bims-tucedo 2022-06-12 papers

bims-tucedo

Biomed News

on Tumor cell dormancy

Issue of 2022–06–12
23 papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology

Aged Lungs Enable Metastatic Outgrowth of Dormant Melanoma Cells.
Cyclocreatine suppresses creatine metabolism and impairs prostate cancer progression.
PRMT7: a survive-or-die switch in cancer stem cells.
IN VIVO SYNGENEIC TUMOR MODELS WITH ACQUIRED RESISTANCE TO ANTI-PD-1/PD-L1 THERAPIES.
RB loss determines selective resistance and novel vulnerabilities in ER-positive breast cancer models.
Engineered KRAS G12D-Reactive T Cells Show Promise in Pancreatic Cancer.
Exosomal EPHA2 derived from highly metastatic breast cancer cells promotes angiogenesis by activating the AMPK signaling pathway through Ephrin A1-EPHA2 forward signaling.
RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition.
Delivery of an ectonucleotidase inhibitor with ROS-responsive nanoparticles overcomes adenosine-mediated cancer immunosuppression.
Activation of tumor-cell STING primes NK-cell therapy.
Downregulation of HINFP induces senescence-associated secretory phenotype to promote metastasis in a non-cell-autonomous manner in bladder cancer.
Nodal interferon exposure drives tumour-specific tolerance.
The drug-induced phenotypic landscape of colorectal cancer organoids.
The role of Jagged1 as a dynamic switch of cancer cell plasticity in PDAC assembloids.
Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells.
Dysadherin awakens mechanical forces and promotes colorectal cancer progression.
Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.
Drug-induced self-assembled nanovesicles for doxorubicin resistance reversal via autophagy inhibition and delivery synchronism.
CircVAPA promotes small cell lung cancer progression by modulating the miR-377-3p and miR-494-3p/IGF1R/AKT axis.
Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer.
Targeting type Iγ phosphatidylinositol phosphate kinase overcomes oxaliplatin resistance in colorectal cancer.
Mutation and tissue lineage lead to organ-specific cancer.
Resolving mutational signatures in cancer development.

Cancer Discov. 2022 Jun 10. OF1

Aged Lungs Enable Metastatic Outgrowth of Dormant Melanoma Cells.

Aged lung fibroblasts promote reactivation of dormant melanoma cells by secreting a WNT antagonist.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-108
Cancer Res. 2022 Jun 08. pii: canres.1301.2021-5-4 10:59:25.103. [Epub ahead of print]

Cyclocreatine suppresses creatine metabolism and impairs prostate cancer progression.

Rachana Patel, Catriona A Ford, Lisa Rodgers, Linda K Rushworth, Janis Fleming, Ernest Mui, Tong Zhang, David Watson, Victoria Lynch, Gillian Mackay, David Sumpton, Owen J Sansom, Johan Vande Voorde, Hing Y Leung.

Prostate cancer is the second most common cause of cancer mortality in men worldwide. Applying a novel genetically engineered mouse model (GEMM) of aggressive prostate cancer driven by deficiency of the tumour suppressors PTEN and SPRY2 (Sprouty 2), we identified enhanced creatine metabolism as a central component of progressive disease. Creatine treatment was associated with enhanced cellular basal respiration in vitro and increased tumour cell proliferation in vivo. Stable isotope tracing revealed that intracellular levels of creatine in prostate cancer cells are predominantly dictated by exogenous availability rather than by de novo synthesis from arginine. Genetic silencing of creatine transporter SLC6A8 depleted intracellular creatine levels and reduced the colony-forming capacity of human prostate cancer cells. Accordingly, in vitro treatment of prostate cancer cells with cyclocreatine, a creatine analog, dramatically reduced intracellular levels of creatine and its derivatives phosphocreatine and creatinine and suppressed proliferation. Supplementation with cyclocreatine impaired cancer progression in the PTEN and SPRY-deficient prostate cancer GEMMs and in a xenograft liver metastasis model. Collectively, these results identify a metabolic vulnerability in prostate cancer and demonstrate a rational therapeutic strategy to exploit this vulnerability to impede tumour progression.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-1301
Mol Cancer. 2022 Jun 10. 21(1): 127

PRMT7: a survive-or-die switch in cancer stem cells.

Christophe Nicot.

DOI: https://doi.org/10.1186/s12943-022-01602-z
Cancer Immunol Res. 2022 Jun 09. pii: canimm.0802.2021-9-22 03:49:01.593. [Epub ahead of print]

IN VIVO SYNGENEIC TUMOR MODELS WITH ACQUIRED RESISTANCE TO ANTI-PD-1/PD-L1 THERAPIES.

Morgane Denis, Chloé Grasselly, Pierre-Antoine Choffour, Anne Wierinckx, Doriane Mathe, Kamel Chettab, Anne Tourette, Nolan Talhi, Aurore Bourguignon, Fabian Birzele, Elsa Kress, Lars Petter Jordheim, Christian Klein, Eva Laure Matera, Charles Dumontet.

