bims-tucedo 2022-08-28 papers

bims-tucedo

Biomed News

on Tumor cell dormancy

Issue of 2022–08–28
fiveteen papers selected by
Isabel Puig Borreil, Vall d’Hebron Institute of Oncology

Dll1-mediated Notch signaling drives tumor cell crosstalk with cancer associated fibroblasts to promote radioresistance in breast cancer.
Combinatorial treatment with statins and niclosamide prevents CRC dissemination by unhinging the MACC1-β-catenin-S100A4 axis of metastasis.
Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence.
IL20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer.
Metastatic triple negative breast cancer adapts its metabolism to destination tissues while retaining key metabolic signatures.
Single-cell analysis of hepatoblastoma identifies tumor signatures that predict chemotherapy susceptibility using patient-specific tumor spheroids.
METTL3 potentiates progression of cervical cancer by suppressing ER stress via regulating m6A modification of TXNDC5 mRNA.
Proteogenomic markers of chemotherapy resistance and response in triple negative breast cancer.
Translatome proteomics identifies autophagy as a resistance mechanism to on-target FLT3 inhibitors in acute myeloid leukemia.
CEP63 upregulates YAP1 to promote colorectal cancer progression through stabilizing RNA binding protein FXR1.
Epithelial SOX9 drives progression and metastases of gastric adenocarcinoma by promoting immunosuppressive tumour microenvironment.
Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment.
Transposon-activated POU5F1B promotes colorectal cancer growth and metastasis.
How splicing confers treatment resistance in prostate cancer.
Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer.

Cancer Res. 2022 Aug 24. pii: CAN-21-1225. [Epub ahead of print]

Dll1-mediated Notch signaling drives tumor cell crosstalk with cancer associated fibroblasts to promote radioresistance in breast cancer.

Ajeya Nandi, Rahul Debnath, Anupma Nayak, Tsun Ki Jerrick To, Gatha Thacker, Megan Reilly, Sanjeev Gumber, Ilias Karagounis, Ning Li, Christopher J Lengner, Malay Haldar, Alana L Welm, M Andres Blanco, Christoforos Thomas, Rumela Chakrabarti.

Resistance to radiotherapy is a major obstacle for effective cancer treatment. Both cancer-associated fibroblasts (CAF) within the tumor microenvironment (TME) and Notch signaling are implicated in radioresistance, but their potential interrelationship is unclear. Here, we report that irradiated samples obtained from luminal breast cancer patient tumors express higher levels of the Notch ligand Dll1 and have a greater number of αSMA- and FAP-expressing activated CAFs. Single cell transcriptomic profiles further revealed enrichment of an αSMA+ myofibroblastic subpopulation of CAF in Dll1+ tumors. In murine and human PDX models, Dll1+ tumor cells were more radioresistant than Dll1- tumor cells, and genetic and pharmacological blocking of Dll1-mediated Notch signaling decreased the number of Dll1+ cancer stem cells (CSC) and CAFs and increased Dll1+ tumor cell radiosensitivity. Dll1+ cells recruited CAFs in an IL-6-dependent fashion and promoted Wnt ligand secretion by Notch2/3-expressing CAFs, thereby driving Wnt/β-catenin-dependent increases in Dll1+ CSC function to promote metastasis. Treatment with the porcupine inhibitor LGK-974 that inhibits Wnt ligand secretion or pharmacological blockade of IL-6 or Dll1 suppressed CAF-dependent enhancement of Dll1+ CSC function and metastasis in radioresistant tumors. Together, these findings reveal an essential crosstalk between Dll1+ cancer cells and CAFs that promotes metastasis and radioresistance, which could be therapeutically exploited to improve the outcome of breast cancer patients.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-1225
Oncogene. 2022 Aug 25.

Combinatorial treatment with statins and niclosamide prevents CRC dissemination by unhinging the MACC1-β-catenin-S100A4 axis of metastasis.

Benedikt Kortüm, Harikrishnan Radhakrishnan, Fabian Zincke, Christoph Sachse, Susen Burock, Ulrich Keilholz, Mathias Dahlmann, Wolfgang Walther, Gunnar Dittmar, Dennis Kobelt, Ulrike Stein.

