bims-instec 2022-01-02 papers

Genes Dev. 2021 Dec 30.

Transcription factor-mediated intestinal metaplasia and the role of a shadow enhancer.

Harshabad Singh, Davide Seruggia, Shariq Madha, Madhurima Saxena, Ankur K Nagaraja, Zhong Wu, Jin Zhou, Aaron J Huebner, Adrianna Maglieri, Juliette Wezenbeek, Konrad Hochedlinger, Stuart H Orkin, Adam J Bass, Jason L Hornick, Ramesh A Shivdasani.

Barrett's esophagus (BE) and gastric intestinal metaplasia are related premalignant conditions in which areas of human stomach epithelium express mixed gastric and intestinal features. Intestinal transcription factors (TFs) are expressed in both conditions, with unclear causal roles and cis-regulatory mechanisms. Ectopic CDX2 reprogrammed isogenic mouse stomach organoid lines to a hybrid stomach-intestinal state transcriptionally similar to clinical metaplasia; squamous esophageal organoids resisted this CDX2-mediated effect. Reprogramming was associated with induced activity at thousands of previously inaccessible intestine-restricted enhancers, where CDX2 occupied DNA directly. HNF4A, a TF recently implicated in BE pathogenesis, induced weaker intestinalization by binding a novel shadow Cdx2 enhancer and hence activating Cdx2 expression. CRISPR/Cas9-mediated germline deletion of that cis-element demonstrated its requirement in Cdx2 induction and in the resulting activation of intestinal genes in stomach cells. dCas9-conjugated KRAB repression mapped this activity to the shadow enhancer's HNF4A binding site. Altogether, we show extensive but selective recruitment of intestinal enhancers by CDX2 in gastric cells and that HNF4A-mediated ectopic CDX2 expression in the stomach occurs through a conserved shadow cis-element. These findings identify mechanisms for TF-driven intestinal metaplasia and a likely pathogenic TF hierarchy.

Keywords: Barrett's esophagus; CDX2; HNF4A; gastric intestinal metaplasia; transcriptional control of cell identity

DOI: https://doi.org/10.1101/gad.348983.121

Front Endocrinol (Lausanne). 2021 ;12 725708

Thyroid Hormone Nuclear Receptor TRα1 and Canonical WNT Pathway Cross-Regulation in Normal Intestine and Cancer.

Maria Sirakov, Leo Claret, Michelina Plateroti.

A pivotal role of thyroid hormones and their nuclear receptors in intestinal development and homeostasis have been described, whereas their involvement in intestinal carcinogenesis is still controversial. In this perspective article we briefly summarize the recent advances in this field and present new data regarding their functional interaction with one of the most important signaling pathway, such as WNT, regulating intestinal development and carcinogenesis. These complex interactions unveil new concepts and will surely be of importance for translational research.

Keywords: canonical WNT pathway; intestinal carcinogenesis; intestinal epithelium; thyroid hormone receptors; thyroid hormones

DOI: https://doi.org/10.3389/fendo.2021.725708

Cancer Sci. 2021 Dec 28.

A modified MethyLight assay predicts the clinical outcomes of anti-EGFR treatment in metastatic colorectal cancer.

Kota Ouchi, Shin Takahashi, Akira Okita, Yasuhiro Sakamoto, Osamu Muto, Kenji Amagai, Takaho Okada, Hisatsugu Ohori, Eiji Shinozaki, Chikashi Ishioka.

The DNA methylation status correlates with clinical outcomes of anti-epidermal growth factor receptor (EGFR) treatment. There is a strong need to develop a simple assay for measuring DNA methylation status for the clinical application of drug selection based on it. In this study, we collected data from 186 patients with metastatic colorectal cancer (mCRC) who previously received anti-EGFR treatment. We modified MethyLite to develop a novel assay to classify patients as having highly-methylated colorectal cancer (HMCC) or low-methylated colorectal cancer (LMCC) based on the methylation status of 16 CpG sites of tumor-derived genomic DNA in the development cohort (n = 30). Clinical outcomes were then compared between the HMCC and LMCC groups in the validation cohort (n = 156). The results showed that HMCC had a significantly worse response rate (4.2% vs 33.3%; p = 0.004), progression-free survival (median: 2.5 vs 6.6 months, p < 0.001, hazard ratio [HR] = 0.22), and overall survival (median: 5.6 vs 15.5 months, p < 0.001, HR = 0.23) than did LMCC in patients with RAS wild-type mCRC who were refractory or intolerable to oxaliplatin- and irinotecan-based chemotherapy (n = 101). The DNA methylation status was an independent predictive factor and a more accurate biomarker than was the primary site of anti-EGFR treatment. In conclusion, our novel DNA methylation measurement assay based on MethyLight was simple and useful, suggesting its implementation as a complementary diagnostic tool in a clinical setting.

Keywords: DNA methylation; MethyLight; anti-EGFR antibodies; metastatic CRC; predictive biomarker

DOI: https://doi.org/10.1111/cas.15252

Drug Resist Updat. 2021 Dec 16. pii: S1368-7646(21)00057-1. [Epub ahead of print] 100797

Impact of cancer metabolism on therapy resistance - Clinical implications.

Ana Cristina Gonçalves, Elena Richiardone, Joana Jorge, Bárbara Polónia, Cristina P R Xavier, Iris Chiara Salaroglio, Chiara Riganti, M Helena Vasconcelos, Cyril Corbet, Ana Bela Sarmento-Ribeiro.

Despite an increasing arsenal of anticancer therapies, many patients continue to have poor outcomes due to the therapeutic failures and tumor relapses. Indeed, the clinical efficacy of anticancer therapies is markedly limited by intrinsic and/or acquired resistance mechanisms that can occur in any tumor type and with any treatment. Thus, there is an urgent clinical need to implement fundamental changes in the tumor treatment paradigm by the development of new experimental strategies that can help to predict the occurrence of clinical drug resistance and to identify alternative therapeutic options. Apart from mutation-driven resistance mechanisms, tumor microenvironment (TME) conditions generate an intratumoral phenotypic heterogeneity that supports disease progression and dismal outcomes. Tumor cell metabolism is a prototypical example of dynamic, heterogeneous, and adaptive phenotypic trait, resulting from the combination of intrinsic [(epi)genetic changes, tissue of origin and differentiation dependency] and extrinsic (oxygen and nutrient availability, metabolic interactions within the TME) factors, enabling cancer cells to survive, metastasize and develop resistance to anticancer therapies. In this review, we summarize the current knowledge regarding metabolism-based mechanisms conferring adaptive resistance to chemo-, radio-and immunotherapies as well as targeted therapies. Furthermore, we report the role of TME-mediated intratumoral metabolic heterogeneity in therapy resistance and how adaptations in amino acid, glucose, and lipid metabolism support the growth of therapy-resistant cancers and/or cellular subpopulations. We also report the intricate interplay between tumor signaling and metabolic pathways in cancer cells and discuss how manipulating key metabolic enzymes and/or providing dietary changes may help to eradicate relapse-sustaining cancer cells. Finally, in the current era of personalized medicine, we describe the strategies that may be applied to implement metabolic profiling for tumor imaging, biomarker identification, selection of tailored treatments and monitoring therapy response during the clinical management of cancer patients.

Keywords: Cancer metabolism; Glycolysis; Intratumor heterogeneity; Metabolic plasticity; Oxidative phosphorylation; Therapy resistance; Tumor microenvironment

DOI: https://doi.org/10.1016/j.drup.2021.100797