Antibodies targeting PD-1 and PD-L1 have produced durable responses in a subset of cancer patients. However, a majority of these patients will ultimately relapse due to acquired resistance. To explore the underlying mechanisms of this secondary resistance, we developed five syngeneic murine tumor variants with acquired resistance to anti-PD-1 and/or PD-L1 antibodies in vivo. Resistant in vivo models were obtained by serial treatment/reimplantation cycles of the MC38 colorectal, MB49 and MBT2 bladder, TyrNras melanoma and RENCA kidney models. Tumor immune infiltrates were characterized for wild type and resistant tumors using spectral cytometry and their molecular alterations analyzed using RNA-seq analyses. Alterations in the tumor immune microenvironment were strongly heterogeneous amongst resistant models, involving select lymphoid and/or myeloid subpopulations. Molecular alterations in resistant models included previously identified pathways as well as novel candidate genes found to be deregulated in several resistant models. Among these, Serpinf1, coding for Pigment Epithelial Derived Factor was further explored in the MC38 and the MBT2 models. Overexpression of Serpinf1 induced resistance to anti-PD-1 antibodies in the MC38 model, whereas knock-down of Serpinf1 sensitized this model as well as the primarily resistant MBT2 model. Serpinf1 overexpression was associated with increased production of free fatty acids and reduced activation of CD8+ cells, while orlistat, a compound that reduces the production of free fatty acids, reversed resistance to anti-PD-1 therapy. Our results suggest that a panel of syngeneic resistant models constitutes a useful tool to model the heterogeneity of resistance mechanisms encountered in the clinic.

DOI: https://doi.org/10.1158/2326-6066.CIR-21-0802
Oncogene. 2022 Jun 09.

RB loss determines selective resistance and novel vulnerabilities in ER-positive breast cancer models.

Vishnu Kumarasamy, Ram Nambiar, Jianxin Wang, Hanna Rosenheck, Agnieszka K Witkiewicz, Erik S Knudsen.

The management of metastatic estrogen receptor (ER) positive HER2 negative breast cancer (ER+) has improved; however, therapeutic resistance and disease progression emerges in majority of cases. Using unbiased approaches, as expected PI3K and MTOR inhibitors emerge as potent inhibitors to delay proliferation of ER+ models harboring PIK3CA mutations. However, the cytostatic efficacy of these drugs is hindered due to marginal impact on the expression of cyclin D1. Different combination approaches involving the inhibition of ER pathway or cell cycle result in durable growth arrest via RB activation and subsequent inhibition of CDK2 activity. However, cell cycle alterations due to RB loss or ectopic CDK4/cyclin D1 activation yields resistance to these cytostatic combination treatments. To define means to counter resistance to targeted therapies imparted with RB loss; complementary drug screens were performed with RB-deleted isogenic cell lines. In this setting, RB loss renders ER+ breast cancer models more vulnerable to drugs that target DNA replication and mitosis. Pairwise combinations using these classes of drugs defines greater selectivity for RB deficiency. The combination of AURK and WEE1 inhibitors, yields synergistic cell death selectively in RB-deleted ER+ breast cancer cells via apoptosis and yields profound disease control in vivo. Through unbiased efforts the XIAP/CIAP inhibitor birinapant was identified as a novel RB-selective agent. Birinapant further enhances the cytotoxic effect of chemotherapies and targeted therapies used in the treatment of ER+ breast cancer models selectively in the RB-deficient setting. Using organoid culture and xenograft models, we demonstrate the highly selective use of birinapant based combinations for the treatment of RB-deficient tumors. Together, these data illustrate the critical role of RB-pathway in response to many agents used to treat ER+ breast cancer, whilst informing new therapeutic approaches that could be deployed against resistant disease.

DOI: https://doi.org/10.1038/s41388-022-02362-2
Cancer Discov. 2022 Jun 10. OF1

Engineered KRAS G12D-Reactive T Cells Show Promise in Pancreatic Cancer.

T cells with engineered KRAS G12D-specific TCRs mediated regression of metastases in a patient with pancreatic cancer.

DOI: https://doi.org/10.1158/2159-8290.CD-RW2022-103
Theranostics. 2022 ;12(9): 4127-4146

Exosomal EPHA2 derived from highly metastatic breast cancer cells promotes angiogenesis by activating the AMPK signaling pathway through Ephrin A1-EPHA2 forward signaling.

Baoai Han, He Zhang, Ruinan Tian, Hui Liu, Zhaosong Wang, Zhiyong Wang, Jianfei Tian, Yanfen Cui, Sixin Ren, Xiaoyan Zuo, Ran Tian, Ruifang Niu, Fei Zhang.

