌気的解糖代謝への切り替え(ワールブルグ効果)により蓄積した乳酸がNBS1のラクチル化を促進し、ホモロジー組換え修復を活性化させることで、DNA修復能力を高め、化学療法耐性を獲得する。


Lactylation of NBS1 by TIP60 promotes homologous recombination-driven DNA repair and resistance to chemotherapy in cancer cells and links altered cancer cell metabolism to increase genome stability.

NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance - Nature

がん細胞の乳酸代謝がdna修復と化学療法耐性に必要不可欠であることを明らかにする


がん細胞の乳酸代謝がDNA修復と化学療法耐性に必要不可欠であることを明らかにする



大腸がんの転移にはDickkopf-2 (DKK2)が必須であり、DKK2はパネート細胞様の性質を持つがん細胞の生成を促進する。


Metastasis is the leading cause of cancer-related mortality. Paneth cells provide stem cell niche factors in homeostatic conditions, but the underlying mechanisms of cancer stem cell niche development are unclear. Here we report that Dickkopf-2 (DKK2) is essential for the generation of cancer cells with Paneth cell properties during colon cancer metastasis. Splenic injection of Dkk2 -knockout (KO) cancer organoids into C57BL/6 mice resulted in a significant reduction of liver metastases. Transcriptome analysis showed reduction of Paneth cell markers such as lysozymes in KO organoids. Single cell RNA sequencing analyses of murine metastasized colon cancer cells and patient samples identified the presence of lysozyme positive cells with Paneth cell properties including enhanced glycolysis. Further analyses of transcriptome and chromatin accessibility suggested Hepatocyte nuclear factor 4-alpha (HNF4A) as a downstream target of DKK2. Chromatin immunoprecipitation followed by sequencing analysis revealed that HNF4A binds to the promoter region of Sox9 , a well-known transcription factor for Paneth cell differentiation. In the liver metastatic foci, DKK2 knockout rescued HNF4A protein levels followed by reduction of lysozyme positive cancer cells. Taken together, DKK2-mediated reduction of HNF4A protein promotes the generation of lysozyme positive cancer cells with Paneth cell properties in the metastasized colon cancers.

### Competing Interest Statement

The authors have declared no competing interest.

Metastasis of colon cancer requires Dickkopf-2 to generate cancer cells with Paneth cell properties

大腸がんの転移にはパネート細胞様の性質を持つがん細胞の生成にdickkopf-2が必要である


大腸がんの転移にはパネート細胞様の性質を持つがん細胞の生成にDickkopf-2が必要である



WIN site inhibitors of the chromatin-associated protein WDR5 induce depletion of the ribosome inventory, leading to a broad translational choke and activation of the p53-MDM4 axis, which drives apoptosis in MLL-rearranged cancer cells.


The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the "WIN" site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small molecule WIN site inhibitors, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anti-cancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anti-cancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

### Competing Interest Statement

Fesik, S. W., Stauffer, S. R., Salovich, J. M., Tansey, W. P., Wang, F., Phan, J., Olejniczak, E. T., inventors. WDR5 inhibitors and modulators. United States Patent US 10,501,466. 10 December 2019. Fesik, S. W., Stauffer, S. R., Tansey, W. P., Olejniczak, E. T., Phan, J., Wang, F., Jeon, K., Gogliotti, R. D., inventors. WDR5 inhibitors and modulators. United States Patent US 10,160,763. 25 December 2018.

Ribosome subunit attrition and activation of the p53–MDM4 axis dominate the response of MLL-rearranged cancer cells to WDR5 WIN site inhibition

ribosome-depletion-and-p53-axis-activation-drive-the-response-of-mll-rearranged-cancer-cells-to-wdr5-inhibition


Ribosome Depletion and p53 Axis Activation Drive the Response of MLL-Rearranged Cancer Cells to WDR5 Inhibition



DUX4 expression is a common feature of diverse metastatic cancers, where it suppresses anti-tumor immunity and is associated with decreased response and survival in patients treated with immune checkpoint inhibitors.


Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that DUX4 expression is a common feature of metastatic tumors, with ∼10-50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing DUX4 . DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. DUX4 expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with DUX4 expression associated with a median reduction in survival of over one year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance.

### Competing Interest Statement

R.K.B. is an inventor on a patent application submitted by Fred Hutchinson Cancer Center that covers DUX4 expression in cancers and response to immunotherapy. R.K.B. is a founder and scientific advisor of Codify Therapeutics and Synthesize Bio and holds equity in both companies. R.K.B. has received research funding from Codify Therapeutics unrelated to the current work. The remaining authors declare no competing interests.

DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers

dux4-expression-is-prevalent-in-metastatic-cancers-and-predicts-poor-response-to-immune-checkpoint-inhibition


DUX4 Expression is Prevalent in Metastatic Cancers and Predicts Poor Response to Immune Checkpoint Inhibition