Colorectal cancer (CRC) is the second-most common malignant disease worldwide, and metastasis is the main culprit of CRC-related death. Metachronous metastases remain to be an unpredictable, unpreventable, and fatal complication, and tracing the molecular chain of events that lead to metastasis would provide mechanistically linked biomarkers for the maintenance of remission in CRC patients after curative treatment. We hypothesized, that Metastasis-associated in colorectal cancer-1 (MACC1) induces a secretory phenotype to enforce metastasis in a paracrine manner, and found, that the cell-free culture medium of MACC1-expressing CRC cells induces migration. Stable isotope labeling by amino acids in cell culture mass spectrometry (SILAC-MS) of the medium revealed, that S100A4 is significantly enriched in the MACC1-specific secretome. Remarkably, both biomarkers correlate in expression data of independent cohorts as well as within CRC tumor sections. Furthermore, combined elevated transcript levels of the metastasis genes MACC1 and S100A4 in primary tumors and in blood plasma robustly identifies CRC patients at high risk for poor metastasis-free (MFS) and overall survival (OS). Mechanistically, MACC1 strengthens the interaction of β-catenin with TCF4, thus inducing S100A4 synthesis transcriptionally, resulting in elevated secretion to enforce cell motility and metastasis. In cell motility assays, S100A4 was indispensable for MACC1-induced migration, as shown via knock-out and pharmacological inhibition of S100A4. The direct transcriptional and functional relationship of MACC1 and S100A4 was probed by combined targeting with repositioned drugs. In fact, the MACC1-β-catenin-S100A4 axis by statins (MACC1) and niclosamide (S100A4) synergized in inhibiting cancer cell motility in vitro and metastasis in vivo. The MACC1-β-catenin-S100A4 signaling axis is causal for CRC metastasis. Selectively repositioned drugs synergize in restricting MACC1/S100A4-driven metastasis with cross-entity potential.

DOI: https://doi.org/10.1038/s41388-022-02407-6
Nat Commun. 2022 Aug 25. 13(1): 4975

Epithelial-mesenchymal plasticity determines estrogen receptor positive breast cancer dormancy and epithelial reconversion drives recurrence.

Patrick Aouad, Yueyun Zhang, Fabio De Martino, Céline Stibolt, Simak Ali, Giovanna Ambrosini, Sendurai A Mani, Kelly Maggs, Hazel M Quinn, George Sflomos, Cathrin Brisken.

More than 70% of human breast cancers (BCs) are estrogen receptor α-positive (ER+). A clinical challenge of ER+ BC is that they can recur decades after initial treatments. Mechanisms governing latent disease remain elusive due to lack of adequate in vivo models. We compare intraductal xenografts of ER+ and triple-negative (TN) BC cells and demonstrate that disseminated TNBC cells proliferate similarly as TNBC cells at the primary site whereas disseminated ER+ BC cells proliferate slower, they decrease CDH1 and increase ZEB1,2 expressions, and exhibit characteristics of epithelial-mesenchymal plasticity (EMP) and dormancy. Forced E-cadherin expression overcomes ER+ BC dormancy. Cytokine signalings are enriched in more active versus inactive disseminated tumour cells, suggesting microenvironmental triggers for awakening. We conclude that intraductal xenografts model ER + BC dormancy and reveal that EMP is essential for the generation of a dormant cell state and that targeting exit from EMP has therapeutic potential.

DOI: https://doi.org/10.1038/s41467-022-32523-6
J Clin Invest. 2022 Aug 25. pii: e157917. [Epub ahead of print]

IL20RB mediates tumoral response to osteoclastic niches and promotes bone metastasis of lung cancer.

Yunfei He, Wenqian Luo, Yingjie Liu, Yuan Wang, Chengxin Ma, Qiuyao Wu, Pu Tian, Dasa He, Zhenchang Jia, Xianzhe Lv, Yu-Shui Ma, Haitang Yang, Ke Xu, Xue Zhang, Yansen Xiao, Peiyuan Zhang, Yajun Liang, Da Fu, Feng Yao, Guohong Hu.