  Rationale: Angiogenesis is a fundamental process of tumorigenesis, growth, invasion and metastatic spread. Extracellular vesicles, especially exosomes, released by primary tumors promote angiogenesis and cancer progression. However, the mechanism underlying the pro-angiogenic potency of cancer cell-derived exosomes remains poorly understood. Methods: Exosomes were isolated from breast cancer cells with high metastatic potential (HM) and low metastatic potential (LM). The pro-angiogenic effects of these exosomes were evaluated by in vitro tube formation assays, wound healing assays, rat arterial ring budding assays and in vivo Matrigel plug assays. Subsequently, RNA sequencing, shRNA-mediated gene knockdown, overexpression of different EPHA2 mutants, and small-molecule inhibitors were used to analyze the angiogenesis-promoting effect of exosomal EPHA2 and its potential downstream mechanism. Finally, xenograft tumor models were established using tumor cells expressing different levels of EPHA2 to mimic the secretion of exosomes by tumor cells in vivo, and the metastasis of cancer cells were monitored using the IVIS Spectrum imaging system and Computed Tomography. Results: Herein, we demonstrated that exosomes produced by HM breast cancer cells can promote angiogenesis and metastasis. EPHA2 was rich in HM-derived exosomes and conferred the pro-angiogenic effect. Exosomal EPHA2 can be transferred from HM breast cancer cells to endothelial cells. Moreover, it can stimulate the migration and tube-forming abilities of endothelial cells in vitro and promote angiogenesis and tumor metastasis in vivo. Mechanistically, exosomal EPHA2 activates the AMPK signaling via the ligand Ephrin A1-dependent canonical forward signaling pathway. Moreover, inhibition of the AMPK signaling impairs exosomal EPHA2-mediated pro-angiogenic effects. Conclusion: Our findings identify a novel mechanism of exosomal EPHA2-mediated intercellular communication from breast cancer cells to endothelial cells in the tumor microenvironment to provoke angiogenesis and metastasis. Targeting the exosomal EPHA2-AMPK signaling may serve as a potential strategy for breast cancer therapy.

Keywords:  EPHA2; angiogenesis; breast cancer; exosomes; high metastatic potential cells

DOI:  https://doi.org/10.7150/thno.72404
Nat Commun. 2022 Jun 08. 13(1): 3181

RNF43 G659fs is an oncogenic colorectal cancer mutation and sensitizes tumor cells to PI3K/mTOR inhibition.

Lishan Fang, Dane Ford-Roshon, Max Russo, Casey O'Brien, Xiaozhe Xiong, Carino Gurjao, Maximilien Grandclaudon, Srivatsan Raghavan, Steven M Corsello, Steven A Carr, Namrata D Udeshi, James Berstler, Ewa Sicinska, Kimmie Ng, Marios Giannakis.

The RNF43_p.G659fs mutation occurs frequently in colorectal cancer, but its function remains poorly understood and there are no specific therapies directed against this alteration. In this study, we find that RNF43_p.G659fs promotes cell growth independent of Wnt signaling. We perform a drug repurposing library screen and discover that cells with RNF43_p.G659 mutations are selectively killed by inhibition of PI3K signaling. PI3K/mTOR inhibitors yield promising antitumor activity in RNF43659mut isogenic cell lines and xenograft models, as well as in patient-derived organoids harboring RNF43_p.G659fs mutations. We find that RNF43659mut binds p85 leading to increased PI3K signaling through p85 ubiquitination and degradation. Additionally, RNA-sequencing of RNF43659mut isogenic cells reveals decreased interferon response gene expression, that is reversed by PI3K/mTOR inhibition, suggesting that RNF43659mut may alter tumor immunity. Our findings suggest a therapeutic application for PI3K/mTOR inhibitors in treating RNF43_p.G659fs mutant cancers.

DOI: https://doi.org/10.1038/s41467-022-30794-7
Sci Transl Med. 2022 Jun 08. 14(648): eabh1261

Delivery of an ectonucleotidase inhibitor with ROS-responsive nanoparticles overcomes adenosine-mediated cancer immunosuppression.

Chengqiong Mao, Stacy Yeh, Juan Fu, Mercedes Porosnicu, Alexandra Thomas, Gregory L Kucera, Konstantinos I Votanopoulos, Shaomin Tian, Xin Ming.

Tumor evasion of immune destruction is associated with the production of immunosuppressive adenosine in the tumor microenvironment (TME). Anticancer therapies can trigger adenosine triphosphate (ATP) release from tumor cells, causing rapid formation of adenosine by the ectonucleotidases CD39 and CD73, thereafter exacerbating immunosuppression in the TME. The goal of this study was to develop an approach to facilitate cancer therapy-induced immunogenic cell death including ATP release and to limit ATP degradation into adenosine, in order to achieve durable antitumor immune response. Our approach was to construct reactive oxygen species (ROS)-producing nanoparticles that carry an ectonucleotidase inhibitor ARL67156 by electronic interaction and phenylboronic ester. Upon near-infrared irradiation, nanoparticle-produced ROS induced ATP release from MOC1 cancer cells in vitro and triggered the cleavage of phenylboronic ester, facilitating the release of ARL67156 from the nanoparticles. ARL67156 prevented conversion of ATP to adenosine and enhanced anticancer immunity in an MOC1-based coculture model. We tested this approach in mouse tumor models. Nanoparticle-based ROS-responsive drug delivery reprogramed the immunogenic landscape in tumors, eliciting tumor-specific T cell responses and tumor regression, conferring long-term survival in mouse models. We demonstrated that TME reprograming sets the stage for response to anti-programmed cell death protein 1 (PD1) immunotherapy, and the combination resulted in tumor regression in a 4T1 breast cancer mouse model that was resistant to PD1 blockade. Furthermore, our approach also induced immunological effects in patient-derived organotypic tumor spheroid model, suggesting potential translation of our nanoparticle approach for treating human cancers.

