bims-tucedo 2020-03-08 papers

bims-tucedo

Biomed News

on Tumor cell dormancy

Issue of 2020–03–08
27 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology

Epithelial Plasticity, Autophagy and Metastasis: Potential Modifiers of the Crosstalk to Overcome Therapeutic Resistance.
Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing.
Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer.
The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer.
Mutations in the coat complex II component SEC23B promote colorectal cancer metastasis.
Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation.
TCF21 promotes luminal-like differentiation and suppresses metastasis in bladder cancer.
RANKL/RANK System-Based Mechanism for Breast Cancer Bone Metastasis and Related Therapeutic Strategies.
The Engagement Between MDSCs and Metastases: Partners in Crime.
Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer.
An in vitro hyaluronic acid hydrogel based platform to model dormancy in brain metastatic breast cancer cells.
Verification of EZH2 as a druggable target in metastatic uveal melanoma.
Role of non-coding RNAs and RNA modifiers in cancer therapy resistance.
The functional activity of E-cadherin controls tumor cell metastasis at multiple steps.
SIRT2-dependent IDH1 deacetylation inhibits colorectal cancer and liver metastases.
YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy.
MAPK pathway alterations correlate with poor survival and drive resistance to therapy in patients with lung cancers driven by ROS1 fusions.
Hepatocellular carcinoma-derived exosomes in organotropic metastasis, recurrence and early diagnosis application.
WDR63 inhibits Arp2/3-dependent actin polymerization and mediates the function of p53 in suppressing metastasis.
HER2-positive breast cancer resistance to trastuzumab is associated with metabolic switch.
Research progress on the effect of autophagy-lysosomal pathway on tumor drug resistance.
Metabolism of pancreatic cancer: paving the way to better anticancer strategies.
First step to metastasis: MiRNAome abnormalities impair cell-cell adhesion and facilitate detachment of breast cancer cells.
Cyp2c44 regulates prostaglandin synthesis, lymphangiogenesis, and metastasis in a mouse model of breast cancer.
NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors.
Interferon-induced IDO1 mediates radiation resistance and is a therapeutic target in colorectal cancer.
Interplay between DNA damage repair and apoptosis shapes cancer evolution through aneuploidy and microsatellite instability.

Stem Cell Rev Rep. 2020 Mar 03.

Epithelial Plasticity, Autophagy and Metastasis: Potential Modifiers of the Crosstalk to Overcome Therapeutic Resistance.

Minal Garg.

  Epithelial-to-mesenchymal transition (EMT) initiates malignant transformation of cancer cells and is responsible for the generation of heterogenic subsets of cancer stem cells (CSCs). Signals in the form of environmental cues and paracrine factors within tumor microenvironment (TME) niche, support the possibility of generation of pool of CSCs with two distinct functional transition states. Cyclic CSCs with predominant epithelial phenotype, self-renew and differentiate into mature cancer cells. Subsets of autophagic/ non-cyclic CSCs with predominant mesenchymal phenotype have capacity to invade, metastasize, resist to apoptosis, escape immunosurveillance, survive chemotherapies and are majorly responsible for cancer mortality. Differences in phenotypic plasticity may form the basis of differential impact of therapeutic outcomes on heterogeneous subpopulations of CSCs. Activation of autophagy is responsible for the recycling of damaged organelles and protein aggregates, regulates EMT, confers the survival advantage to neoplastic cells to anti-cancer therapies, significantly affects the invasive potential of cancer cells and supports their metastatic dissemination in a tissue and tumor stage dependent manner. Therapy resistance is the primary obstacle in the complete ablation of tumor cells. Combinational treatments based on targeting autophagic CSCs and inhibiting EMT regulators may represent potential anticancer strategies for the prevention of cancer invasion, metastatic spread and disease relapse.

Keywords:  Autophagy; Cancer stem cells; Epithelial-to-mesenchymal transition; Metastatic potential; Therapeutic resistance

DOI:  https://doi.org/10.1007/s12015-019-09945-9
Nat Cell Biol. 2020 Mar;22(3): 310-320

Transcriptional diversity and bioenergetic shift in human breast cancer metastasis revealed by single-cell RNA sequencing.

Ryan T Davis, Kerrigan Blake, Dennis Ma, Mari B Ishak Gabra, Grace A Hernandez, Anh T Phung, Ying Yang, Dustin Maurer, Austin E Y T Lefebvre, Hamad Alshetaiwi, Zhengtao Xiao, Juan Liu, Jason W Locasale, Michelle A Digman, Eric Mjolsness, Mei Kong, Zena Werb, Devon A Lawson.

Although metastasis remains the cause of most cancer-related mortality, mechanisms governing seeding in distal tissues are poorly understood. Here, we establish a robust method for the identification of global transcriptomic changes in rare metastatic cells during seeding using single-cell RNA sequencing and patient-derived-xenograft models of breast cancer. We find that both primary tumours and micrometastases display transcriptional heterogeneity but micrometastases harbour a distinct transcriptome program conserved across patient-derived-xenograft models that is highly predictive of poor survival of patients. Pathway analysis revealed mitochondrial oxidative phosphorylation as the top pathway upregulated in micrometastases, in contrast to higher levels of glycolytic enzymes in primary tumour cells, which we corroborated by flow cytometric and metabolomic analyses. Pharmacological inhibition of oxidative phosphorylation dramatically attenuated metastatic seeding in the lungs, which demonstrates the functional importance of oxidative phosphorylation in metastasis and highlights its potential as a therapeutic target to prevent metastatic spread in patients with breast cancer.