  Bone is a common site of metastasis in lung cancer but the regulatory mechanism remains incompletely understood. Osteoclasts are known to play crucial roles in osteolytic bone metastasis by digesting bone matrix and indirectly enhancing tumor colonization. In this study, we found that IL20RB mediated a direct tumoral response to osteoclasts. Tumoral expression of IL20RB was associated with bone metastasis of lung cancer, and functionally IL20RB promoted metastatic growth of lung cancer cells in bone. Mechanistically, tumor cells induced osteoclasts to secrete the IL20RB ligand IL19, and IL19 stimulated IL20RB-expressing tumor cells to activate the downstream JAK1-STAT3 signaling and enhanced proliferation of tumor cells in bone. Importantly, blocking IL20RB with a neutralizing antibody significantly suppressed bone metastasis of lung cancer. Overall, our data revealed a direct pro-tumor role of osteoclastic niche in bone metastasis and supported IL20RB-targeting approaches for metastasis treatment.

Keywords:  Cancer; Cell Biology

DOI:  https://doi.org/10.1172/JCI157917
Proc Natl Acad Sci U S A. 2022 Aug 30. 119(35): e2205456119

Metastatic triple negative breast cancer adapts its metabolism to destination tissues while retaining key metabolic signatures.

Fariba Roshanzamir, Jonathan L Robinson, Daniel Cook, Mohammad Hossein Karimi-Jafari, Jens Nielsen.

  Triple negative breast cancer (TNBC) metastases are assumed to exhibit similar functions in different organs as in the original primary tumor. However, studies of metastasis are often limited to a comparison of metastatic tumors with primary tumors of their origin, and little is known about the adaptation to the local environment of the metastatic sites. We therefore used transcriptomic data and metabolic network analyses to investigate whether metastatic tumors adapt their metabolism to the metastatic site and found that metastatic tumors adopt a metabolic signature with some similarity to primary tumors of their destinations. The extent of adaptation, however, varies across different organs, and metastatic tumors retain metabolic signatures associated with TNBC. Our findings suggest that a combination of anti-metastatic approaches and metabolic inhibitors selected specifically for different metastatic sites, rather than solely targeting TNBC primary tumors, may constitute a more effective treatment approach.

Keywords:  gene expression; genome-scale metabolic models; metastasis; systems biology; triple negative breast cancer

DOI:  https://doi.org/10.1073/pnas.2205456119
Nat Commun. 2022 Aug 25. 13(1): 4878

Single-cell analysis of hepatoblastoma identifies tumor signatures that predict chemotherapy susceptibility using patient-specific tumor spheroids.

Hanbing Song, Simon Bucher, Katherine Rosenberg, Margaret Tsui, Deviana Burhan, Daniel Hoffman, Soo-Jin Cho, Arun Rangaswami, Marcus Breese, Stanley Leung, María V Pons Ventura, E Alejandro Sweet-Cordero, Franklin W Huang, Amar Nijagal, Bruce Wang.

Pediatric hepatoblastoma is the most common primary liver cancer in infants and children. Studies of hepatoblastoma that focus exclusively on tumor cells demonstrate sparse somatic mutations and a common cell of origin, the hepatoblast, across patients. In contrast to the homogeneity these studies would suggest, hepatoblastoma tumors have a high degree of heterogeneity that can portend poor prognosis. In this study, we use single-cell transcriptomic techniques to analyze resected human pediatric hepatoblastoma specimens, and identify five hepatoblastoma tumor signatures that may account for the tumor heterogeneity observed in this disease. Notably, patient-derived hepatoblastoma spheroid cultures predict differential responses to treatment based on the transcriptomic signature of each tumor, suggesting a path forward for precision oncology for these tumors. In this work, we define hepatoblastoma tumor heterogeneity with single-cell resolution and demonstrate that patient-derived spheroids can be used to evaluate responses to chemotherapy.

DOI: https://doi.org/10.1038/s41467-022-32473-z
Oncogene. 2022 Aug 20.