DOI: https://doi.org/10.1126/scitranslmed.abh1261
Cancer Immunol Res. 2022 Jun 09. pii: canimm.CIR-22-0017-A.2022-1-7 14:36:45.603. [Epub ahead of print]

Activation of tumor-cell STING primes NK-cell therapy.

Erik H Knelson, Elena V Ivanova, Mubin Tarannum, Marco Campisi, Patrick H Lizotte, Matthew A Booker, Ismail Ozgenc, Moataz Noureddine, Brittany Meisenheimer, Minyue Chen, Brandon Piel, Nathaniel Spicer, Bonje Obua, Cameron M Messier, Erin Shannon, Navin R Mahadevan, Tetsuo Tani, Pieter J Schol, Anna M Lee-Hassett, Ari Zlota, Ha V Vo, Minh Ha, Arrien A Bertram, Saemi Han, Tran C Thai, Corinne E Gustafson, Kartika Venugopal, Timmothy J Haggerty, Thomas P Albertson, Antja-Voy Hartley, Pınar Ozden Eser, Ze-Hua Li, Israel Canadas, Marina Vivero, Assunta De Rienzo, William G Richards, Adnan O Abu-Yousif, Vicky A Appleman, Richard C Gregory, Alexander Parent, Neil Lineberry, Eric L Smith, Pasi A Janne, Juan J Miret, Michael Y Tolstorukov, Rizwan Romee, Cloud P Paweletz, Raphael Bueno, David A Barbie.

Activation of the stimulator of interferon genes (STING) pathway promotes antitumor immunity but STING agonists have yet to achieve clinical success. Increased understanding of the mechanism of action of STING agonists in human tumors is key to developing therapeutic combinations that activate effective innate antitumor immunity. Here, we report that malignant pleural mesothelioma cells robustly express STING and are responsive to STING agonist treatment ex vivo. Using dynamic single-cell RNA sequencing of explants treated with a STING agonist we observed CXCR3 chemokine activation primarily in tumor cells and cancer-associated fibroblasts, as well as T-cell cytotoxicity. In contrast, primary NK cells resisted STING agonist-induced cytotoxicity. STING agonists enhanced migration and killing of NK cells and mesothelin-targeted chimeric antigen receptor (CAR)-NK cells, improving therapeutic activity in patient-derived organotypic tumor spheroids. These studies reveal the fundamental importance of using human tumor samples to assess innate and cellular immune therapies. By functionally profiling mesothelioma tumor explants with elevated STING expression in tumor cells, we uncovered distinct consequences of STING agonist treatment in humans that support testing combining STING agonists with NK and CAR-NK cell therapies.

DOI: https://doi.org/10.1158/2326-6066.CIR-22-0017
Oncogene. 2022 Jun 06.

Downregulation of HINFP induces senescence-associated secretory phenotype to promote metastasis in a non-cell-autonomous manner in bladder cancer.

Xianchong Zheng, Zefu Liu, Jianliang Zhong, Liwen Zhou, Jiawei Chen, Lisi Zheng, Zhiyong Li, Ruhua Zhang, Jingxuan Pan, Yuanzhong Wu, Zhuowei Liu, Tiebang Kang.

Transcription dysregulation is a salient characteristic of bladder cancer (BC), but no appropriate therapeutic target for it has been established. Here, we found that heterogeneous downregulation of histone H4 transcription factor (HINFP) was associated with senescence in BC tissues and that lower HINFP expression could predict an unfavorable outcome in BC patients. Knockout of HINFP transcriptionally inhibited H1F0 and H1FX to trigger DNA damage, consequently inducing cell senescence to repress the proliferation and growth of BC cells. However, the senescence-associated secretory phenotype, characterized by increases in MMP1/3, enhances the invasion and metastasis of non-senescent BC cells. Histone deacetylase inhibitors (HDACis) could efficiently eliminate the senescent cells induced by HINFP knockout to suppress the invasion and metastasis of BC cells. Our study suggests that HDACis, widely used in multiple cancer types in a clinical context, may also benefit BC patients with metastases induced by cell senescence.

DOI: https://doi.org/10.1038/s41388-022-02371-1
Nat Rev Cancer. 2022 Jun 06.

Nodal interferon exposure drives tumour-specific tolerance.