DOI: https://doi.org/10.1038/s41556-020-0477-0
J Hematol Oncol. 2020 Mar 05. 13(1): 17

Long non-coding RNA HUMT hypomethylation promotes lymphangiogenesis and metastasis via activating FOXK1 transcription in triple-negative breast cancer.

Shaoquan Zheng, Lu Yang, Yutian Zou, Jie-Ying Liang, Peng Liu, Guanfeng Gao, Anli Yang, Hailin Tang, Xiaoming Xie.

   BACKGROUND: Triple-negative breast cancer (TNBC) is the most malignant subtype of breast cancer with highly invasive ability and metastatic nature to the lymph nodes. Long non-coding RNAs (lncRNAs) have been widely explored in cancer tumorigenesis and progression. However, their roles in TNBC lymph node metastasis remains rarely studied.
METHODS: The expression of lncRNA highly upregulated in metastatic TNBC (HUMT) in cell lines and tissues was detected by quantitative real-time PCR (qRT-PCR) and in situ hybridization (ISH). RNA immunoprecipitation (RIP) and RNA pulldown were used to verify the interaction between lncRNA and protein. Chromatin immunoprecipitation (CHIP) and dCas9-gRNA-guided chromatin immunoprecipitation (dCas9-CHIP) were conducted to identify the specific binding site of HUMT-YBX1 complex. Western blot was used to detect the downstream of HUMT.
RESULTS: HUMT was significantly upregulated in lymph node invasive cells and predicted poorer clinical prognosis. Functional study indicated that HUMT promoted lymphangiogenesis and lymph node metastasis. Bioinformatic analysis and qRT-PCR showed that the high expression of HUMT was correlated with the hypomethylation status of its promoter region. Further, HUMT recruited Y-box binding protein 1 (YBX1) to form a novel transcription complex and activated the expression of forkhead box k1 (FOXK1), thus enhancing the expression of vascular endothelial growth factor C (VEGFC). The therapeutic value was further validated in patient-derived xenograft (PDX) models, and a combined marker panel exhibited a better prognostic value for TNBC in receiver operating characteristic (ROC) analysis.
CONCLUSIONS: Our study identified a novel TNBC lymph node metastasis-associated lncRNA, which promoted TNBC progression and indicated a novel biomarker and potential therapeutic target for TNBC lymph node metastasis.

Keywords:  Forkhead box k1; Long non-coding RNA; Lymph node metastasis; Triple-negative breast cancer; Y-box binding protein 1

DOI:  https://doi.org/10.1186/s13045-020-00852-y
Oncogene. 2020 Mar 03.

The CUL4B-miR-372/373-PIK3CA-AKT axis regulates metastasis in bladder cancer.

Xiaochen Liu, Jianfeng Cui, Li Gong, Fei Tian, Yangli Shen, Lipeng Chen, Yong Wang, Yangyang Xia, Lei Liu, Xiang Ye, Molin Wang, Guangyi Liu, Baichun Jiang, Changshun Shao, Yongxin Zou, Yaoqin Gong.

CUL4B, which acts as a scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complexes, participates in a variety of biological processes. Previous studies have shown that CUL4B is often overexpressed and exhibits oncogenic activities in a variety of solid tumors. However, the roles and the underlying mechanisms of CUL4B in bladder cancer (BC) were poorly understood. Here, we showed that CUL4B levels were overexpressed and positively correlated with the malignancy of BC, and CUL4B could confer BC cells increased motility, invasiveness, stemness, and chemoresistance. The PIK3CA/AKT pathway was identified as a critical downstream mediator of CUL4B-driven oncogenicity in BC cells. Furthermore, we demonstrated that CRL4B epigenetically repressed the transcription of miR-372/373, via catalyzing monoubiquitination of H2AK119 at the gene cluster encoding miR-372/373, leading to upregulation of PIK3CA and activation of AKT. Our findings thus establish a critical role for the CUL4B-miR-372/373-PIK3CA/AKT axis in the pathogenesis of BC and have important prognostic and therapeutic implications in BC.

DOI: https://doi.org/10.1038/s41388-020-1236-1
Cell Death Dis. 2020 Mar 02. 11(3): 157

Mutations in the coat complex II component SEC23B promote colorectal cancer metastasis.

Chunyuan Yang, Nan Chen, Xiang Li, Dan Lu, Zhiyuan Hou, Yuhua Li, Yan Jin, Jin Gu, Yuxin Yin.

Metastasis is the leading cause of death for colorectal cancer (CRC). However, the protein transport process involved in CRC metastasis remains unclear. In this report, we use whole-exome sequencing and bioinformatics analysis to identify somatic mutations in CRC samples and found mutations of the protein transport gene Sec23 homolog B (SEC23B) in patients with metachronous liver metastasis. We show that deletion of SEC23B suppresses the membrane localization of adhesion proteins and augments cell mobility. SEC23B mutations either cause a premature stop (C649T) or impair its protein transport activity (C1467G and T488C + G791A + G2153A). Furthermore, SEC23B mutations inhibit the transport of epithelial cell adhesion molecule (EPCAM) and CD9 molecule, thereby attenuating cell adhesion and promoting invasiveness both in vitro and in vivo. Taken together, these data demonstrate the important impact of SEC23B mutations on metastasis, and we propose that SEC23B is a potential suppressor of CRC metastasis.

DOI: https://doi.org/10.1038/s41419-020-2358-7
Nat Commun. 2020 Mar 05. 11(1): 1211

Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation.

Qing Ji, Lihong Zhou, Hua Sui, Liu Yang, Xinnan Wu, Qing Song, Ru Jia, Ruixiao Li, Jian Sun, Ziyuan Wang, Ningning Liu, Yuanyuan Feng, Xiaoting Sun, Gang Cai, Yu Feng, Jianfeng Cai, Yihai Cao, Guoxiang Cai, Yan Wang, Qi Li.