METTL3 potentiates progression of cervical cancer by suppressing ER stress via regulating m6A modification of TXNDC5 mRNA.

Qiu-Ying Du, Fu-Chun Huo, Wen-Qi Du, Xiao-Lin Sun, Xin Jiang, Lan-Sheng Zhang, Dong-Sheng Pei.

N6-methyladenosine (m6A) is the most abundant chemical modification on mRNA and plays significant roles in many bioprocesses. However, the functions of m6A on cervical cancer (CC) tumorigenesis remain unclear. Here we found methyltransferase-like 3 (METTL3), a core member of the m6A methyltransferase family, was greatly upregulated as an independent prognostic factor in CC. Mechanistically, the transcription factor ETS1 recruited P300 and WDR5 which separately mediated H3K27ac and H3K4me3 histone modification in the promoter of METTL3 and induced METTL3 transcription activation. Furthermore, we identified TXNDC5 as a target of METTL3-mediated m6A modification through MeRIP-seq, and revealed that METTL3-mediated TXNDC5 expression relied on the m6A reader-dependent manner. Functionally, we verified that METTL3 promoted proliferation and metastasis of CC cells by regulating of TXNDC5 expression through in vitro and in vivo experiments. In addition, our study verified the effect of METTL3/TXNDC5 axis on ER stress. Taken together, METTL3 facilitates the malignant progression of CC, suggesting that METTL3 might be a potential prognostic biomarker and therapeutic target for CC.

DOI: https://doi.org/10.1038/s41388-022-02435-2
Cancer Discov. 2022 Aug 24. pii: CD-22-0200. [Epub ahead of print]

Proteogenomic markers of chemotherapy resistance and response in triple negative breast cancer.

Meenakshi Anurag, Eric J Jaehnig, Karsten Krug, Jonathan T Lei, Erik J Bergstrom, Beom-Jun Kim, Tanmayi D Vashist, Anh Minh Tran Huynh, Yongchao Dou, Xuxu Gou, Chen Huang, Zhiao Shi, Bo Wen, Viktoriya Korchina, Richard A Gibbs, Donna M Muzny, Harshavardhan Doddapaneni, Lacey E Dobrolecki, Henry Rodriguez, Ana I Robles, Tara Hiltke, Michael T Lewis, Julie R Nangia, Maryam Nemati Shafaee, Shunqiang Li, Ian S Hagemann, Jeremy Hoog, Bora Lim, C Kent Osborne, D R Mani, Michael A Gillette, Bing Zhang, Gloria V Echeverria, George Miles, Mothaffar F Rimawi, Steven A Carr, Foluso O Ademuyiwa, Shankha Satpathy, Matthew J Ellis.

Microscaled proteogenomics was deployed to probe the molecular basis for differential response to neoadjuvant carboplatin and docetaxel combination chemotherapy for triple-negative breast cancer (TNBC). Proteomic analyses of pre-treatment patient biopsies uniquely revealed metabolic pathways, including oxidative phosphorylation, adipogenesis and fatty acid metabolism, that were resistance-associated. Both proteomics and transcriptomics revealed sensitivity was marked by elevation of DNA repair, E2F targets, G2M checkpoint, interferon-gamma signaling and immune checkpoint components. Proteogenomic analyses of somatic copy number aberrations identified a resistance-associated 19q13.31-33 deletion where LIG1, POLD1 and XRCC1 are located. In orthogonal datasets, LIG1 (DNA ligase I) gene deletion and/or low mRNA expression levels were associated with lack of pathological complete response, higher chromosomal instability (CIN) and poor prognosis in TNBC, as well as carboplatin-selective resistance in TNBC pre-clinical models. Hemizygous loss of LIG1 was also associated with higher CIN and poor prognosis in other cancer types, demonstrating broader clinical implications.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0200
Leukemia. 2022 Aug 23.

Translatome proteomics identifies autophagy as a resistance mechanism to on-target FLT3 inhibitors in acute myeloid leukemia.