Caroline Barranco.

DOI: https://doi.org/10.1038/s41568-022-00489-8
Nat Commun. 2022 Jun 06. 13(1): 3135

The drug-induced phenotypic landscape of colorectal cancer organoids.

Johannes Betge, Niklas Rindtorff, Jan Sauer, Benedikt Rauscher, Clara Dingert, Haristi Gaitantzi, Frank Herweck, Kauthar Srour-Mhanna, Thilo Miersch, Erica Valentini, Kim E Boonekamp, Veronika Hauber, Tobias Gutting, Larissa Frank, Sebastian Belle, Timo Gaiser, Inga Buchholz, Ralf Jesenofsky, Nicolai Härtel, Tianzuo Zhan, Bernd Fischer, Katja Breitkopf-Heinlein, Elke Burgermeister, Matthias P Ebert, Michael Boutros.

Patient-derived organoids resemble the biology of tissues and tumors, enabling ex vivo modeling of human diseases. They have heterogeneous morphologies with unclear biological causes and relationship to treatment response. Here, we use high-throughput, image-based profiling to quantify phenotypes of over 5 million individual colorectal cancer organoids after treatment with >500 small molecules. Integration of data using multi-omics modeling identifies axes of morphological variation across organoids: Organoid size is linked to IGF1 receptor signaling, and cystic vs. solid organoid architecture is associated with LGR5 + stemness. Treatment-induced organoid morphology reflects organoid viability, drug mechanism of action, and is biologically interpretable. Inhibition of MEK leads to cystic reorganization of organoids and increases expression of LGR5, while inhibition of mTOR induces IGF1 receptor signaling. In conclusion, we identify shared axes of variation for colorectal cancer organoid morphology, their underlying biological mechanisms, and pharmacological interventions with the ability to move organoids along them.

DOI: https://doi.org/10.1038/s41467-022-30722-9
Theranostics. 2022 ;12(9): 4431-4445

The role of Jagged1 as a dynamic switch of cancer cell plasticity in PDAC assembloids.

Jae-Il Choi, John Hoon Rim, Sung Ill Jang, Joon Seong Park, Hak Park, Jae Hee Cho, Jong-Baeck Lim.

  Background: Pancreatic ductal adenocarcinoma (PDAC), which commonly relapses due to chemotherapy resistance, has a poor 5-year survival rate (< 10%). The ability of PDAC to dynamically switch between cancer-initiating cell (CIC) and non-CIC states, which is influenced by both internal and external events, has been suggested as a reason for the low drug efficacy. However, cancer cell plasticity using patient-derived PDAC organoids remains poorly understood. Methods: First, we successfully differentiated CICs, which were the main components of PDAC organoids, toward epithelial ductal carcinomas. We further established PDAC assembloids of organoid-derived differentiated ductal cancer cells with endothelial cells (ECs) and autologous immune cells. To investigate the mechanism for PDAC plasticity, we performed single-cell RNA sequencing analysis after culturing the assembloids for 7 days. Results: In the PDAC assembloids, the ECs and immune cells acted as tumor-supporting cells and induced plasticity in the differentiated ductal carcinomas. We also observed that the transcriptome dynamics during PDAC re-programming were related to the WNT/beta-catenin pathway and apoptotic process. Interestingly, we found that WNT5B in the ECs was highly expressed by trans interaction with a JAG1. Furthermore, JAG1 was highly expressed on PDAC during differentiation, and NOTCH1/NOTCH2 were expressed on the ECs at the same time. The WNT5B expression level correlated positively with those of JAG1, NOTCH1, and NOTCH2, and high JAG1 expression correlated with poor survival. Additionally, we experimentally demonstrated that neutralizing JAG1 inhibited cancer cell plasticity. Conclusions: Our results indicate that JAG1 on PDAC plays a critical role in cancer cell plasticity and maintenance of tumor heterogeneity.

Keywords:  Human cancer organoid; cancer-initiating cells; plasticity; tumor microenvironment

DOI:  https://doi.org/10.7150/thno.71364
Mol Cancer. 2022 Jun 10. 21(1): 126

Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells.

Mareike Berlak, Elizabeth Tucker, Mathurin Dorel, Annika Winkler, Aleixandria McGearey, Elias Rodriguez-Fos, Barbara Martins da Costa, Karen Barker, Elicia Fyle, Elizabeth Calton, Selma Eising, Kim Ober, Deborah Hughes, Eleni Koutroumanidou, Paul Carter, Reda Stankunaite, Paula Proszek, Neha Jain, Carolina Rosswog, Heathcliff Dorado-Garcia, Jan Jasper Molenaar, Mike Hubank, Giuseppe Barone, John Anderson, Peter Lang, Hedwig Elisabeth Deubzer, Annette Künkele, Matthias Fischer, Angelika Eggert, Charlotte Kloft, Anton George Henssen, Michael Boettcher, Falk Hertwig, Nils Blüthgen, Louis Chesler, Johannes Hubertus Schulte.