Tumor metastasis is a hallmark of cancer. Metastatic cancer cells often reside in distal tissues and organs in their dormant state. Mechanisms underlying the pre-metastatic niche formation are poorly understood. Here we show that in a colorectal cancer (CRC) model, primary tumors release integrin beta-like 1 (ITGBL1)-rich extracellular vesicles (EVs) to the circulation to activate resident fibroblasts in remote organs. The activated fibroblasts induce the pre-metastatic niche formation and promote metastatic cancer growth by secreting pro-inflammatory cytokine, such as IL-6 and IL-8. Mechanistically, the primary CRC-derived ITGBL1-enriched EVs stimulate the TNFAIP3-mediated NF-κB signaling pathway to activate fibroblasts. Consequently, the activated fibroblasts produce high levels of pro-inflammatory cytokines to promote metastatic cancer growth. These findings uncover a tumor-stromal interaction in the metastatic tumor microenvironment and an intimate signaling communication between primary tumors and metastases through the ITGBL1-loaded EVs. Targeting the EVs-ITGBL1-CAFs-TNFAIP3-NF-κB signaling axis provides an attractive approach for treating metastatic diseases.

DOI: https://doi.org/10.1038/s41467-020-14869-x
Mol Cancer Res. 2020 Mar 02. pii: molcanres.0766.2019. [Epub ahead of print]

TCF21 promotes luminal-like differentiation and suppresses metastasis in bladder cancer.

Sharada Mokkapati, Sima P Porten, Vikram M Narayan, Amy H Lim, Isuru S Jayaratna, Beat Roth, Tiewei Cheng, Neema Navai, Matthew Wszolek, Jonathan Melquist, Ganiraju Manyam, Woonyoung Choi, Bradley M Broom, Shanna Pretzsch, Bogdan Czerniak, David J McConkey, Colin P N Dinney.

Little is known regarding the subclone evolution process in advanced bladder cancer (BLCA), particularly with respect to the genomic alterations that lead to the development of metastatic lesions. In this project, we identify gene expression signatures associated with metastatic BLCA through mRNA expression profiling of RNA isolated from 33 primary BLCA and corresponding lymph node (LN) metastasis samples. Gene expression profiling (GEP) was performed on RNA isolated using the Illumina DASL platform. We identified the developmental transcription factor TCF21 as being significantly higher in primary BLCA compared to LN metastasis samples. To elucidate its function in BLCA, loss- and gain-of-function experiments were conducted in BLCA cell lines with high and low expression of TCF21, respectively. We also performed GEP in BLCA cell lines following TCF21 overexpression. We identified 2390 genes differentially expressed in primary BLCA and corresponding LN metastasis pairs at an FDR cutoff of 0.1 and a fold change of 1. Among those significantly altered, expression of TCF21 was higher in the primary tumor compared to LN metastasis. We validated this finding with Q-PCR and IHC on patient samples. Moreover, TCF21 expression was higher in luminal cell lines and knockdown of TCF21 increased invasion, tumor cell dissemination and metastasis. In contrast, overexpression of TCF21 in highly metastatic basal BLCA cell lines decreased their invasive and metastatic potential. Implications: TCF21 is differentially overexpressed in primary BLCA compared to matched LN metastasis, with in vitro and in vivo studies demonstrating a metastasis suppressor function of this transcription factor.

DOI: https://doi.org/10.1158/1541-7786.MCR-19-0766
Front Cell Dev Biol. 2020 ;8 76

RANKL/RANK System-Based Mechanism for Breast Cancer Bone Metastasis and Related Therapeutic Strategies.

Xiaoqiu Wu, Fangfei Li, Lei Dang, Chao Liang, Aiping Lu, Ge Zhang.

  Breast cancer remains one of the most life-threatening tumors affecting women. Most patients with advanced breast cancer eventually develop metastatic diseases, which cause significant morbidity and mortality. Approximately two-thirds of patients with advanced breast cancer exhibit osteolytic-type bone metastasis, which seriously reduce the quality of life. Therefore, development of novel therapeutic strategies for treating breast cancer patients with bone metastasis is urgently required. The "seed and soil" theory, which describes the interaction between the circulating breast cancer cells (seeds) and bone microenvironment (soil), is widely accepted as the mechanism underlying metastasis. Disruption of any step in this cycle might have promising anti-metastasis implications. The interaction of receptor activator of nuclear factor-κB ligand (RANKL) and its receptor RANK is fundamental in this vicious cycle and has been shown to be a novel effective therapeutic target. A series of therapeutic strategies have been developed to intervene in this cross-talk. Therefore, in this review, we have systematically introduced the functions of the RANKL/RANK signaling system in breast cancer and discussed related therapeutic strategies.

Keywords:  RANK; RANKL; bone metastasis; breast cancer; denosumab; vicious cycle

DOI:  https://doi.org/10.3389/fcell.2020.00076
Front Oncol. 2020 ;10 165

The Engagement Between MDSCs and Metastases: Partners in Crime.

Rosalinda Trovato, Stefania Canè, Varvara Petrova, Silvia Sartoris, Stefano Ugel, Francesco De Sanctis.