Sebastian E Koschade, Kevin Klann, Shabnam Shaid, Binje Vick, Jan A Stratmann, Marlyn Thölken, Laura M Meyer, The Duy Nguyen, Julia Campe, Laura M Moser, Susanna Hock, Fatima Baker, Christian T Meyer, Frank Wempe, Hubert Serve, Evelyn Ullrich, Irmela Jeremias, Christian Münch, Christian H Brandts.

Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in 25 % of acute myeloid leukemia (AML) patients, drive leukemia progression and confer a poor prognosis. Primary resistance to FLT3 kinase inhibitors (FLT3i) quizartinib, crenolanib and gilteritinib is a frequent clinical challenge and occurs in the absence of identifiable genetic causes. This suggests that adaptive cellular mechanisms mediate primary resistance to on-target FLT3i therapy. Here, we systematically investigated acute cellular responses to on-target therapy with multiple FLT3i in FLT3-ITD + AML using recently developed functional translatome proteomics (measuring changes in the nascent proteome) with phosphoproteomics. This pinpointed AKT-mTORC1-ULK1-dependent autophagy as a dominant resistance mechanism to on-target FLT3i therapy. FLT3i induced autophagy in a concentration- and time-dependent manner specifically in FLT3-ITD + cells in vitro and in primary human AML cells ex vivo. Pharmacological or genetic inhibition of autophagy increased the sensitivity to FLT3-targeted therapy in cell lines, patient-derived xenografts and primary AML cells ex vivo. In mice xenografted with FLT3-ITD + AML cells, co-treatment with oral FLT3 and autophagy inhibitors synergistically impaired leukemia progression and extended overall survival. Our findings identify a molecular mechanism responsible for primary FLT3i treatment resistance and demonstrate the pre-clinical efficacy of a rational combination treatment strategy targeting both FLT3 and autophagy induction.

DOI: https://doi.org/10.1038/s41375-022-01678-y
Oncogene. 2022 Aug 22.

CEP63 upregulates YAP1 to promote colorectal cancer progression through stabilizing RNA binding protein FXR1.

Han Ling, Chen-Hui Cao, Kai Han, Yong-Rui Lv, Xiao-Dan Ma, Jing-Hua Cao, Jie-Wei Chen, Si Li, Jin-Long Lin, Yu-Jing Fang, Zhi-Zhong Pan, Dan Xie, Feng-Wei Wang.

Abnormal regulation of centrosome components can induce chromosome instability and tumorigenesis. Centrosomal protein 63 (CEP63) is a vital member for assembling centrosome. Yet, the involvement of CEP63 in cancer pathogenesis remains unclear. Here we identify CEP63 as an important mediator for RNA-binding proteins (RBPs) to facilitate regulation on their RNA targets in colorectal cancer (CRC). We demonstrate that CEP63 protein is upregulated in a large cohort of colorectal cancer tissues and predicts poor prognosis, and USP36 is identified for stabilizing CEP63 by enhancing its K48-dependent deubiquitination. CEP63 overexpression promotes the proliferation and tumor growth of CRC cells in vitro and in vivo. Furthermore, we find that CEP63 can promote cancer stem-like cell properties by enhancing YAP1 expression through binding with and inhibiting the K63-ubiquitylation degradation of RBP FXR1 in CRC cells. Importantly, we further verify that the KH domain of FXR1 is necessary for the interaction between CEP63 and FXR1. Moreover, microtube motor proteins can form a complex with CEP63 and FXR1 to mediate the regulation of FXR1 on RNA targets. Additionally, we also confirm that CEP63 can bind and regulate multiple RBPs. In conclusion, our findings unveil an unrecognized CEP63/RBPs/RNA axis that CEP63 may perform as an adapter facilitating the formation of RBPs complex to regulate RNA progression and discover the role of CEP63 involved in signal transduction and RNA regulation, providing potential therapeutic target for CRC patients.

DOI: https://doi.org/10.1038/s41388-022-02439-y
Gut. 2022 Aug 24. pii: gutjnl-2021-326581. [Epub ahead of print]

Epithelial SOX9 drives progression and metastases of gastric adenocarcinoma by promoting immunosuppressive tumour microenvironment.

