Resf1 is a compound G4 quadruplex-associated tumor suppressor for triple negative breast cancer.

Patients with ER-negative breast cancer have the worst prognosis of all breast cancer subtypes, often experiencing rapid recurrence or progression to metastatic disease shortly after diagnosis. Given that metastasis is the primary cause of mortality in most solid tumors, understanding metastatic biology is crucial for effective intervention. Using a mouse systems genetics approach, we previously identified 12 genes associated with metastatic susceptibility. Here, we extend those studies to identify Resf1, a poorly characterized gene, as a novel metastasis susceptibility gene in ER- breast cancer. Resf1 is a large, unstructured protein with an evolutionarily conserved intron-exon structure, but with poor amino acid conservation. CRISPR or gene trap mouse models crossed to the Polyoma Middle-T antigen genetically engineered mouse model (MMTV-PyMT) demonstrated that reduction of Resf1 resulted in a significant increase in tumor growth, a shortened overall survival time, and increased incidence and number of lung metastases, consistent with patient data. Furthermore, an analysis of matched tail and primary tissues revealed loss of the wildtype copy in tumor tissue, consistent with Resf1 being a tumor suppressor. Mechanistic analysis revealed a potential role of Resf1 in transcriptional control through association with compound G4 quadruplexes in expressed sequences, particularly those associated with ribosomal biogenesis. These results suggest that loss of Resf1 enhances tumor progression in ER- breast cancer through multiple alterations in both transcriptional and translational control.

Advocating for specialized STEM interpreters for Deaf scientists.

Majocha in the laboratory, doing an experiment under the hood.

SMARCD1 is an essential expression-restricted metastasis modifier.

Breast cancer is the most frequently diagnosed cancer worldwide, constituting 15% of cases in 2023. The predominant cause of breast cancer-related mortality is metastasis, and a lack of metastasis-targeted therapies perpetuates dismal outcomes for late-stage patients. By using meiotic genetics to study inherited transcriptional network regulation, we have identified, to the best of our knowledge, a new class of "essential expression-restricted" genes as potential candidates for metastasis-targeted therapeutics. Building upon previous work implicating the CCR4-NOT RNA deadenylase complex in metastasis, we demonstrate that RNA-binding proteins NANOS1, PUM2, and CPSF4 also regulate metastatic potential. Using various models and clinical data, we pinpoint Smarcd1 mRNA as a target of all three RNA-BPs. Strikingly, both high and low expression of Smarcd1 correlate with positive clinical outcomes, while intermediate expression significantly reduces the probability of survival. Applying the theory of "essential genes" from evolution, we identify 50 additional genes that require precise expression levels for metastasis to occur. Specifically, small perturbations in Smarcd1 expression significantly reduce metastasis in mouse models and alter splicing programs relevant to the ER+/HER2-enriched breast cancer. Identification subtype-specific essential expression-restricted metastasis modifiers introduces a novel class of genes that, when therapeutically "nudged" in either direction, may significantly improve late-stage breast cancer patients.

SMARCD1 is a "Goldilocks" metastasis modifier.

Breast cancer is the most frequently diagnosed cancer worldwide, constituting around 15% of all diagnosed cancers in 2023. The predominant cause of breast cancer-related mortality is metastasis to distant essential organs, and a lack of metastasis-targeted therapies perpetuates dismal outcomes for late-stage patients. However, through our use of meiotic genetics to study inherited transcriptional network regulation, we have identified a new class of "Goldilocks" genes that are promising candidates for the development of metastasis-targeted therapeutics. Building upon previous work that implicated the CCR4-NOT RNA deadenylase complex in metastasis, we now demonstrate that the RNA-binding proteins (RNA-BPs) NANOS1, PUM2, and CPSF4 also regulate metastatic potential. Using cell lines, 3D culture, mouse models, and clinical data, we pinpoint Smarcd1 mRNA as a key target of all three RNA-BPs. Strikingly, both high and low expression of Smarcd1 is associated with positive clinical outcomes, while intermediate expression significantly reduces the probability of survival. Applying the theory of "essential genes" from evolution, we identify an additional 50 genes that span several cellular processes and must be maintained within a discrete window of expression for metastasis to occur. In the case of Smarcd1, small perturbations in its expression level significantly reduce metastasis in laboratory mouse models and alter splicing programs relevant to the ER+/HER2-enriched breast cancer subtype. The identification of subtype-specific "Goldilocks" metastasis modifier genes introduces a new class of genes and potential catalogue of novel targets that, when therapeutically "nudged" in either direction, may significantly improve late-stage patient outcomes.

"Everyone Was Nice But I Was Still Left Out": An Interview Study About Deaf Interns' Research Experiences in STEM.

Science, technology, engineering, and mathematics (STEM) undergraduate research experiences improve success, persistence, and promote a feeling of belonging to a community. Like their hearing peers, deaf STEM majors often participate in undergraduate research experiences. However, deaf students typically interact with hearing faculty lacking experience with deaf students and awareness of Deaf culture, which unintentionally impacts their research experiences. This interview study sought to understand deaf students' research experiences and their relationships with hearing mentors. Findings indicate that lack of awareness of Deaf culture and lack of communication access impact students' experiences. We make recommendations on improving deaf students' research experiences.

Welcoming Deaf Students into STEM: Recommendations for University Science Education.

Scientists are shaped by their unique life experiences and bring these perspectives to their research. Diversity in life and cultural experiences among scientists, therefore, broadens research directions and, ultimately, scientific discoveries. Deaf individuals, for example, have successfully contributed their unique perspectives to scientific inquiry. However, deaf individuals still face challenges in university science education. Most deaf students in science, technology, engineering, and mathematics (STEM) disciplines interact with faculty who have little to no experience working with deaf individuals and who often have preconceptions or simply a lack of knowledge about deaf individuals. In addition to a lack of communication access, deaf students may also feel unwelcome in STEM, as do other underrepresented groups. In this essay, we review evidence from the literature and, where data are lacking, contribute the expert opinions of the authors, most of whom are deaf scientists themselves, to identify strategies to best support deaf students in university STEM education. We describe the journey of a hypothetical deaf student and methods for faculty to create a welcoming environment. We describe and provide recommendations for classroom seating and layout, accommodations, teaching strategies, and research mentoring. We also discuss the importance of including deaf scientists in research about deaf individuals.