  Tumor metastases represent the major cause of cancer-related mortality, confirming the urgent need to identify key molecular pathways and cell-associated networks during the early phases of the metastatic process to develop new strategies to either prevent or control distal cancer spread. Several data revealed the ability of cancer cells to establish a favorable microenvironment, before their arrival in distant organs, by manipulating the cell composition and function of the new host tissue where cancer cells can survive and outgrow. This predetermined environment is termed "pre-metastatic niche" (pMN). pMN development requires that tumor-derived soluble factors, like cytokines, growth-factors and extracellular vesicles, genetically and epigenetically re-program not only resident cells (i.e., fibroblasts) but also non-resident cells such as bone marrow-derived cells. Indeed, by promoting an "emergency" myelopoiesis, cancer cells switch the steady state production of blood cells toward the generation of pro-tumor circulating myeloid cells defined as myeloid-derived suppressor cells (MDSCs) able to sustain tumor growth and dissemination. MDSCs are a heterogeneous subset of myeloid cells with immunosuppressive properties that sustain metastatic process. In this review, we discuss current understandings of how MDSCs shape and promote metastatic dissemination acting in each fundamental steps of cancer progression from primary tumor to metastatic disease.

Keywords:  MDSCs (myeloid-derived suppressor cells); immunosuppression; metastases; metastatic process; pre-metastatic niche

DOI:  https://doi.org/10.3389/fonc.2020.00165
EMBO Mol Med. 2020 Mar 02. e11177

Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer.

Lidia Moyano-Galceran, Elina A Pietilä, S Pauliina Turunen, Sara Corvigno, Elisabet Hjerpe, Daria Bulanova, Ulrika Joneborg, Twana Alkasalias, Yuichiro Miki, Masakazu Yashiro, Anastasiya Chernenko, Joonas Jukonen, Madhurendra Singh, Hanna Dahlstrand, Joseph W Carlson, Kaisa Lehti.

  Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non-genetic resistance mechanisms was long neglected. Using high-grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy-induced ERK1/2-RSK1/2-EphA2-GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2-S897 phosphorylation and EphA2-GPRC5A co-regulation, thereby facilitating a signaling shift to the canonical tumor-suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum-resistant EphA2high , GPRC5Ahigh cells to the therapy-induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo-resistant cells to RSK1/2-EphA2-pS897 pathway inhibition.

Keywords:   HGSC ; EphA2; GPRC5A; chemotherapy; resistance

DOI:  https://doi.org/10.15252/emmm.201911177
Acta Biomater. 2020 Feb 28. pii: S1742-7061(20)30127-6. [Epub ahead of print]

An in vitro hyaluronic acid hydrogel based platform to model dormancy in brain metastatic breast cancer cells.

Akshay A Narkhede, James H Crenshaw, David K Crossman, Lalita A Shevde, Shreyas S Rao.

  Breast cancer cells (BCCs) can remain dormant at the metastatic site, which when revoked leads to formation of metastasis several years after the treatment of primary tumor. Particularly, awakening of dormant BCCs in the brain results in breast cancer brain metastasis (BCBrM) which marks the most advanced stage of the disease with a median survival period of ∼4-16 months. However, our understanding of dormancy associated with BCBrM remains obscure, in part, due to the lack of relevant in vitro platforms to model dormancy associated with BCBrM. To address this need, we developed an in vitro hyaluronic acid (HA) hydrogel platform to model dormancy in brain metastatic BCCs via exploiting the bio-physical cues provided by HA hydrogels while bracketing the normal brain and metastatic brain malignancy relevant stiffness range. In this system, we observed that MDA-MB-231Br and BT474Br3 brain metastatic BCCs exhibited a dormant phenotype when cultured on soft (0.4 kPa) HA hydrogel compared to stiff (4.5 kPa) HA hydrogel as characterized by significantly lower EdU and Ki67 positivity. Further, we demonstrated the nuclear localization of p21 and p27 (markers associated with dormancy) in dormant MDA-MB-231Br cells contrary to their cytoplasmic localization in the proliferative population. We also demonstrated that the stiffness-based dormancy in MDA-MB-231Br cells was reversible and was, in part, mediated by focal adhesion kinases and the initial cell seeding density. Finally, RNA sequencing confirmed the dormant phenotype in MDA-MB-231Br cells. This platform could further our understanding of dormancy in BCBrM and could be adapted for anti-metastatic drug screening.

Keywords:  Cancer dormancy; breast cancer brain metastasis; hyaluronic acid (HA) hydrogel; in vitro model

DOI:  https://doi.org/10.1016/j.actbio.2020.02.039
Mol Cancer. 2020 Mar 04. 19(1): 52

Verification of EZH2 as a druggable target in metastatic uveal melanoma.

Bei Jin, Ping Zhang, Hailin Zou, Huijing Ye, Yun Wang, Jing Zhang, Huasheng Yang, Jingxuan Pan.

   BACKGROUND: Hepatic metastasis develops in ~ 50% of uveal melanoma (UM) patients with no effective treatments. Although GNAQ/GNA11 mutations are believed to confer pathogenesis of UM, the underlying mechanism of liver metastasis remains poorly understood. Given that profound epigenetic evolution may occur in the long journey of circulating tumor cells (CTCs) to distant organs, we hypothesized that EZH2 endowed tumor cells with enhanced malignant features (e.g., stemness and motility) during hepatic metastasis in UM. We aimed to test this hypothesis and explore whether EZH2 was a therapeutic target for hepatic metastatic UM patients.
METHODS: Expression of EZH2 in UM was detected by qRT-PCR, Western blotting and immunohistochemistry staining. Proliferation, apoptosis, cancer stem-like cells (CSCs) properties, migration and invasion were evaluated under circumstances of treatment with either EZH2 shRNA or EZH2 inhibitor GSK126. Antitumor activity and frequency of CSCs were determined by xenografted and PDX models with NOD/SCID mice. Hepatic metastasis was evaluated with NOG mice.
RESULTS: We found that EZH2 overexpressed in UM promoted the growth of UM; EZH2 increased the percentage and self-renewal of CSCs by miR-29c-DVL2-β-catenin signaling; EZH2 facilitates migration and invasion of UM cells via RhoGDIγ-Rac1 axis. Targeting EZH2 either by genetics or small molecule inhibitor GSK126 decreased CSCs and motility and abrogated the liver metastasis of UM.
CONCLUSIONS: These findings validate EZH2 as a druggable target in metastatic UM patients, and may shed light on the understanding and interfering the complicated metastatic process.