   BACKGROUND: Development of resistance to targeted therapies has tempered initial optimism that precision oncology would improve poor outcomes for cancer patients. Resistance mechanisms, however, can also confer new resistance-specific vulnerabilities, termed collateral sensitivities. Here we investigated anaplastic lymphoma kinase (ALK) inhibitor resistance in neuroblastoma, a childhood cancer frequently affected by activating ALK alterations.
METHODS: Genome-wide forward genetic CRISPR-Cas9 based screens were performed to identify genes associated with ALK inhibitor resistance in neuroblastoma cell lines. Furthermore, the neuroblastoma cell line NBLW-R was rendered resistant by continuous exposure to ALK inhibitors. Genes identified to be associated with ALK inhibitor resistance were further investigated by generating suitable cell line models. In addition, tumor and liquid biopsy samples of four patients with ALK-mutated neuroblastomas before ALK inhibitor treatment and during tumor progression under treatment were genomically profiled.
RESULTS: Both genome-wide CRISPR-Cas9-based screens and preclinical spontaneous ALKi resistance models identified NF1 loss and activating NRASQ61K mutations to confer resistance to chemically diverse ALKi. Moreover, human neuroblastomas recurrently developed de novo loss of NF1 and activating RAS mutations after ALKi treatment, leading to therapy resistance. Pathway-specific perturbations confirmed that NF1 loss and activating RAS mutations lead to RAS-MAPK signaling even in the presence of ALKi. Intriguingly, NF1 loss rendered neuroblastoma cells hypersensitive to MEK inhibition.
CONCLUSIONS: Our results provide a clinically relevant mechanistic model of ALKi resistance in neuroblastoma and highlight new clinically actionable collateral sensitivities in resistant cells.

Keywords:  ALK; CRISPR screening; Ceritinib; Collateral sensitivity; Lorlatinib; NF1; NRAS; Neuroblastoma; Resistance; Trametinib

DOI:  https://doi.org/10.1186/s12943-022-01583-z
Theranostics. 2022 ;12(9): 4399-4414

Dysadherin awakens mechanical forces and promotes colorectal cancer progression.

So-Yeon Park, Choong-Jae Lee, Jang-Hyun Choi, Jee-Heun Kim, Won-Jae Lee, Tae-Young Jang, So-El Jeon, Jae-Hyun Kim, Sang-Hee Cho, Ji-Shin Lee, Jeong-Seok Nam.

  Rationale: Dysadherin is a tumor-associated, membrane-embedded antigen found in multiple types of cancer cells, and associated with malignant behavior of cancer cells; however, the fundamental molecular mechanism by which dysadherin drives aggressive phenotypes of cancer is not yet fully determined. Methods: To get a mechanistic insight, we explored the physiological relevance of dysadherin on intestinal tumorigenesis using dysadherin knockout mice and investigated its impact on clinicopathological features in patients with advanced colorectal cancer (CRC). Next, to discover the downstream signaling pathways of dysadherin, we applied bioinformatic analysis using gene expression data of CRC patient tumors and dysadherin knockout cancer cells. Additionally, comprehensive proteomic and molecular analyses were performed to identify dysadherin-interacting proteins and their functions. Results: Dysadherin deficiency suppressed intestinal tumorigenesis in both genetic and chemical mouse models. Moreover, increased dysadherin expression in cancer cells accounted for shorter survival in CRC patients. Comprehensive bioinformatics analyses suggested that the effect of dysadherin deletion is linked to a reduction in the extracellular matrix receptor signaling pathway. Mechanistically, the extracellular domain of dysadherin bound fibronectin and enhanced cancer cell adhesion to fibronectin, facilitating the activation of integrin-mediated mechanotransduction and leading to yes-associated protein 1 activation. Dysadherin-fibronectin interaction promoted cancer cell growth, survival, migration, and invasion, effects collectively mediated the protumor activity of dysadherin. Conclusion: Our results highlight a novel function of dysadherin as a driver of mechanotransduction that stimulates CRC progression, providing a potential therapy strategy for CRC.

Keywords:  Colorectal Cancer; Dysadherin; Fibronectin; Mouse Model; Yes-associated Protein 1

DOI:  https://doi.org/10.7150/thno.72354
Nat Cancer. 2022 Jun 09.

Limited nutrient availability in the tumor microenvironment renders pancreatic tumors sensitive to allosteric IDH1 inhibitors.

Ali Vaziri-Gohar, Joel Cassel, Farheen S Mohammed, Mehrdad Zarei, Jonathan J Hue, Omid Hajihassani, Hallie J Graor, Yellamelli V V Srikanth, Saadia A Karim, Ata Abbas, Erin Prendergast, Vanessa Chen, Erryk S Katayama, Katerina Dukleska, Imran Khokhar, Anthony Andren, Li Zhang, Chunying Wu, Bernadette Erokwu, Chris A Flask, Mahsa Zarei, Rui Wang, Luke D Rothermel, Andrea M P Romani, Jessica Bowers, Robert Getts, Curtis Tatsuoka, Jennifer P Morton, Ilya Bederman, Henri Brunengraber, Costas A Lyssiotis, Joseph M Salvino, Jonathan R Brody, Jordan M Winter.

