We have long been intrigued by the potential regulatory role of interactions between RNA transcripts. Given the ubiquity and potential regulatory role of antisense RNAs, we decided to conduct an unbiased study of antisense RNA in cancer. Using a developed pipeline to profile antisense RNAs, we applied it to an established model of breast cancer metastasis. From our analyses, we identified an antisense RNA, NQO1-AS, whose upregulation promotes breast cancer metastasis. We found that NQO1-AS, by binding directly to its complementary region, stabilizes the NQO1 mRNA, leading to an upregulation of the NQO1 gene product. This enzyme protects cells against oxidative stress, meaning NQO1-AS enables breast cancer cells to become resistant to oxidative damage, reducing their sensitivity to ferroptosis. We established that during metastasis to the lung, cells depend on this NQO1 pathway. We demonstrated that the downregulation of either NQO1 or NQO1-AS significantly decreases lung metastatic burden in a mouse model. This work is published in Nature Cancer and see the excellent blog post written by Kristle Garcia, one of the co-first authors of the study.
The impact of translational control on cancer progression is an area of active research. In this study, we employed ribosome profiling to assess the genome-wide translation efficiencies in low and high metastatic breast cancer cells, as well as patient-derived xenografts. Our findings indicate that HNRNPC is downregulated in highly metastatic cells, resulting in the lengthening of the 3' untranslated region in HNRNPC-bound mRNAs and, subsequently, translational suppression. We demonstrated that altering HNRNPC expression affects the metastatic potential of breast cancer cells in xenograft mouse models. Furthermore, lower expression of HNRNPC and its regulon correlates with worse outcomes in breast cancer patient groups. Our results, now published in Nature Cell Bio, also describes a number of computational tools we have developed to study translational control and alternative poly-adenylation. An accompanying News and Views article also puts our work in its broader context here.
American Cancer Society presented the 11th annual San Francisco Discovery Gala on October 15, 2022. Hani was named as the scientific honoree for this event. This Gala is an annual fundraising event to support the American Cancer Society’s mission to save lives, celebrate lives, and lead the fight for a world without cancer. SF Discovery Gala is one of the premier fundraising events for cancer, both locally and across the nation. It garners the support of major corporate partners within the Bay Area and is led by an extraordinary volunteer Board of Ambassadors who champion the mission year-round. See the announcement here.
The NIH Director's Transformative Research Award, established in 2009, supports exceptionally innovative, high-risk, original and/or unconventional research projects that have the potential to create or overturn fundamental paradigms. The award is part of the High-Risk, High-Reward Research program of the National Institutes of Health (NIH), which was created to accelerate the pace of biomedical, behavioral, and social science discoveries. We received this award together with our colleagues in Dr. Justin Ichida's group, for a study titled: "Leveraging Natural Phenotypic Variations of Heterogenous ALS Populations-In-A-Dish to Enable Scalable Drug Discovery". This project will extends our GENEVA platform, which was initiatlly developed for cancer research, to neurodegenerative diseases. See the announcement here.
The Chan Zuckerberg Biohub Investigator Program, open to faculty from Stanford University, UC San Francisco, and UC Berkeley, funds innovative, visionary research with the goal of building engaged, collaborative scientific communities to help solve critical challenges in biomedicine.The 86 awardees in our new cohort, who were chosen from nearly 700 applicants through a competitive process judged by nationally recognized external reviewers and a blue-ribbon Selection Advisory Committee, represent a diverse range of disciplines, including basic biological sciences, clinical biomedical sciences, physics, chemistry, engineering, computer and data sciences, statistics, and public health. See the announcement here.
Exai Bio, a next-generation liquid biopsy company, recently launched to bring our orphan non-coding RNA species (oncRNAs) to the clinic. With $65M in financing will bring to bear resources that is needed to not only detect the presence of tumors, but also peer into their biology without a need for invasive biopsies. This work was spearhead by Dr. Lisa Fish, a former postdoc in the lab (and now Director of Research at Exai Bio). See the press release here.
The Vilcek Prizes for Creative Promise in Biomedical Science are awarded to young foreign- born scientists living and working in the United States. Prizewinners are selected for the innovative promise of their early-career work: research and discoveries that represent a major step forward in their respective area of study, and advance the landscape of scientific research in the United States. Markita del Carpio Landry, Hani Goodarzi, and Harris Wang are the recipients of the 2022 Vilcek Prizes for Creative Promise in Biomedical Science. The Vilcek Foundation raises awareness of immigrant contributions in the United States and fosters appreciation for the arts and sciences. The foundation was established in 2000 by Jan and Marica Vilcek, immigrants from the former Czechoslovakia. See the announcement here.
Cancer progression accompanies broad dysregulations in the splicing landscape of the cell. Building on our earlier work on RNA structural elements, we have now discovered a previously unknown structured element that is associated with increased exon inclusion. We revealed that SNRPA1, a core component of the spliceosome, moonlights as a regualtor of RNA splicing via its interactions with these elements. We also showed that SNRPA1, which is up-regulated in highly metastatic cells, acts as a driver of breast cancer metastasis by modulating isoform levels for specific target genes. Morpholino-based reversal of SNRPA1-mediated changes converts the cell into a less malignant state. Our results, now published in Science, also demonstrates the utility of hybrid computational/experimental platforms as potent engines of discovery. For a lay description of this study, see the write up by Jeff Norris puiblished here.
AACR and MPM Oncology Charitable Foundation announced three grants to support transformative cancer research and our lab was one of the recipients. This funding mechanism is an innovative partnership between the American Association for Cancer Research (AACR) and the UBS Oncology Impact Fund (OIF) managed by MPM Capital. With support from this grant, we will expand on our research on the role of our newly discovered orpan non-coding RNAs to serve as building blocks for cancer-engineered regulatory programs.