Keywords:  Cancer stem-like cells; EZH2; Hepatic metastasis; Motility; Uveal melanoma

DOI:  https://doi.org/10.1186/s12943-020-01173-x
Mol Cancer. 2020 Mar 02. 19(1): 47

Role of non-coding RNAs and RNA modifiers in cancer therapy resistance.

Xinyi Zhang, Kai Xie, Honghua Zhou, Yuwei Wu, Chan Li, Yating Liu, Zhaoya Liu, Qian Xu, Shuang Liu, Desheng Xiao, Yongguang Tao.

  As the standard treatments for cancer, chemotherapy and radiotherapy have been widely applied to clinical practice worldwide. However, the resistance to cancer therapies is a major challenge in clinics and scientific research, resulting in tumor recurrence and metastasis. The mechanisms of therapy resistance are complicated and result from multiple factors. Among them, non-coding RNAs (ncRNAs), along with their modifiers, have been investigated to play key roles in regulating tumor development and mediating therapy resistance within various cancers, such as hepatocellular carcinoma, breast cancer, lung cancer, gastric cancer, etc. In this review, we attempt to elucidate the mechanisms underlying ncRNA/modifier-modulated resistance to chemotherapy and radiotherapy, providing some therapeutic potential points for future cancer treatment.

Keywords:  Chemoresistance; RNA modifiers; Radioresistance; ncRNAs

DOI:  https://doi.org/10.1186/s12943-020-01171-z
Proc Natl Acad Sci U S A. 2020 Mar 03. pii: 201918167. [Epub ahead of print]

The functional activity of E-cadherin controls tumor cell metastasis at multiple steps.

Tae-Young Na, Leslayann Schecterson, Alisha M Mendonsa, Barry M Gumbiner.

  E-cadherin is a tumor suppressor protein, and the loss of its expression in association with the epithelial mesenchymal transition (EMT) occurs frequently during tumor metastasis. However, many metastases continue to express E-cadherin, and a full EMT is not always necessary for metastasis; also, positive roles for E-cadherin expression in metastasis have been reported. We hypothesize instead that changes in the functional activity of E-cadherin expressed on tumor cells in response to environmental factors is an important determinant of the ability of the tumor cells to metastasize. We find that E-cadherin expression persists in metastatic lung nodules and circulating tumor cells (CTCs) in two mouse models of mammary cancer: genetically modified MMTV-PyMT mice and orthotopically grafted 4T1 tumor cells. Importantly, monoclonal antibodies that bind to and activate E-cadherin at the cell surface reduce lung metastasis from endogenous genetically driven tumors and from tumor cell grafts. E-cadherin activation inhibits metastasis at multiple stages, including the accumulation of CTCs from the primary tumor and the extravasation of tumor cells from the vasculature. These activating mAbs increase cell adhesion and reduce cell invasion and migration in both cell culture and three-dimensional spheroids grown from primary tumors. Moreover, activating mAbs increased the frequency of apoptotic cells without affecting proliferation. Although the growth of the primary tumors was unaffected by activating mAbs, CTCs and tumor cells in metastatic nodules exhibited increased apoptosis. Thus, the functional state of E-cadherin is an important determinant of metastatic potential beyond whether the gene is expressed.

Keywords:  E-cadherin; E-cadherin-positive tumors; MMTV-PyMT breast cancer model; breast cancer metastasis; circulating tumor cells

DOI:  https://doi.org/10.1073/pnas.1918167117
EMBO Rep. 2020 Mar 05. e48183

SIRT2-dependent IDH1 deacetylation inhibits colorectal cancer and liver metastases.

Bo Wang, Yingjiang Ye, Xin Yang, Boya Liu, Zhe Wang, Shuaiyi Chen, Kewei Jiang, Wei Zhang, Hongpeng Jiang, Harri Mustonen, Pauli Puolakkainen, Shan Wang, Jianyuan Luo, Zhanlong Shen.

  Protein lysine acetylation affects colorectal cancer (CRC) distant metastasis through multiple pathways. In a previous proteomics screen, we found that isocitrate dehydrogenase 1 (IDH1) is hyperacetylated in CRC primary tumors and liver metastases. Here, we further investigate the function of IDH1 hyperacetylation at lysine 224 in CRC progression. We find that IDH1 K224 deacetylation promotes its enzymatic activity and the production of α-KG, and we identify sirtuin-2 (SIRT2) as a major deacetylase for IDH1. SIRT2 overexpression significantly inhibits CRC cell proliferation, migration, and invasion. IDH1 acetylation is modulated in response to intracellular metabolite concentration and regulates cellular redox hemostasis. Moreover, IDH1 acetylation reversely regulates HIF1α-dependent SRC transcription which in turn controls CRC progression. Physiologically, our data indicate that IDH1 deacetylation represses CRC cell invasion and migration in vitro and in vivo, while the hyperacetylation of IDH1 on K224 is significantly correlated to distant metastasis and poor survival of colorectal cancer patients. In summary, our study uncovers a novel mechanism through which SIRT2-dependent IDH1 deacetylation regulates cellular metabolism and inhibits liver metastasis of colorectal cancer.

Keywords:  IDH1; SIRT2; acetylation; colorectal cancer; metastasis

DOI:  https://doi.org/10.15252/embr.201948183
Bioessays. 2020 Mar 04. e1900162

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy.