Nutrient-deprived conditions in the tumor microenvironment (TME) restrain cancer cell viability due to increased free radicals and reduced energy production. In pancreatic cancer cells a cytosolic metabolic enzyme, wild-type isocitrate dehydrogenase 1 (wtIDH1), enables adaptation to these conditions. Under nutrient starvation, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate (αKG) for anaplerosis and NADPH to support antioxidant defense. In this study, we show that allosteric inhibitors of mutant IDH1 (mIDH1) are potent wtIDH1 inhibitors under conditions present in the TME. We demonstrate that low magnesium levels facilitate allosteric inhibition of wtIDH1, which is lethal to cancer cells when nutrients are limited. Furthermore, the Food & Drug Administration (FDA)-approved mIDH1 inhibitor ivosidenib (AG-120) dramatically inhibited tumor growth in preclinical models of pancreatic cancer, highlighting this approach as a potential therapeutic strategy against wild-type IDH1 cancers.

DOI: https://doi.org/10.1038/s43018-022-00393-y
Theranostics. 2022 ;12(8): 3977-3994

Drug-induced self-assembled nanovesicles for doxorubicin resistance reversal via autophagy inhibition and delivery synchronism.

Juan Wang, Liyan Qiu.

  Background: As a classical autophagy inhibitor, CQ has been supposed to increase the sensitivity of tumors to chemotherapeutics. However, there exists a quite huge gap between laboratory research and clinical application, which is related to the distinct pharmacokinetic behavior of CQ to a great extent. Methods: Based on amphiphilic copolymer PPAP, a pH-responsive drug-induced self-assembled nanovesicle, named DC-DIV/C, was constructed to load DOX⋅HCl and CQ. The physicochemical properties of DC-DIV/C were characterized. To validate the cooperative action and delivery synchronism of DOX⋅HCl and CQ, cytotoxicity, apoptosis, cellular uptake and autophagy assay were investigated in DOX⋅HCl resistant cancer cells. The pharmacokinetic character and antitumor effect of DC-DIV/C were evaluated on rats and nude mice bearing xenograft drug-resistant K562/ADR tumors, respectively. Results: DC-DIV/C could simultaneously encapsulate DOX·HCl and CQ at the optimal ratio of 1:2. In vitro and in vivo tests confirmed that DC-DIV/C acted as an excellent vehicle for the synchronous delivery of DOX⋅HCl and CQ during the process of blood circulation, cellular uptake and intracellular release. Furthermore, CQ accomplished autophagy inhibition to reduce the IC50 of DOX⋅HCl resistant cancer cells. Consequently, DC-DIV/C exhibited the extremely improved anti-tumor effect with 84.52% TIR on K562/ADR tumor. Conclusion: This study provides a promising and powerful strategy to achieve enhanced treatment outcomes for the precise combination therapy.

Keywords:  autophagy; chloroquine; doxorubicin; multidrug resistance; nanovesicle

DOI:  https://doi.org/10.7150/thno.70852
Mol Cancer. 2022 Jun 06. 21(1): 123

CircVAPA promotes small cell lung cancer progression by modulating the miR-377-3p and miR-494-3p/IGF1R/AKT axis.

Jinghan Hua, Xiaolin Wang, Liying Ma, Jingxin Li, Guozhen Cao, Shaobo Zhang, Wenchu Lin.

   BACKGROUND: Multiple lines of evidence have demonstrated that circular RNAs (circRNAs) play oncogenic or tumor-suppressive roles in various human cancers. Nevertheless, the biological functions of circRNAs in small cell lung cancer (SCLC) are still elusive.
METHODS: CircVAPA (annotated as hsa_circ_0006990) was identified by mining the circRNA profiling dataset of six paired SCLC tissues and the RNA-seq data of serum samples from 36 SCLC patients and 118 healthy controls. The circVAPA expression level was evaluated using quantitative real-time PCR in SCLC cells and tissues. Cell viability, colony formation, cell cycle and apoptosis analysis assays and in vivo tumorigenesis were used to reveal the biological roles of circVAPA. The underlying mechanism of circVAPA was investigated by Western blot, RNA pulldown, RNA immunoprecipitation, dual-luciferase reporter assay and rescue experiments.
RESULTS: We revealed that circVAPA, derived from exons 2-4 of the vesicle-associated membrane protein-associated protein A (VAPA) gene, exhibited higher expression levels in SCLC cell lines, clinical tissues, and serum from SCLC patients than the controls, and facilitated SCLC progression in vitro and in vivo. Mechanistically, circVAPA activated the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway by modulating the miR-377-3p and miR-494-3p/insulin-like growth factor 1 receptor (IGF1R) axis to accelerate SCLC progression. Furthermore, circVAPA depletion markedly enhanced the inhibitory effects of BMS-536924, an IGF1R kinase inhibitor in cellular and xenograft mouse models.
CONCLUSIONS: CircVAPA promotes SCLC progression via the miR-377-3p and miR-494-3p/IGF1R/AKT axis. We hope to develop clinical protocols of combinations of circVAPA inhibition and BMS-536924 addition for treating SCLC with circVAPA upregulation.