Yibo Fan, Yuan Li, Xiaodan Yao, Jiangkang Jin, Ailing Scott, Bovey Liu, Shan Wang, Longfei Huo, Ying Wang, Ruiping Wang, Melissa Pool Pizzi, Lang Ma, Shan Shao, Matheus Sewastjanow-Silva, Rebecca Waters, Deyali Chatterjee, Bin Liu, Namita Shanbhag, Guang Peng, George Adrian Calin, Pawel Karol Mazur, Samir M Hanash, Jo Ishizawa, Yuki Hirata, Osamu Nagano, Zhenning Wang, Linghua Wang, Wa Xian, Frank McKeon, Jaffer A Ajani, Shumei Song.

   OBJECTIVE: Many cancers engage embryonic genes for rapid growth and evading the immune system. SOX9 has been upregulated in many tumours, yet the role of SOX9 in mediating immunosuppressive tumour microenvironment is unclear. Here, we aim to dissect the role of SOX9-mediated cancer stemness attributes and immunosuppressive microenvironment in advanced gastric adenocarcinoma (GAC) for novel therapeutic discoveries.
METHODS: Bulk RNAseq/scRNA-seq, patient-derived cells/models and extensive functional studies were used to identify the expression and functions of SOX9 and its target genes in vitro and in vivo. Immune responses were studied in PBMCs or CD45+ immune cells cocultured with tumour cells with SOX9high or knockout and the KP-Luc2 syngeneic models were used for efficacy of combinations.
RESULTS: SOX9 is one of the most upregulated SOX genes in GAC and highly expressed in primary and metastatic tissues and associated with poor prognosis. Depletion of SOX9 in patient-derived GAC cells significantly decreased cancer stemness attributes, tumour formation and metastases and consistently increased CD8+ T cell responses when cocultured with PBMCs/CD45+ cells from GAC patients. RNA sequencing identified the leukaemia inhibitory factor (LIF) as the top secreted molecule regulated by SOX9 in tumour cells and was enriched in malignant ascites and mediated SOX9-induced M2 macrophage repolarisation and inhibited T cell function.
CONCLUSION: Epithelial SOX9 is critical in suppressing CD8+ T cell responses and modified macrophage function in GAC through the paracrine LIF factor. Cotargeting LIF/LIFR and CSF1R has great potential in targeting SOX9-mediated cancer stemness, T cell immunosuppression and metastases suggesting the novel combination therapy against advanced GAC.

Keywords:  GASTRIC CANCER; GENE REGULATION; IMMUNOTHERAPY; MOLECULAR ONCOLOGY; STEM CELLS

DOI:  https://doi.org/10.1136/gutjnl-2021-326581
Nat Commun. 2022 Aug 26. 13(1): 5018

Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and an immune-suppressive microenvironment.

Yan Tang, David J Kwiatkowski, Elizabeth P Henske.

mTORC1 is hyperactive in multiple cancer types1,2. Here, we performed integrative analysis of single cell transcriptomic profiling, paired T cell receptor (TCR) sequencing, and spatial transcriptomic profiling on Tuberous Sclerosis Complex (TSC) associated tumors with mTORC1 hyperactivity, and identified a stem-like tumor cell state (SLS) linked to T cell dysfunction via tumor-modulated immunosuppressive macrophages. Rapamycin and its derivatives (rapalogs) are the primary treatments for TSC tumors, and the stem-like tumor cells showed rapamycin resistance in vitro, reminiscent of the cytostatic effects of these drugs in patients. The pro-angiogenic factor midkine (MDK) was highly expressed by the SLS population, and associated with enrichment of endothelial cells in SLS-dominant samples. Inhibition of MDK showed synergistic benefit with rapamycin in reducing the growth of TSC cell lines in vitro and in vivo. In aggregate, this study suggests an autocrine rapamycin resistance mechanism and a paracrine tumor survival mechanism via immune suppression adopted by the stem-like state tumor cells with mTORC1 hyperactivity.

DOI: https://doi.org/10.1038/s41467-022-32673-7
Nat Commun. 2022 Aug 20. 13(1): 4913

Transposon-activated POU5F1B promotes colorectal cancer growth and metastasis.