Barry J Thompson.

  The transcriptional co-activators YAP (or YAP1) and TAZ (or WWTR1) are frequently activated during the growth and progression of many solid tumors, including lung, colorectal, breast, pancreatic, and liver carcinomas as well as melanoma and glioma. YAP/TAZ bind to TEAD-family co-activators to drive cancer cell survival, proliferation, invasive migration, and metastasis. YAP/TAZ activation may also confer resistance to chemotherapy, radiotherapy, or immunotherapy. YAP-TEAD cooperates with the RAS-induced AP-1 (FOS/JUN) transcription factor to drive tumor growth and cooperates with MRTF-SRF to promote activation of cancer-associated fibroblasts, matrix stiffening, and metastasis. The key upstream repressor of YAP/TAZ activation is the Hippo (MST1/2-LATS1/2) pathway and the key upstream activators are mechanically induced Integrin-SRC and E-cadherin-AJUBA/TRIP6/LIMD1, growth factor induced PI3K-AKT, and inflammation-induced G-protein coupled receptor (GPCR) signals, all of which antagonize the Hippo pathway. In this review, strategies to target YAP/TAZ activity in cancer are discussed along with the prospects for synergy with established pillars of cancer therapy.

Keywords:  Hippo pathway; YAP/TAZ; cancer; tissue growth

DOI:  https://doi.org/10.1002/bies.201900162
Clin Cancer Res. 2020 Mar 02. pii: clincanres.3321.2019. [Epub ahead of print]

MAPK pathway alterations correlate with poor survival and drive resistance to therapy in patients with lung cancers driven by ROS1 fusions.

Hiroki Sato, Adam J Schoenfeld, Evan Siau, Yue Christine Lu, Huichun Tai, Ken Suzawa, Daisuke Kubota, Allan Jw Lui, Besnik Qeriqi, Marissa Mattar, Michael Offin, Masakiyo Sakaguchi, Shinichi Toyooka, Alexander Drilon, Neal Rosen, Mark G Kris, David B Solit, Elisa de Stanchina, Monika Ashok Davare, Gregory J Riely, Marc Ladanyi, Romel Somwar.

PURPOSE: ROS1 tyrosine kinase inhibitors (TKIs) provide significant benefit in lung adenocarcinoma (LUAD) patients with ROS1 fusions. However, as observed with all targeted therapies, resistance arises. Detecting mechanisms of acquired resistance (AR) is crucial to finding novel therapies and improve patient outcomes.
EXPERIMENTAL DESIGN: ROS1 fusions were expressed in in HBEC and NIH-3T3 cells either by cDNA overexpression (CD74/ROS1, SLC34A2/ROS1) or CRISPR-Cas9-mediated genomic engineering (EZR/ROS1). We reviewed targeted large-panel sequencing data (using the MSK-IMPACT assay) patients treated with ROS1 TKIs, and genetic alterations hypothesized to confer AR were modeled in these cell lines.
RESULTS: Eight of the 75 patients with a ROS1 fusion had a concurrent MAPK pathway alteration and this correlated with shorter overall survival. In addition, the induction of ROS1 fusions stimulated activation of MEK/ERK signaling in comparison with AKT signaling, suggesting the importance of the MAPK pathway in driving ROS1 fusion-positive cancers. Of 8 patients, 2 patients harbored novel in-frame deletions in MEK1 (MEK1delE41_L54) and MEKK1 (MEKK1delH907_C916) that were acquired after ROS1-TKIs, and 2 patients harbored NF1 loss-of-function mutations. Expression of MEK1del or MEKK1del, and knockdown of NF1 in ROS1 fusion-positive cells activated MEK/ERK signaling and conferred resistance to ROS1-TKIs. Combined targeting of ROS1 and MEK inhibited growth of cells expressing both ROS1 fusion and MEK1del.
CONCLUSIONS: We demonstrate that the activation of MAPK pathway is mechanisms of innate or acquired resistance and that patients harboring ROS1 fusion and concurrent MAPK alterations have worse survival. Our findings suggest a treatment strategy to target both aberrations.

DOI: https://doi.org/10.1158/1078-0432.CCR-19-3321
Cancer Lett. 2020 Feb 26. pii: S0304-3835(20)30065-3. [Epub ahead of print]

Hepatocellular carcinoma-derived exosomes in organotropic metastasis, recurrence and early diagnosis application.

Yang Ge, Wei Mu, Qian Ba, Jingquan Li, Yiguo Jiang, Qiang Xia, Hui Wang.

  Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, despite improvements in the clinical trial and diagnosis, HCC still remains high mortality due to the 70% recurrence and lung metastasis after surgical resection. Exosomes are small membrane vesicles, which are shuttled from donor cells to recipient cells, contributing to the recruitment and reprogramming of constituents via an autocrine or paracrine fashion. HCC derived exosomes could redirect metastasis of tumor cells which lack the capacity to metastasize to a specific organ via generating pre-metastatic niche. These findings emphasize a practical and potentially feasible role of exosomes in the treatment of patients with HCC, both as a target and a vehicle for drug design. We herein summarize recent findings that implicate oncogenes and non-canonical signaling of HCC exosomes, as well as the impact of exosomal bioactive molecules in high recurrence induced by organ-specific metastasis. The aim of review is to illustrate the underlying mechanism of exosomes in tumor metastasis, immune evasion, and the potential application of prognostic biomarker in HCC process.

Keywords:  HCC derived exosomes; diagnosis biomarker; exosomal oncogene; immunosuppressive; organotropic metastasis

DOI:  https://doi.org/10.1016/j.canlet.2020.02.003
EMBO Rep. 2020 Mar 04. e49269

WDR63 inhibits Arp2/3-dependent actin polymerization and mediates the function of p53 in suppressing metastasis.