Keywords:  AKT; BMS-536924; CircVAPA; IGF1R; Progression; SCLC; miR-377-3p; miR-494-3p

DOI:  https://doi.org/10.1186/s12943-022-01595-9
Nat Genet. 2022 Jun 09.

Genomic analysis defines clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancer.

Grand Challenge PRECISION consortium

Ductal carcinoma in situ (DCIS) is the most common form of preinvasive breast cancer and, despite treatment, a small fraction (5-10%) of DCIS patients develop subsequent invasive disease. A fundamental biologic question is whether the invasive disease arises from tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial DCIS lesion and paired invasive recurrent tumors in 95 patients together with single-cell DNA sequencing in a subset of cases. Our data show that in 75% of cases the invasive recurrence was clonally related to the initial DCIS, suggesting that tumor cells were not eliminated during the initial treatment. Surprisingly, however, 18% were clonally unrelated to the DCIS, representing new independent lineages and 7% of cases were ambiguous. This knowledge is essential for accurate risk evaluation of DCIS, treatment de-escalation strategies and the identification of predictive biomarkers.

DOI: https://doi.org/10.1038/s41588-022-01082-3
Theranostics. 2022 ;12(9): 4386-4398

Targeting type Iγ phosphatidylinositol phosphate kinase overcomes oxaliplatin resistance in colorectal cancer.

Minhao Yu, Hao Wang, Wei Zhao, Xiaoxiao Ge, Wei Huang, Fengjuan Lin, Wenbo Tang, Ang Li, Sailiang Liu, Rong-Kun Li, Shu-Heng Jiang, Junli Xue.

  Rationale: Oxaliplatin is a widely used chemotherapy drug for advanced colorectal cancer (CRC) and its resistance is a major challenge for disease treatment. However, the molecular mechanism underlying oxaliplatin resistance remains largely elusive. Methods: An integrative analysis was performed to determine differentially expressed genes involved in oxaliplatin resistance. Loss- and gain-of-function studies were employed to investigate the roles of type Iγ phosphatidylinositol phosphate kinase (PIPKIγ) on oxaliplatin resistance in CRC cells. Exosomes derived from CRC cell lines were assessed for PD-L1 level and the ability to promote oxaliplatin resistance. Quantitative real-time PCR, immunofluorescence, luciferase reporter assay, Western blotting and other techniques were conducted to decipher the molecular mechanism. Results: PIPKIγ was identified as a critical gene related to oxaliplatin resistance in CRC. Genetic manipulation studies revealed that PIPKIγ profoundly facilitated oxaliplatin resistance and affected the expression of DNA damage repair proteins. Mechanistically, PIPKIγ promoted the expression of the immune checkpoint molecule PD-L1 via activation of NF-κB signaling pathway. Genetic silencing of PD-L1 did not affect CRC cell proliferation but significantly sensitized CRC cells to oxaliplatin. Notably, PD-L1 was revealed to be encapsulated in the exosomes, and the addition of exosomal PD-L1 to sh-PD-L1 CRC cells restored oxaliplatin resistance. Pharmacological hijacking PIPKIγ-exosomal PD-L1 axis largely reduced oxaliplatin resistance in CRC cells. In vivo experiments showed that PD-L1 loss significantly blocked oxaliplatin resistance and the addition of PD-L1-enriched exosomes promoted tumor growth and reduced mouse survival time. Conclusion: Our findings reveal a previous unprecedented role of PIPKIγ in oxaliplatin resistance and provide a key mechanism of exosomal PD-L1 in CRC with potential therapeutics.

Keywords:  CD274; Chemotherapy resistance; DNA damage; Exosome; PIP5K1C; Phosphatidylinositol kinase

DOI:  https://doi.org/10.7150/thno.69863
Nature. 2022 Jun 08.

Mutation and tissue lineage lead to organ-specific cancer.

Emily N Arner, W Kimryn Rathmell.



Keywords:  Cancer; Medical research

DOI:  https://doi.org/10.1038/d41586-022-01535-z
Cancer Cell. 2022 Jun 02. pii: S1535-6108(22)00224-0. [Epub ahead of print]

Resolving mutational signatures in cancer development.

Tianyuan Liu, Yuan Lin, Chen Wu.

In a recent Science study, an advanced mutational signature analysis was performed on an unprecedentedly large set of cancer whole-genome sequences across multiple organs. This work introduces a computational framework to identify common and rare mutational signatures and provides insights into their biological interpretation.

DOI: https://doi.org/10.1016/j.ccell.2022.05.011