Laia Simó-Riudalbas, Sandra Offner, Evarist Planet, Julien Duc, Laurence Abrami, Sagane Dind, Alexandre Coudray, Mairene Coto-Llerena, Caner Ercan, Salvatore Piscuoglio, Claus Lindbjerg Andersen, Jesper Bertram Bramsen, Didier Trono.

The treatment of colorectal cancer (CRC) is an unmet medical need in absence of early diagnosis. Here, upon characterizing cancer-specific transposable element-driven transpochimeric gene transcripts (TcGTs) produced by this tumor in the SYSCOL cohort, we find that expression of the hominid-restricted retrogene POU5F1B through aberrant activation of a primate-specific endogenous retroviral promoter is a strong negative prognostic biomarker. Correlating this observation, we demonstrate that POU5F1B fosters the proliferation and metastatic potential of CRC cells. We further determine that POU5F1B, in spite of its phylogenetic relationship with the POU5F1/OCT4 transcription factor, is a membrane-enriched protein that associates with protein kinases and known targets or interactors as well as with cytoskeleton-related molecules, and induces intracellular signaling events and the release of trans-acting factors involved in cell growth and cell adhesion. As POU5F1B is an apparently non-essential gene only lowly expressed in normal tissues, and as POU5F1B-containing TcGTs are detected in other tumors besides CRC, our data provide interesting leads for the development of cancer therapies.

DOI: https://doi.org/10.1038/s41467-022-32649-7
Elife. 2022 Aug 23. pii: e82070. [Epub ahead of print]11

How splicing confers treatment resistance in prostate cancer.

Prathyusha Konda, Srinivas R Viswanathan.

  A splice variant of the androgen receptor that drives prostate cancer resistance translocates into the nucleus using a different mechanism from the full-length receptor and exhibits distinct molecular properties once inside.

Keywords:  AR-V7; androgen receptor; cancer biology; human; intranuclear mobility; nuclear import; prostate cancer; transcriptional activity

DOI:  https://doi.org/10.7554/eLife.82070
Nat Genet. 2022 Aug 22.

Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer.

Daniel Cui Zhou, Reyka G Jayasinghe, Siqi Chen, John M Herndon, Michael D Iglesia, Pooja Navale, Michael C Wendl, Wagma Caravan, Kazuhito Sato, Erik Storrs, Chia-Kuei Mo, Jingxian Liu, Austin N Southard-Smith, Yige Wu, Nataly Naser Al Deen, John M Baer, Robert S Fulton, Matthew A Wyczalkowski, Ruiyang Liu, Catrina C Fronick, Lucinda A Fulton, Andrew Shinkle, Lisa Thammavong, Houxiang Zhu, Hua Sun, Liang-Bo Wang, Yize Li, Chong Zuo, Joshua F McMichael, Sherri R Davies, Elizabeth L Appelbaum, Keenan J Robbins, Sara E Chasnoff, Xiaolu Yang, Ashley N Reeb, Clara Oh, Mamatha Serasanambati, Preet Lal, Rajees Varghese, Jay R Mashl, Jennifer Ponce, Nadezhda V Terekhanova, Lijun Yao, Fang Wang, Lijun Chen, Michael Schnaubelt, Rita Jui-Hsien Lu, Julie K Schwarz, Sidharth V Puram, Albert H Kim, Sheng-Kwei Song, Kooresh I Shoghi, Ken S Lau, Tao Ju, Ken Chen, Deyali Chatterjee, William G Hawkins, Hui Zhang, Samuel Achilefu, Milan G Chheda, Stephen T Oh, William E Gillanders, Feng Chen, David G DeNardo, Ryan C Fields, Li Ding.

Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival. We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia. Pathology-assisted deconvolution of spatial transcriptomic data identified tumor and transitional subpopulations with distinct histological features. We showed coordinated expression of TIGIT in exhausted and regulatory T cells and Nectin in tumor cells. Chemo-resistant samples contain a threefold enrichment of inflammatory cancer-associated fibroblasts that upregulate metallothioneins. Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease.

DOI: https://doi.org/10.1038/s41588-022-01157-1