Kailiang Zhao, Decai Wang, Xiaolong Zhao, Chenfeng Wang, Yongxiang Gao, Kaiyue Liu, Fang Wang, Xianning Wu, Xuejuan Wang, Linfeng Sun, Jianye Zang, Yide Mei.

  Accumulating evidence suggests that p53 plays a suppressive role in cancer metastasis, yet the underlying mechanism remains largely unclear. Regulation of actin dynamics is essential for the control of cell migration, which is an important step in metastasis. The Arp2/3 complex is a major nucleation factor to initiate branched actin polymerization that drives cell migration. However, it is unknown whether p53 could suppress metastasis through modulating Arp2/3 function. Here, we report that WDR63 is transcriptionally upregulated by p53. We show with migration assays and mouse xenograft models that WDR63 negatively regulates cell migration, invasion, and metastasis downstream of p53. Mechanistically, WDR63 interacts with the Arp2/3 complex and inhibits Arp2/3-mediated actin polymerization. Furthermore, WDR63 overexpression is sufficient to dampen the increase in cell migration, invasion, and metastasis induced by p53 depletion. Together, these findings suggest that WDR63 is an important player in the regulation of Arp2/3 function and also implicate WDR63 as a critical mediator of p53 in suppressing metastasis.

Keywords:  Arp2/3; WDR63; metastasis; p53

DOI:  https://doi.org/10.15252/embr.201949269
Ann Oncol. 2018 Oct;pii: S0923-7534(19)48444-5. [Epub ahead of print]29 Suppl 8 viii5

HER2-positive breast cancer resistance to trastuzumab is associated with metabolic switch.

R Dubianski, E Sarnowska, M Leszczynski, S Kubala, W Olszewski, N Rusetska, A I Jagiello-Gruszfeld, R Konopinski, T J Sarnowski, J A Siedlecki, Z I Nowecki.

DOI: https://doi.org/10.1093/annonc/mdy268.016
Exp Cell Res. 2020 Feb 26. pii: S0014-4827(20)30130-0. [Epub ahead of print] 111925

Research progress on the effect of autophagy-lysosomal pathway on tumor drug resistance.

Jiaxin Li, Gui Liu, Long Li, Zhigang Yao, Junhui Huang.

  Autophagy is an intracellular degradation pathway that is highly conserved during the evolution of eukaryotes and is based on lysosome. Under nutritional deficiencies or stress, cells can clear damaged and necrotic organelles and proteins through autophagy to maintain the homeostasis of cells and organisms. Studies have found that abnormal autophagy is closely related to the occurrence and development of neurodegenerative diseases and tumors. In order to further understand the relationship between lysosomes and autophagy, tumorigenesis and drug resistance, the role of autophagy-lysosomal pathway in tumor resistance and related mechanisms and the relationship between drug resistance and hypoxia-induced autophagy are discussed in this paper.

Keywords:  Autophagy; Drug resistance; Hypoxia; Lysosome; Tumor

DOI:  https://doi.org/10.1016/j.yexcr.2020.111925
Mol Cancer. 2020 Mar 02. 19(1): 50

Metabolism of pancreatic cancer: paving the way to better anticancer strategies.

Cheng Qin, Gang Yang, Jinshou Yang, Bo Ren, Huanyu Wang, Guangyu Chen, Fangyu Zhao, Lei You, Weibin Wang, Yupei Zhao.

  Pancreatic cancer is currently one of the most lethal diseases. In recent years, increasing evidence has shown that reprogrammed metabolism may play a critical role in the carcinogenesis, progression, treatment and prognosis of pancreatic cancer. Affected by internal or external factors, pancreatic cancer cells adopt extensively distinct metabolic processes to meet their demand for growth. Rewired glucose, amino acid and lipid metabolism and metabolic crosstalk within the tumor microenvironment contribute to unlimited pancreatic tumor progression. In addition, the metabolic reprogramming involved in pancreatic cancer resistance is also closely related to chemotherapy, radiotherapy and immunotherapy, and results in a poor prognosis. Reflective of the key role of metabolism, the number of preclinical and clinical trials about metabolism-targeted therapies for pancreatic cancer is increasing. The poor prognosis of pancreatic cancer patients might be largely improved after employing therapies that regulate metabolism. Thus, investigations of metabolism not only benefit the understanding of carcinogenesis and cancer progression but also provide new insights for treatments against pancreatic cancer.

Keywords:  Chemoresistance; Clinical trials; Gemcitabine; Immunosuppression; Metabolism; Pancreatic cancer; Radioresistance

DOI:  https://doi.org/10.1186/s12943-020-01169-7
Ann Oncol. 2018 Oct;pii: S0923-7534(19)48468-8. [Epub ahead of print]29 Suppl 8 viii11-viii12

First step to metastasis: MiRNAome abnormalities impair cell-cell adhesion and facilitate detachment of breast cancer cells.

V Halytskiy.

DOI: https://doi.org/10.1093/annonc/mdy268.040
Proc Natl Acad Sci U S A. 2020 Mar 02. pii: 201921381. [Epub ahead of print]

Cyp2c44 regulates prostaglandin synthesis, lymphangiogenesis, and metastasis in a mouse model of breast cancer.

Rushendhiran Kesavan, Timo Frömel, Sven Zukunft, Hebatullah Laban, Alexandra Geyer, Zumer Naeem, Juliana Heidler, Ilka Wittig, Eiman Elwakeel, Bernhard Brüne, Andreas Weigert, Rüdiger Popp, Ingrid Fleming.