With widespread societal and economical devastation, the new coronovirus pandemic has deeply reshaped our approach to life and how we do science. The heterogeneity of patient response to this virus remains a baffling mystery that complicates clinical response. Age was determined as a clear risk factor; however, it was soon discovered that risk of mortality from this infection is substantially higher in men. Recently, members of the Fattahi lab carried out a systematic in vitro screening of stem-cell derived cardiomyocites to identify regulators of ACE2 expression, an enzyme that acts as the receptor for SARS-CoV-2. We levergaed this valuable screen to train a deep learning model that is capable of large-scale in silico screens to identify other compounds that can target ACE2 expression. Systematic analyses of these hit compounds revealed Andregen signaling as a key pathway involved in ACE2 expression. Confirmatory analyses in the UK Biobank dataset revealed a consistent association between androgen levels and COVID-19 risk. This work is published as a research article in Cell Stem Cell and an eariler manuscript describing these results was published as a preprint. You can also read an interview with Dr. Faranak Fattahi putting some of these findings in context.
Identifying master regulators that drive pathological gene expression is a key challenge in precision oncology. Here, we have developed an analytical framework, named PRADA, that identifies oncogenic RNA-binding proteins through the systematic detection of coordinated changes in their target regulons. Application of this approach to data collected from clinical samples, patient-derived xenografts, and cell line models of colon cancer metastasis revealed the RNA-binding protein RBMS1 as a suppressor of colon cancer progression. We observed that silencing RBMS1 results in increased metastatic capacity in xenograft mouse models, and that restoring its expression blunts metastatic liver colonization. We have found that RBMS1 functions as a post-transcriptional regulator of RNA stability by directly binding its target mRNAs. Together, our findings establish a role for RBMS1 as a previously unknown regulator of RNA stability and as a suppressor of colon cancer metastasis with clinical utility for risk stratification of patients. We recently reported these findings in the journal Cancer Discovery. You can also read the commentary graciously written by Dr. Hannah Carter for this work in the same issue.
In our most recent paper, we have reported the functional dissection of a previously unknown pathway of RNA decay. This study was a follow-up to our discvoery of TARBP2 as a promoter of breast cancer metastasis (see here). In this collaborative work, we systematically dissected the molecular mechanism through which TARBP2 regulates the expression and stability of its target regulon. Based on our model, TARBP2 binds target pre-mRNAs co-transcriptionally and recruits the RNA methylation machinery to add m6A marks. RNA methylation, in turn, influences the binding patterns of splicing factors such as SRSF1 and diminishes efficient splicing of introns. Through its interaction with components of the nuclear surveillance machinery, TARBP2 delivers these mis-spliced products to the exosome complex for degradation. Finally, we also showed that TARBP2 not only promotes breast cancer metastasis, but also acts as an oncogene in lung cancer cells. See our published work here.
We have recently annotated a new class of small RNAs, which we have named oncRNAs. These are largely absent in normal cells but emerge in cancer cells as a result of cellular transformation. We have demonstrated that cancer cells can "adopt" these orphan RNAs to carry out new functions relevant to the progression of the disease. Another benefit of oncRNAs became apparent once we realized that a large fraction of oncRNAs are released by cancer cells in exosomes. We think that since every tumor can be assigned a digital oncRNA barcode, i.e. a profile of oncRNA presence/absence, finding evidence of this barcode outside the cell can point to the existence of an underlying cancer cell from which these RNAs originate. You can read the paper in November's issue of Nature Medicine. You can also read a new release by UCSF on our work.
Read Hani's opinion piece on the impact of the travel ban on students and scholars, and the scientific community published in the Scientistl. You can also read an interview by a number of UCSF faculty with the Washington Post on this issue.
Hani Goodarzi was named the recipient of the AAAS Martin And Rose Wachtel Cancer Research Award. The annual AAAS Martin and Rose Wachtel Cancer Research Award recognizes early-career scientists who have already made outstanding contributions to the field of cancer research. See the anouncement here. The prize was awarded in July at National Institute of Health (NCI) (see here for the NIH record of the talk).
Hani Goodarzi was awarded the AACR-Takeda Oncology NextGen Grant for Transformative Research by the American Association for Cancer Research (AACR). This award represents the AACR’s flagship funding initiative to stimulate highly innovative research from young investigators. This grant mechanism is intended to promote and support creative, paradigm-shifting cancer research that may not be funded through conventional channels.
Hani Goodarzi was named a Kimmel Scholar by the Sidney Kimmel Foundation. Begun in 1997, the Kimmel Scholars Program was designed to jump-start the careers of the most promising and creative researchers and physician-scientists seeking solutions to the riddle of cancer. Over the two decades, the Program has contributed some of the most successful members to the next generation, or maybe two, of the nation’s leading cancer researchers.
Congratulations to our 2016 rotation students. Johnny Yu (BMS) and Bushra Bibi (Tetrad) for receiving the fellowship and Myles Hochman (Tetrad) for honorable mention. The NSF Graduate Research Fellowship Program recognizes and supports outstanding graduate students in NSF-supported science, technology, engineering, and mathematics disciplines who are pursuing research-based Master's and doctoral degrees at accredited United States institutions.
Transfer-RNAs are tranditionally viewed as a static component of the protein synthesis machinery. Recently, several studies have raised the possibility that tRNAs are more dynamic and can support different cellular states and phenotypes. Although generally debated, some evidence has emerged that tRNA levels in the cell imapct the gene expression landscape in the cell. In a recent study, we demonstrated that the tRNA landscape is drastically modified in highly metastatic cells and that these modulations drive the expression of key promoters of metastasis. These results were published in Cell. You can also read a short preview about this study.
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