  Arachidonic acid epoxides generated by cytochrome P450 (CYP) enzymes have been linked to increased tumor growth and metastasis, largely on the basis of overexpression studies and the application of exogenous epoxides. Here we studied tumor growth and metastasis in Cyp2c44-/- mice crossed onto the polyoma middle T oncogene (PyMT) background. The resulting PyMT2c44 mice developed more primary tumors earlier than PyMT mice, with increased lymph and lung metastasis. Primary tumors from Cyp2c44-deficient mice contained higher numbers of tumor-associated macrophages, as well as more lymphatic endothelial cells than tumors from PyMT mice. While epoxide and diol levels were comparable in tumors from both genotypes, prostaglandin (PG) levels were higher in the PyMTΔ2c44 tumors. This could be accounted for by the finding that Cyp2c44 metabolized the PG precursor, PGH2 to 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT), thus effectively reducing levels of effector PGs (including PGE2). Next, proteomic analyses revealed an up-regulation of WD repeating domain FYVE1 (WDFY1) in tumors from PyMTΔ2c44 mice, a phenomenon that was reproduced in Cyp2c44-deficient macrophages as well as by PGE2 Mechanistically, WDFY1 was involved in Toll-like receptor signaling, and its down-regulation in human monocytes attenuated the LPS-induced phosphorylation of IFN regulatory factor 3 and nuclear factor-κB. Taken together, our results indicate that Cyp2c44 protects against tumor growth and metastasis by preventing the synthesis of PGE2 The latter eicosanoid influenced macrophages at least in part by enhancing Toll-like receptor signaling via the up-regulation of WDFY1.

Keywords:  WDFY1; cytochrome P450; lymphangiogenesis; metastasis

DOI:  https://doi.org/10.1073/pnas.1921381117
Cancer Res. 2020 Mar 02.

NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors.

Kirsty Ford, Christopher J Hanley, Massimiliano Mellone, Cedric Szyndralewiez, Freddy Heitz, Philippe Wiesel, Oliver Wood, Maria Machado, Maria-Antoinette Lopez, Anusha-Preethi Ganesan, Chuan Wang, Ankur Chakravarthy, Tim R Fenton, Emma V King, Pandurangan Vijayanand, Christian H Ottensmeier, Aymen Al-Shamkhani, Natalia Savelyeva, Gareth J Thomas.

Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 "normalized" CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers. SIGNIFICANCE: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8+ T-cell exclusion. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/00/0/000/F1.large.jpg.

DOI: https://doi.org/10.1158/0008-5472.CAN-19-3158
Cancer Immunol Res. 2020 Mar 03. pii: canimm.0282.2019. [Epub ahead of print]

Interferon-induced IDO1 mediates radiation resistance and is a therapeutic target in colorectal cancer.

Baosheng Chen, David M Alvarado, Micah Iticovici, Nathan S Kau, Haeseong Park, Parag J Parikh, Dinesh Thotala, Matthew A Ciorba.

Colorectal cancer (CRC) is a major cause of mortality worldwide. Chemotherapy and radiation remain standard treatment for locally advanced disease, with current immune-targeting therapies applying to only a small subset of patients. Expression of the immuno-oncology target indoleamine 2,3 dioxygenase 1 (IDO1) is associated with poor CRC clinical outcomes but is understudied as a potential treatment target. In this study, we examined the interaction between the IDO1 pathway and radiation therapy in CRC. We used human and mouse CRC cell lines, organoids, mouse syngeneic CRC tumor graft models, and CRC tissues from patients who received radiation therapy. IDO1 activity was blocked using the clinical IDO1 inhibitor epacadostat and by genetic disruption. We found that radiation-induced IDO1 overexpression in CRC through Type I and II interferon signaling. IDO1 enzymatic activity directly influenced CRC radiation sensitivity. IDO1 inhibition sensitized CRC to radiation-induced cell death, whereas the IDO1 metabolite kynurenine promoted radioprotection. IDO1 inhibition also potentiated Th1 cytokines and myeloid cell-modulating factors in the tumor microenvironment and promoted an abscopal effect on tumors outside the radiation field. Conversely, IDO1 blockade protected the normal small intestinal epithelium from radiation toxicity and accelerated recovery from radiation-induced weight loss, indicating a role in limiting side-effects. These data demonstrated that IDO1 inhibition potentiates radiation therapy effectiveness in colorectal cancer. The findings also provide rationale and mechanistic insight for the study of IDO1 inhibitors as adjuvant therapy to radiation in patients with locally advanced sporadic and colitis-associated colorectal cancer.

DOI: https://doi.org/10.1158/2326-6066.CIR-19-0282
Nat Commun. 2020 Mar 06. 11(1): 1234

Interplay between DNA damage repair and apoptosis shapes cancer evolution through aneuploidy and microsatellite instability.

Noam Auslander, Yuri I Wolf, Eugene V Koonin.

Driver mutations and chromosomal aneuploidy are major determinants of tumorigenesis that exhibit complex relationships. Here, we identify associations between driver mutations and chromosomal aberrations that define two tumor clusters, with distinct regimes of tumor evolution underpinned by unique sets of mutations in different components of DNA damage response. Gastrointestinal and endometrial tumors comprise a separate cluster for which chromosomal-arm aneuploidy and driver mutations are mutually exclusive. The landscape of driver mutations in these tumors is dominated by mutations in DNA repair genes that are further linked to microsatellite instability. The rest of the cancer types show a positive association between driver mutations and aneuploidy, and a characteristic set of mutations that involves primarily genes for components of the apoptotic machinery. The distinct sets of mutated genes derived here show substantial prognostic power and suggest specific vulnerabilities of different cancers that might have therapeutic potential.

DOI: https://doi.org/10.1038/s41467-020-15094-2